animals

Review
Using Nutritional Strategies to Shape the Gastro-Intestinal
Tracts of Suckling and Weaned Piglets
Anne M.S. Huting † , Anouschka Middelkoop † , Xiaonan Guan and Francesc Molist *

Research & Development, Schothorst Feed Research B.V., 8218 NA Lelystad, The Netherlands;
[email protected] (A.M.S.H.); [email protected] (A.M.); [email protected] (X.G.)
* Correspondence: [email protected]
† These authors contributed equally to this work.

Simple Summary: Throughout the world, piglet mortality and morbidity in large litters are a major
welfare concern and source of economic losses. Gastro-intestinal problems rank amongst the highest
causes of morbidity, mortality and antimicrobial use. As evidenced in the recent literature, nutritional
interventions before and after weaning can modulate gut development, thereby reducing the risk of
gastro-intestinal problems. In particular, early-life nutrition has begun to receive increasing interest,
given its potential to modulate gut health in the long-term. The literature nevertheless contains
little information on how pre-weaning and post-weaning nutritional strategies can be combined to
sustain optimal gut health throughout the challenging process of weaning. To address this gap in
current knowledge, this review summarises a large body of literature on nutritional strategies aimed
at supporting gut health in piglets, combining individual strategies into a structured nutritional
approach over time, starting from a few days after birth to 5–6 weeks post-weaning. The review also



contains propositions concerning potential avenues for future research that may contribute to the

 reduction in gastro-intestinal problems and the associated use of antimicrobials in the pig industry.
Citation: Huting, A.M.S.;
Middelkoop, A.; Guan, X.; Molist, F. Abstract: This is a comprehensive review on the use of nutritional strategies to shape the functioning
Using Nutritional Strategies to Shape of the gastro-intestinal tract in suckling and weaned piglets. The progressive development of a piglet’s
the Gastro-Intestinal Tracts of gut and the associated microbiota and immune system offers a unique window of opportunity for
Suckling and Weaned Piglets. Animals supporting gut health through dietary modulation. This is particularly relevant for large litters,
2021, 11, 402. https://doi.org/ for which sow colostrum and milk are insufficient. The authors have therefore proposed the use
10.3390/ani11020402
of supplemental milk and creep feed with a dual purpose. In addition to providing nutrients to
piglets, supplemental milk can also serve as a gut modulator in early life by incorporating functional
Academic Editors: Claudio Oliviero
ingredients with potential long-term benefits. To prepare piglets for weaning, it is important to
and Shah Hasan
stimulate the intake of solid feed before weaning, in addition to stimulating the number of piglets
Received: 11 January 2021
Accepted: 1 February 2021
eating. The use of functional ingredients in creep feed and a transition diet around the time of
Published: 5 February 2021 weaning helps to habituate piglets to solid feed in general, while also preparing the gut for the
digestion and fermentation of specific ingredients. In the first days after weaning (i.e., the acute
Publisher’s Note: MDPI stays neutral phase), it is important to maintain high levels of feed intake and focus on nutritional strategies
with regard to jurisdictional claims in that support good gastric (barrier) function and that avoid overloading the impaired digestion and
published maps and institutional affil- fermentation capacity of the piglets. In the subsequent maturation phase, the ratio of lysine to energy
iations. can be increased gradually in order to stimulate piglet growth. This is because the digestive and
fermentation capacity of the piglets is more mature at this stage, thus allowing the inclusion of
more fermentable fibres. Taken together, the nutritional strategies addressed in this review provide a
structured approach to preparing piglets for success during weaning and the period that follows. The
Copyright: © 2021 by the authors. implementation of this approach and the insights to be developed through future research can help
Licensee MDPI, Basel, Switzerland. to achieve some of the most important goals in pig production: reducing piglet mortality, morbidity
This article is an open access article and antimicrobial use.
distributed under the terms and
conditions of the Creative Commons Keywords: creep feed; early life; feed intake; gut function; health; nutrition; pig; pre-weaning;
Attribution (CC BY) license (https://
post-weaning; supplemental milk
creativecommons.org/licenses/by/
4.0/).

Animals 2021, 11, 402. https://doi.org/10.3390/ani11020402 https://www.mdpi.com/journal/animals

Animals 2021, 11, 402 2 of 36

1. Introduction
With the objective of improving overall efficiency within the swine industry, breeding
has traditionally focussed on carcass traits and growth rate, as well as on the number of
piglets produced per sow/year (prolificacy). Litter size has thereby increased considerably
in recent decades, resulting in complications relating to animal management, health and
welfare, as reflected in increased morbidity and prenatal and neonatal mortality [1].
Increases in prolificacy have also led to an increase in the number of piglets with
low birth weight (see Figure 1; [1,2]) and piglets that have been subjected to intra-uterine
growth retardation (IUGR), which currently affects 30–40% of all piglets [3]. In addition to
being at greater risk of pre-weaning mortality [4,5], light-born and IUGR piglets that do
survive tend to thrive less efficiently [6–8] and to be more susceptible to diseases [1,9,10].
In addition, the genetic selection for leaner meat has resulted in piglets being born with
limited body reserves [11], which fail to meet their early-life requirements for maintenance,
thermoregulation and activity [12]. At the same time, colostrum yield is independent of
litter size, meaning that increases in litter size decrease the amount of colostrum consumed
per piglet [13]. On top, IUGR piglets consume less colostrum than piglets with a normal head
morphology [14] and also have a lower stomach capacity to do so [15]. This is important,
as timely and sufficient colostrum is essential to the survival and lifetime performance
of piglets [9,16,17]. In addition, the number of teats has not increased in relation to the
number of piglets born alive [18], thereby increasing competition for the already limited
resources. Taken together, reductions in the intake of colostrum and milk increase the risk of
malnutrition or even starvation, as well as the risk of hypothermia and disease susceptibility,
ultimately resulting in variable growth rates within litters [1]. This has introduced new
challenges with regard to keeping all piglets alive and healthy throughout production. The
progressing development of a piglet’s gut, as well as the associated gut microbiota and
immune system during the first weeks of life [19], offers a unique window of opportunity
for the early life programming of the gastro-intestinal tract.

25.0
22.5 Birth weight

20.0
< <500
500 gg
17.5 500 ‐600 gg
500–600
Number of piglets

700‐800
700–800g g
15.0
900‐1100
900–1100g g
12.5 1100‐1300
1100–1300gg
10.0 1300‐1500
1300–1500gg
1500–1700gg
1500‐1700
7.5 1700–1900gg
1700‐1900
5.0 1900–2100gg
1900‐2100
>>2100
2100 g
2.5
0.0
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Litter size
Figure 1. Effect of litter size on birth-weight distribution. The data were collected at Schothorst Feed Research B.V. (Lelystad,
The Netherlands) from 2011 to 2019, based on 97,552 piglets born alive from 7888 litters.

The various stressors to which piglets are exposed at weaning in combination with
their impaired gut and immune function make newly weaned piglets extremely vulnerable
to post-weaning diseases, which consist largely of gastro-intestinal infections [20]. As a
result, most antimicrobials (i.e., antibiotics and microminerals) within the context of pig
production are used in the nursery barn [21]. Risk factors for post-weaning diseases include
weaning age, weaning weight, low feed intake during the immediate post-weaning period,
Animals 2021, 11, 402 3 of 36

overeating (i.e., large amounts of feed consumed in a low number of meals), large amounts
of undigested nutrients arriving at the end of the ileum and several management factors
(e.g., hygiene, temperature, draught, feeding spaces) [22,23]. In the past, nutritionists could
mask gastro-intestinal infections by using in-feed antibiotics, pharmaceutical levels of zinc
(Zn) and/or high levels of copper (Cu) in piglet diets [21]. Since 2006, however, the use of
in-feed antibiotics has been prohibited in Europe [24], and further restrictions with respect
to Cu and Zn in piglet diets are either already in place or are expected to be implemented
in the near future [25–27]. Combined with the fact that gastro-intestinal problems rank
amongst the highest causes of morbidity and mortality in pig production [28–30], these
restrictions have created a need for other dietary interventions aimed at improving the
health of the gastro-intestinal tract (“gut health”, as discussed by Pluske et al. [31]).
In response to the developments outlined above, this review focusses on nutritional
solutions intended to prepare piglets for success during the weaning process and the
period thereafter (5–6 weeks post-weaning), based on the latest developments in prac-
tical swine nutrition. A varied array of dietary interventions and their relationship to
gut health is discussed and combined into nutritional strategies for supporting piglets
during early life and the subsequent weaning process. Recent reviews have charted the
potential of using nutritional strategies in sows to modulate piglet gut health, particularly
at birth [19,32]. The current review, therefore, focusses on nutritional interventions for suck-
ling and weaned piglets. The strategies addressed include oral supplements (first days after
birth), supplemental milk (first weeks after birth) and solid feed (pre- and post-weaning).
Although several nutritional interventions have been shown to give piglets a good start,
not all weaned piglets are alike. This review therefore proposes a structured nutritional
approach over time, suggesting potential directions to explore in order to shape the gastro-
intestinal tract of all young piglets to reduce morbidity, mortality and antimicrobial use in
pig-production systems.

2. Early Nutrition Interventions

Litters consisting of more piglets than the number of productive sow teats are likely
to require additional management and nutritional interventions to increase pre-weaning
survival, as the sow cannot rear them on her own [1]. The various management strategies
for rearing piglets in large litters, their effectiveness and their implications for animal
welfare have been described in reviews by Baxter et al. [33,34]. This section highlights
the effect of dietary components that can improve gut health and development in oral
supplements and supplemental milk.
As piglets are born without passive immune protection from the sow, they are depen-
dent on the transmission of immunoglobulins through sow colostrum. Colostrum is also an
important source of energy (e.g., for thermoregulation, energy deposition, physical activity
and maintenance), which contributes to early survival [16]. In addition, the ingestion of
colostrum has been associated with substantial growth in the intestine (cellular prolifera-
tion) [35], as well as with major changes in the shape, size and density of villi [36,37]. This
suggests that, in addition to its importance for immune function and providing energy,
colostrum plays an important role in the development of the gastro-intestinal tract. The
increasing trend in the number of piglets per sow has resulted in the birth of less viable
piglets and a lower colostrum intake per piglet. It is therefore not surprising that oral
supplementation (e.g., with colostrum or energy) during the first 12 h after birth—in order
to promote colostrum intake and thus early survival—has gained interest in recent years.
To date, however, only a limited number of studies have evaluated the effectivity of such
products on survival and growth, and the studies that have been published vary consid-
erably with regard to timing of the supplements, category of piglets (e.g., birth weight),
type of product and dosage. In addition, the sow effect on piglet survival is often poorly
controlled [34].
Piglet bacterial diversity during early life has been suggested as an important factor
in gut physiology and immunity, and it might influence the susceptibility of piglets to
Animals 2021, 11, 402 4 of 36

enteric infections in later life [19,21]. At birth, the gut microbiota of piglets is shaped by
the microbiota of their sow, including the microbiota existing in the sow’s vaginal tract,
as well as in faeces, colostrum/milk and on the teats [38,39]. Salivary microbes constitute
another potentially influential source that merits further investigation. The microbiome of
the sow—and therefore of her piglets—is particularly influenced by the sow’s diet during
gestation and lactation. It therefore offers an opportunity to improve piglet health, as
addressed by Ferret-Bernard and Le Huërou-Luron [19] and Jiang et al. [32]. The early gut
colonisers of neonatal piglets also include microbes from the environment [38,39]. There
are thus many avenues for programming the gut during early life that could be beneficial
throughout the entire production life of piglets. This review is limited to the nutritional
aspects of oral supplements, supplemental milk and creep feed.

2.1. Oral Supplementation

Given that feed intake is limited immediately after birth, studies have examined the
oral supplementation of neonatal piglets, including prebiotics (e.g., inulin, β-glucans and
oligosaccharides) and functional amino acids (e.g., glutamine). Although most of these
studies involve the administration of products on a daily basis for periods (i.e., 7 to 28 days)
that are possibly longer than practical, these studies indicate that intestinal morphology and
function can be modulated in the long term (at least up to two weeks after oral administra-
tion; Table 1). Taken together, these results indicate a potential for early-life programming
through dietary modulation. The transplantation of faecal microbiota from the sow or
adult pigs to new-born piglets also has the potential to prevent or reduce intestinal diseases
(e.g., Escherichia coli (E. coli)), as it can influence gut microbiota colonisation, intestinal
barrier and immune function (reviewed by Canibe et al. [40]). Negative results have also
been reported [40], however, indicating that the technique must first be optimised and
pass biosecurity and regulatory barriers before it can be used safely and efficiently in
pig production.
Animals 2021, 11, 402 5 of 36

Table 1. Effects of pre-weaning dietary interventions through oral gavage on the gut development of sow-reared piglets. ↓ Significant decrease at p < 0.05; ↑ Significant increase at p < 0.05;
= No significant difference; BW = body weight.

Effects on Gut Development versus a Control Oral Gavage with Water or

Reference Dietary Intervention(s) 1 Intervention Period (Age) Age at Sampling
Physiological Saline
L-glutamine;
↑ Small-intestine weight, jejunum villus height (after lipopolysaccharide (LPS)
[41] L-alanyl-L-glutamine: 7–16 16
challenge)
0.5 g/kg BW twice daily
Positive effect on gut morphology of the small intestine and a reduction in
Inulin: 0.5 to 2 g; pro-inflammatory cytokines at mRNA level in the large intestine. The low inulin level
[42] 1–28 28
Inulin: 0.75 to 3 g was more beneficial, as it also increased the concentrations of propionate and
iso-butyrate in the large intestine.
Inulin: 0.114 g/kg BW;
[43] Inulin + Lactobacillus acidophilus W37: 5 × 2–23 23 ↑ Health status = Composition and diversity of faecal microbiota
109 CFU/piglet
Bifidogenic effect in the colon, changes in mucosal gene-expression profiles in the
[44] Fructo-oligosaccharides: 10g 2–14 14, 25
jejunum relating to intestinal barrier function and immunity (d14 and d25)
Improves the jejunum barrier function:
↑ Small-intestine length at d8
↓ Crypt depth at d21
↑ mRNA expression of jejunal growth factors (d8 and d21)
[45] Galacto-oligosaccharides: 1 g/kg BW 0–7 8, 21 ↑ Protein expression of jejunal growth factors (d8) and tight junctions (d8 and d21)
↑ mRNA expression of jejunal nutrient transporters (d21)
↑ mRNA expression of cytokine TGF-β at d8, ↓ mRNA expression of cytokine IL-12 at
d8
↑ Jejunal lactase activity on d8, maltase activity and sucrase activity on d21
Modulated the gut microbiota in faeces and improved the intestinal barrier function:
↓ α-diversity at d8 (Sobbs index, but not Shannon index)
↑ α-diversity at d21 (Sobbs and Shannon index)
↑ Lactobacillus (d8), Muribaculaceae, Christensenellaceae, Enterococcus and
Galacto-oligosaccharides + milk fat globule
Romboutsia (d21)
[46] membrane + fructo-oligosaccharides: 1–7 8, 21
↓ Lachnospiraceae (d8), Eubacterium (coprostanoligenes group, d21)
1.2 g/kg BW
↑ Acetate and propionate (ileum), acetate (colon)
↑ Gene expression of short-chain fatty acid receptors (ileum, colon)
↑ Gene expressions of tight junctions, mucins and cytokines
↓ Plasma diamine oxidase (d21)
Modest modulation of the gut microbiota in faeces and immune system:
↓ Shannon diversity in faeces (d4, 8, 14, 26), no differences in jejunum, ileum and
caecum digesta
[47] β-glucans: 50 to 200 mg every other day 2–27 27 ↓ Methanobrevibacter (d8, 14)
↑ Fusobacterium and Ruminococcaceae (several time-points)
↓ Proliferating NK immune cells and γδ T cells in blood at d26
↑ IL-10 cytokine production by mesenteric lymph node cells (ex vivo)
1 Daily administration dose, unless mentioned otherwise.
Animals 2021, 11, 402 6 of 36

2.2. Supplemental Milk

Bioactive compounds are contained in sow milk, including hormones, growth factors,
immune cells, antimicrobial compounds and commensal bacteria, which play a vital role in
establishing a healthy and functional gastro-intestinal tract [48,49]. In some cases, however,
as with large litters and impairments in the milking ability of the sow (e.g., due to heat
stress, sickness), the application of supplemental milk (i.e., formula milk provided to sow-
reared piglets) may help to improve pre-weaning survival and performance by increasing
weaning weight and lowering variability in body weight within the litter. Studies on the
effectivity of this method have yielded inconsistent results [34]. Nonetheless, supplemental
milk may especially be relevant for farms that make little or no use of nurse sows or that
apply minimal or no cross-fostering of piglets.
Evidence also suggests that supplemental milk could potentially alter gut health and
function. For example, de Greeff et al. [50] report that the provision of supplemental milk
(age 1–21 days; average litter size 13–14 piglets) enhanced small intestinal growth and
cell proliferation, as well as increased concentrations of short-chain fatty acids (SCFA) in
the colon (which is the energy source for intestinal cells). These results were accompanied
by softer faeces and an improved weaning weight [50]. In addition to enhanced levels
of SCFA, another study (Jin et al. [51]) reports that the provision of supplemental milk
from 7 to 21 days of age modulated gut microbiota colonisation in the jejunum and colon
(e.g., reduced E. coli abundance) and altered mRNA expression of jejunal inflammatory
cytokines and barrier proteins. As a result, piglets fed with supplemental milk had a lower
incidence of pre-weaning and post-weaning diarrhoea [52]. Taken together, these studies
suggest that supplemental milk, in addition to sow milk, has the potential to improve
piglet gut health in large litters.
Supplemental milk can be formulated in order to serve both a nutritional and a
functional role. The composition of formula milk has been shown to influence gut morphol-
ogy [53,54], digestive function [53,55], mucosal immunology and microbiota in piglets [56].
It is important to note, however, that these studies focus on the provision of formula milk
to artificially reared piglets (further defined as milk replacers in the current review), mostly
as a model for human infant formula, rather than the use of formula milk as a supplement
for sow-reared piglets. Some of these studies indicate that intervention periods of just
3–8 days could be sufficient to affect gut morphology and (immune) function (Table 2).
For example, Le Huërou-Luron et al. [55] suggest that the composition (a variety
of sources) and the structure (a variety of stabilisers) of the added fat used can have an
impact on the immune system and gut physiology. They demonstrate that the use of both
saturated milk fat and vegetable oils that had been stabilised by a mixture of proteins and
milk fat globule membrane fractions given from two days of age could modify intestinal
physiology, mucosal immunity, microbial composition and protein digestion at 7 days of
age [55]. In addition, prebiotics (either alone or in combination) are often added to infant
formulas in order to mimic the effect of “human milk oligosaccharides” (HMO). These
compounds are believed to modulate gut microbiota, to have several antimicrobial actions
and to play a role in immune development. For example, Radlowski [53] studied the effect
of a combination of two prebiotics, polydextrose and short-chain fructo-oligosaccharides
(scFOS) in milk replacer, with regard to their ability to mimic the bioactive compound
HMO. They found evidence that polydextrose and scFOS in the milk replacer provided
during the first two weeks of age yielded effects similar to those of sow milk with respect
to intestinal function (e.g., similar peptidase activity) [53]. Similarly, Alizadeh et al. [54]
studied the effect of the prebiotic galacto-oligosaccharide (GOS) in milk replacer. They
observed morphological changes in the duodenum (e.g., enlarged villus height, villus area
and villus-to-crypt ratio) after GOS supplementation in the milk replacer of very young
piglets (4 days old). These results suggest that the supplementation may improve the
utilisation of nutrients. In the same study, GOS also seemed to improve gut functioning
(e.g., nutrient digestion, barrier function) and mucosal immune functioning, although this
did not become apparent until after a longer period of exposure (age 27 days) [54]. Taken
Animals 2021, 11, 402 7 of 36

together, these studies emphasise the potential of modulating piglet gut development in
early life through formula milk, while clearly highlighting that the effects of functional
ingredients in supplemental milk (for sow-reared piglets) rather than milk replacer (for
artificially reared piglets) as used in the reported studies warrant further investigation, as
their effects may be less pronounced in sow-reared piglets.
When considering the relative success of supplemental milk (and its possible effects
on gut health and development), it is important to understand which piglets within the
litter and in which period the supplemental milk is consumed. Whereas Baumann et al. [57]
report that piglets only seldom ignore supplemental milk, de Greeff et al. [50] observe that
13% of the piglets in their study were consuming supplemental milk at Week 1 after birth,
with 51% doing so at Week 2 and 87% at Week 3. Another study suggests that low birth-
weight piglets (≤1.25 kg) consumed more supplemental milk than their heavier littermates
(1.6 to 2.0 kg; [58]), while other authors have found little evidence to explain variations in
the drinking of supplemental milk by piglets of different body-weight classes [57]. In the
latter study, piglets that used the milk feeder frequently between Day 2 and Day 6 after
birth had gained less weight on Day 6 than piglets that had visited the milk feeder only
occasionally [57]. This suggests that variations in the intake of supplemental milk can likely
be explained by the intake of sow milk, which is the main energy source during lactation.
In addition to within-litter variations, studies have revealed wide variations between litters
with regard to supplemental milk intake, ranging from almost 0 to >20 litres per piglet from
birth to three weeks of age [59]. Factors influencing supplemental milk intake between
litters include room temperature [59] and the milk production of the sow [60].
Although there is no perfect solution, for large litters and in case of poor sow per-
formance, the provision of oral supplements and/or supplemental milk to piglets may
be useful in early life to decrease pre-weaning mortality, while improving gut health and
performance. Sow milk should remain the most important source of nutrients, however,
as supplemental milk (as it is currently applied) does not provide the same nutrients and
bioactive compounds as sow milk. In addition, the economic benefits of a strategy—taking
into account both costs (e.g., labour, cost of the supplement, cost of the system used)
and long-term revenues—should be considered when determining the efficiency of such
strategies, which is likely to differ from one pig producer to another.
Animals 2021, 11, 402 8 of 36

Table 2. Effects of pre-weaning dietary interventions in milk replacer on the gut development of artificially reared piglets. ↓ Significant decrease at p < 0.05; ↑ Significant increase at
p < 0.05; = No significant difference; BW = body weight.

Reference Dietary Intervention(s) Intervention Period (Age) Age at Sampling Effects on Gut Development versus a Control Milk Replacer
Lowers digestive enzyme production at both sampling days:
↓ Lactase, sucrase, disaccharidase and aminopeptidase N activity (ileum)
Polydextrose (2 g/L) + ↓ Dipeptidyl peptidase IV activity (jejunum, ileum)
[53] 1–14 7, 14
Fructo-oligosaccharides (2 g/L) = Small-intestine weight and length
= Cytokine expression (ileum)
= Faecal consistency
= Small-intestine weight and length
Polydextrose (2 g/L) + ↓ Total volatile fatty acids (colon, no differences in caecum and faeces)
[61] 2–33 33
Galacto-oligosaccharides (2 g/L) ↑ Dry matter of colon digesta
↓ Dry matter of faeces
= Small-intestine weight and length
Galacto-oligosaccharides = Immune cell population
[53] 1–21 21
(2 g/L) + Inulin (2 g/L) = Nitric oxide synthase activity
= Cytokines IL-6 and TNF-α in blood
Modulates gut microbial population and improves intestinal morphology and
barrier function:
↑ Duodenum villus height, villus area, villus-to-crypt ratio (d4), villus width (d27)
↑ Jejunum villus height (d27)
↓ Caecum pH (d4, no other pH differences)
↑ Caecum butyric acid (d27)
[54] Galacto-oligosaccharides: 0.8% 1–26 4, 27 ↑ Lactobacillus, bifidobacterium in faeces (d27)
↑ Maltase activity (colon: d4, caecum: d27)
↓ Lactase, sucrase, maltase activity (ileum, d27)
↑ mRNA expression of defensins (colon, d4)
↑ mRNA expression of tight-junction proteins in different segments of the intestine (d4, d27)
↑ Tight-junction protein expression (duodenum, colon, d27)
↑ Secretory IgA from saliva (from d19)
↑ Relative large-intestine weight in males, but not females
[62] Galacto-oligosaccharides: 8 mg/mL 3–25 25 = Small-intestine weight
↓ Haematology and clinical chemistry blood parameters
Modulates gut microbiota population and stimulates gut function:
= Intestinal weight and length, small-intestinal morphology
↓ Colon area
Galacto-oligosaccharides (7 g/L) + milk ↑ Parabacteroides, Clostridium IV, Lutispora (colon)
fat globule membrane-10 (5 g/L) + ↓ Mogibacterium, Collinsella, Klebsiella, Escherichia-Shigella, Eubacterium,
[63] 3–33 33
polydextrose (2.4 g/L) + bovine Roseburia (colon)
lactoferrin (0.6 g/L) ↑ Lactase activity (jejunum), lactase-to-sucrase activity (duodenum, ileum; no difference
in jejunum)
= Sucrose activity (in any part)
↑ Vasoactive intestinal peptide expression (ileum)
Animals 2021, 11, 402 9 of 36

Table 2. Cont.

Reduces colonisation by E. coli and modulates intestinal immune system:

↓ Diarrhoea frequency
↓ E. coli in jejunal and ileal tissue and content in non-inoculated intestinal samples, but not in
[56] Bovine colostrum 23–31 31
ETEC F18-inoculated samples
↓ TLR-4 and IL-2 gene expression (jejunal and ileal mucosa)
= Ig concentrations in mucosa and plasma

VP: palm + rapeseed oil

• VM and MM: ↑ relative jejunum weight and mucosal density at d7 and d28, ↑ ileum
mucosal density at d28, = digestive enzyme activity, = epithelial barrier permeability
VM: VP + milk fat globule membranes
[55] 2–28 7, 28 • MM: ↓ protein digestion (casein),↑ interferon γ secretion from mesenteric lymph node
(MFGM)
MM: VM + sunflower + milk fat cells, x= bacterial diversity, ↑ Parabacteroides, Escherichia/Shigella, Klebsiella, ↓
Clostridiales Family XIII, Veillonellaceae
Fat origin: only plant lipids or a half-half
[64] 2–28 33 = Short-chain fatty acids (faeces)
mixture of plant and dairy lipids
= Small-intestine length and weight
[65] Yeast β-glucans: 5, 50 or 250 mg/L 2–21 7, 21 = Ileal crypt depth, villus height, ascending colon-cuff depth
= T cell phenotypes, cytokine gene expression, cell proliferation
↓ Relative full stomach weight
[66] Wheat: up to 40% 11–25 1 25 ↑ Sucrase, maltase
↑ Leukocytes, neutrophils
• 10 g/L pectin: ↓ feed efficiency, ↓ apparent ileal and total tract digestibility of dry
[67] Pectin: 2 g/L or 10 g/L 2–23 matter, crude protein and energy
• 2 g/L pectin: ↓ apparent total tract digestibility of dry matter
1 A basal milk replacer was given from Day 3 to Day 11 after birth.
Animals 2021, 11, 402 10 of 36

3. Preparing Piglets for Weaning

The dietary transition from mainly sow’s milk to exclusively solid feed is one of the
important stressors that occur at weaning within the field of commercial pig husbandry [68,69],
thus contributing to the post-weaning dip in piglet health and performance. The aim
of providing creep feed is to improve post-weaning piglet performance by habituating
piglets to solid feed prior to weaning, while often having only marginal effects on pre-
weaning production parameters. In a recent review on the effects of creep feed on gut
development [70], the author concludes that the effects are mostly ambiguous, particularly
with regard to the effects of creep feed on the incidence of diarrhoea [71–73]. While most
studies report no effects of the provision or intake (eaters vs. non-eaters) of creep feed
on gut development [72–74], a few studies have reported subtle beneficial effects on gut
morphology, cell proliferation and net absorption in the small intestine, most of which
were observed post-weaning [75–78]. As is the case with supplemental milk, creep feed
could plausibly be expected to affect gut microbiota colonisation [79–83]. It should be
noted, however, that the effects of creep feed on gut (microbiota) development are likely to
be dependent on age at provision [84], dietary and nutrient composition [85], and intake
level. The importance of intake levels is evident in the fact that the effects of creep feed
on piglet performance are pronounced primarily in piglets that consume the creep feed
(i.e., eaters), and particularly in those that consume relatively large amounts (reviewed by
Middelkoop; [70]). These observations correspond to the findings of Choudhury et al. [82],
who report a correlation between the amount of time that piglets spent with their heads
in the trough and the change in observed microbiota colonisation. As the amount and
dietary composition of feed consumed seem largely responsible for success in influencing
gut development, these aspects are discussed in greater detail below.

3.1. Pre-Weaning Nutritional Strategies to Stimulate Individual Dry-Matter Intake

The number of piglets consuming creep feed increases exponentially with age [86,87].
Although no comparison has been made within a single experiment, the number of piglets
consuming creep feed appears to be lower than the number of piglets drinking supplemental
milk, particularly during the first two weeks of lactation (~5% creep-feed eaters [75,86,87] vs.
51% supplemental-milk drinkers [50]). With regard to creep-feed intake, there is evidence
that the intake of sow milk plays a role in determining the extent to which piglets are
attracted to creep feed [88,89]. In general, posterior teats produce lower quantities [90]
and quality [91] of milk than do anterior and middle teats, while teats in the middle part
of the udder are more prone to teat disputes than are the others [92]. More specifically,
piglets suckling the middle and posterior teats have been observed to consume more creep
feed than piglets suckling the anterior teats [86,93]. Birth weight has also been shown
to affect the intake of creep feed, although the published correlations with creep-feed
intake have been both positive [94,95] and negative [96,97]. This suggests that the birth-
weight effects observed might have been confounded by other factors (e.g., teat order and
weight distribution within the litter) [86]. Strategies for increasing creep-feed intake and
the number of piglets eating range from housing strategies (e.g., intermittent suckling
and multi-litter housing) and management strategies (e.g., feeder type and enrichment
materials) to nutritional strategies [70]. The nutritional strategies are discussed below.
While piglets have the ability to suckle and drink from birth, their (pre)molars, oral
motor skills and mastication muscles must develop over time in order to handle, chew
and ingest solid feed [98,99]. To facilitate this process from suckling/drinking (liquid feed)
to eating (solid feed), creep feed can be mixed with water or supplemental milk, starting
with a relatively high liquid content, and gradually decreasing it over time. In addition to
observing that piglets had a higher intake of porridge (creep feed pellets-to-water ratio of
1:3) as compared to pellets in the first three weeks of lactation, Clouard et al. [100] report a
higher intake of the pelleted transition diet that was given in the fourth week of lactation.
Softer pellets may also facilitate the transition to solid diets. They can be produced
either by adapting the production process (e.g., decreasing die thickness on the pellet
Animals 2021, 11, 402 11 of 36

press) or changing the diet composition. The most commonly studied method of soften-
ing pellets involves increasing pellet diameter. Larger (5–12.7 mm), and thereby softer,
pellets have consistently been shown to increase the feed intake of suckling piglets, as
compared to conventionally sized pellets of 2–4 mm in diameter, in either early or late
lactation (e.g., [101–103]). In addition to improving feed intake, a larger pellet diameter
might also have beneficial effects on the gut, including reducing the proportion of med-
icated piglets (mostly for ill thrift) post-weaning when larger pellets (9 vs. 4 mm) were
fed pre-weaning [103] and improving post-weaning feed-conversion ratio when larger
pellets (5.2 vs. 4 mm) were fed post-weaning [104]. The percentage of eaters pre-weaning is
addressed in only one of the studies, with no differences found between pellet diameters of
3.2 and 12.7 mm [102]. In addition, Chen et al. [105] evaluate the effect of pellet hardness on
feed intake by testing a hard-pellet creep feed (i.e., hardness of 2690 g) versus a soft-pellet
creep feed (i.e., hardness of 505 g). According to their data, piglets receiving the soft pellets
from Day 14 to Day 22 after birth had higher creep-feed intake pre-weaning than did those
in the other treatment groups. The authors speculate that this might have been a result of
the higher moisture content and greater concentration of starch gelatinisation in the softer
pellets, which seemed to have a positive influence on the palatability of the feed [105]. The
processing of specific feedstuffs to modulate starch gelatinisation rather than the processing
of the complete diet might also be useful for stimulating pre-weaning feed intake, as has
been observed post-weaning [106].
The composition of the creep feed itself, with a focus on the palatability of the diet, can
also influence feed intake and the number of piglets eating, as reviewed by Middelkoop [70]
and Tokach et al. [107]. In addition, it could be speculated that the nutrient density of pre-
weaning diets should not be excessive, as a nutrient-dense diet is likely to result in the
arrival of excessive amounts of substrate at the end of the ileum, thereby resulting in an
overgrowth of potentially pathogenic bacteria, as well as a prolonged feeling of satiety.
Although some evidence suggests that a lower density of dietary energy may indeed
stimulate post-weaning feed intake [108], this remains to be confirmed for the pre-weaning
stage [71,109].

3.2. Pre-Weaning Nutritional Strategies to Modulate Gut Health

A variety of nutritional strategies (e.g., highly digestible protein sources, feedstuffs
with low fermentability) may also be useful in using creep feed to modulate gut health.
Table 3 provides an overview of nutritional interventions using functional amino acids (e.g.,
glutamine), yeast, prebiotics (e.g., oligofructose), probiotics, synbiotics, fat sources rich in
medium-chain fatty acids (MCFA) and various fibre sources (e.g., insoluble and soluble
fibres) that have been included in creep feed. Although most of the studies listed here report
significant effects on gut morphology, gut microbiota colonisation and maturation of the
mucosal immune system, none considers whether the piglets (which had been humanely
euthanised in order to measure the gut parameters) had actually ingested the creep feed,
and most had studied piglets only until three weeks of age. Nevertheless, these results may
suggest that the effects could be even more pronounced for longer creep-feeding periods
and higher (individual) levels of creep-feed intake. The effect of the dietary composition
of creep feed on post-weaning gut health and performance has yet to be explained. For
example, Fouhse et al. [110] report that yeast-derived mannan-rich fraction had positive
effects on jejunal morphology at one week post-weaning, but not thereafter (at three weeks
post-weaning).
Animals 2021, 11, 402 12 of 36

Table 3. Effects of pre-weaning dietary interventions through creep feed on the gut development of sow-reared piglets. ↓ Significant decrease at p < 0.05; ↑ Significant increase at p < 0.05; =
No significant difference.

Reference Dietary Intervention(s) Intervention Period (Age) Age at Sampling Effects on Gut Development Versus Control Creep Feed
Modulates gut morphology, as well as gut microbial population in small and large
intestine:
= Villus height (duodenum, ileum), crypt depth (ileum)
Oligofructose: 0.2%; Probiotics: 0.3%;
[111] 7–21 21 ↑ Duodenum crypt depth (only when fed oligofructose)
or their combination as synbiotic
↑ Bifidobacteria in ileum (also in colon for probiotic products)
↓ Total coliform in colon
= Haematological blood parameters
Glutamine: 1%; Glutamine + 21–28
[77] 35 = Small-intestine histology and absorptive capacity
glutamate: 0.88% (weaning at Day 28)
= Lactobacillus
[112] Yeast-dried milk: 10% 7–21 7, 14, 21
= Serum IgA
Improves jejunal morphology and alters caecal microbial population at d28, but not at
d42:
Yeast-derived mannan-rich fraction: 7–21 ↑ Jejunal villus height
[110] 28, 42
800 mg/kg (weaning at Day 21) ↑ Gene expression involved in intestinal development, function and immunity
↑ Paraprevotellaceae genera YRC22 and CF231
↓ Sutterella, Prevotella
Modulates the gut microbial population in the large intestine:
Alfalfa: 1.3%; • Alfalfa: ↑ Bacteroidetes (caecum), ↑ Coprococcus eutactus (colon), ↓ Streptococcus
[113] Wheat bran: 2.92%; 7–22 23 suis (colon)
Cellulose: 1% • Wheat bran: ↑ Dorea (caecum), ↓Lactobacillus paracasei (colon)
• Cellulose: ↓ Eubacterium pyruvativorans (caecum), ↓ Acholeplasma (colon), ↓
Gemella haemolysins (colon)
Modulates the abundance and activity of butyrate-producing bacteria in the large
intestine:
• Alfalfa: ↓ Firmicutes, Bacteroidetes (caecum), ↑ Clostridium cluster XIVa (colon),
Alfalfa: 1.3%; ↑ genes encoding proteins involved in butyrate production (colon), ↑ total
[114] 1 Wheat bran: 2.92%; 7–22 23 short-chain fatty acids (colon), ↑ Firmicutes (colon mucosa)
Cellulose: 1% • Wheat bran: ↓ Firmicutes, Bacteroidetes (caecum and colon mucosa), ↑ genes
encoding proteins in butyrate production
• Cellulose: ↑ Clostridium cluster XIVa (caecum, colon), ↓ (iso)valerate (caecum), ↑
total short-chain fatty acids (colon)
= Stomach size, small-intestine permeability
Long-chain arabinoxylan: 2%; • Arabinoxylan: ↑ relative colon weight, ↑ digesta in colon, ↑ propionate in caecum
[85] 2–24 2 23, 24
Cellulose: 5% • Cellulose: ↑ relative colon weight, ↑ colon length, ↑ volatile fatty acids in colon, ↓
ileal pH, minor shifts in specific genera such as ↓ Escherichia-Shigella
1 Same data as Zhang et al. [113], but analysed differently (16S rRNA sequencing versus Pig Intestinal Tract Chip analysis). 2 Day 2–13 as supplemental milk, Day 14–16 gradual transition to creep feed, Day

17–24 creep feed as meal.

Animals 2021, 11, 402 13 of 36

Compared to creep feed, commercial weaner diets have a higher content of non-starch
polysaccharide (NSP) and a higher quantity of fibres, amongst other aspects. It would
therefore seem useful to formulate creep feed as a means of preparing the gut (digestive
system and microbiota) for the weaner diet, rather than as a purely nutritional resource.
For example, in a study by van Hees et al. [85], increasing the fermentable (i.e., long-
chain arabinoxylan) or non-fermentable fibre (i.e., cellulose) content of milk replacer (fed
from Day 2 to Day 13 after birth) and the subsequent creep feed (fed from Day 14 after
birth) had the potential to increase the relative weight and SCFA content of the large
intestine at weaning on Day 25, as compared to piglets fed with a low-fibre diet. Short-
chain fatty acids are degradation products remaining after the fermentation of complex
polysaccharides (e.g., arabinoxylan and cellulose). An example of SCFA includes butyrate,
which plays an important role in maintaining the gut barrier (i.e., stimulating gut epithelial
cell proliferation and degradation). As suggested by this and other studies (Table 3), creep
feed can also serve a functional role, in which the nutrient composition of the creep feed
may be able to modulate gut health. Additional research is nevertheless needed in order to
understand the impact of such strategies on post-weaning growth and gut health [115].

3.3. Transition Diet

The success of providing solid feed in the pre-weaning stage with regard to improving
performance in the post-weaning stage depends on intake level and the dietary composition
of the creep feed and weaner diet, as well as on the similarity amongst these types of
feed [79,116]. If there are large differences between creep feed and the post-weaning diet,
piglets may not adjust to the post-weaning diet, even despite high creep-feed intake in the
pre-weaning stage. This has been demonstrated in a study by Heo et al. [116], in which
piglets were given creep feed, a weaner diet or a sow diet pre-weaning. In the post-weaning
stage, all of the piglets received the same weaner diet that some litters had already received
in the pre-weaning stage. Litters that had been fed creep feed during the pre-weaning
stage had the highest total feed intake pre-weaning, and with a similar number of eaters
as in the other two treatments. In the first two weeks post-weaning, however, piglets that
had received the weaner diet in both the pre-weaning and post-weaning stages had a
higher level of post-weaning feed intake than did the other two groups. They also had
greater post-weaning body-weight gain than did the creep feed group. Interestingly, the
sow-diet group had an intermediate body weight gain in the first two weeks post-weaning,
along with improved feed efficiency between Weeks 2 and 5 post-weaning, as compared
to the groups receiving the other two dietary treatments. Taken together, these results
suggest that the similarity between the composition of pre-weaning and post-weaning
diets is more important to post-weaning performance than is the intake level of solid
feed in the pre-weaning stage. This suggestion is supported by the results reported by
Middelkoop et al. [117], in which two dietary-treatment groups differed substantially
in the intake of solid feed during the pre-weaning stage. The difference in feed intake
did not persist in the post-weaning stage, however, when the piglets received a diet that
differed from the pre-weaning diet (with a similar post-weaning diet across all treatment
groups). Moreover, strong positive relationships were found between feed intake pre-
weaning and immediate post-weaning, as well as between pre-weaning feed intake and
post-weaning piglet growth, when the same diet was given in both the pre-weaning and
post-weaning stages [118,119]. It is therefore important to provide the same diet in the
pre-weaning period (at least in the last week/days) and the initial post-weaning period, so
that piglets will recognise the post-weaning diet in terms of both behaviour (e.g., reduced
food neophobia) and physiology.

4. Are all Weaned Piglets Alike?

Production losses including growth impairments, increases in the number of vet-
erinary treatments and higher mortality rates are factors that pig producers continue to
face during the immediate post-weaning period. The changes that make weaning such a
Animals 2021, 11, 402 14 of 36

stressful and challenging process for piglets have been described in greater detail in several
extended reviews (e.g., Weary et al. [68] and Heo et al. [69]). Briefly stated, they include
separation from their dam and littermates, nutritional challenges (e.g., dietary changes
from highly digestible sow milk to a less digestible complex solid diet, and changes in
feeding habits), mixing with unfamiliar piglets (including establishing a social hierarchy)
and adjusting to a new environment.
Piglets vary greatly within weaning batches with regard to their capacity to encounter
post-weaning stressors, even though piglets are often fed a common diet at weaning. For
example, piglets are weaned at varying weights [7,120], and not all piglets have already
eaten solid feed pre-weaning [86,102,121]. Despite common knowledge that weaning
weight is crucial to subsequent production performance [120,122], it is often assumed that
piglets that are weaned light were also born light [6,123]. Some piglets that are born light
are nevertheless able to catch up in growth [7,120]. In addition, recent literature [8,124,125]
suggests that various morphometric characteristics suggestive of IUGR (e.g., body mass
index, ratio of birth weight to cranial circumference) may explain why some piglets are
more likely to end up light at weaning, regardless of birth weight.
The intake of creep feed during the pre-weaning period is one important factor that
can influence piglet performance and gut absorption during the post-weaning period [126].
As reported in a study by Bruininx et al. [127], piglets that started eating creep feed
pre-weaning had a shorter latency time to eating the post-weaning diet, as compared to
non-eaters, as well as a higher feed intake. These results have been supported in other
studies [121,128]. Piglets that have consumed creep feed pre-weaning may react differently
to the dietary change at weaning than piglets that did not consume creep feed. In a study
by Torrallardona et al. [79], piglets were weaned into post-weaning diets with different
cereal sources (i.e., barley, rice + wheat bran, corn, naked oats, oats, or rice) and fed creep
feed or not during the pre-weaning period. The results suggest that some cereals are more
suitable than others, depending on whether a piglet has or has not had access to creep feed.
For example, rice + wheat bran resulted in the greatest weight gain and feed intake during
the first 21 days post-weaning for piglets that had access to creep feed pre-weaning, whilst
piglets that had no access to creep feed performed worst on this cereal source and best
on naked oats. No differences were observed at the level of the small intestine that could
explain these results. The piglets in the creep-feed group were not classified into eaters
and non-eaters [79], however, even though not all piglets are generally considered eaters.
These results emphasise the importance of a post-weaning diet that helps both non-eaters
and eaters of creep feed to thrive post-weaning.
One possibility for increasing creep-feed intake and the number of eaters could in-
volve increasing the age at weaning [75]. Current changes in legislation with respect to
dietary limitations of minerals and the ban on antibiotics, combined with public attitudes
concerning farm animal welfare [129], have fuelled a discussion (at least in Europe [130])
about weaning piglets at ages older than 3–4 weeks. Studies on the effect of extending
weaning age suggest that delaying weaning from 3 to 4 weeks of age could reduce the
post-weaning growth check [131,132], while decreasing post-weaning mortality and fae-
cal pathogenic bacterial counts [132], and improving the intestinal barrier function [133].
Extending weaning age from 4 to 6–7 weeks of age has been suggested to increase feed
intake during the immediate post-weaning period [75], while decreasing susceptibility to
post-weaning diarrhoea [134]. Taken together, these findings support the proposition that
later weaning might result in a more mature immune and gastro-intestinal tract during the
immediate post-weaning period. Part of the advantages associated with delayed weaning
may be attributed to increased intake of creep feed [75,135], enhanced development of
the immune system and the presence of several components in sow milk that can further
improve the development of the immune and digestive system [48]. It should nevertheless
be noted that weaning later may be beneficial only during the immediate post-weaning
period [131,132], and only for piglets that are otherwise weaned light [132,136,137].
Animals 2021, 11, 402 15 of 36

In general, two kinds of piglets can be observed at weaning: those that are robust at
weaning and thus better able to cope with the associated changes, and those at greater risk
of post-weaning diarrhoea. One major reason for the higher probability of post-weaning
diarrhoea is anorexia, which results in maldigestion and malabsorption, followed by
associated overeating during the subsequent period [22,23]. Especially during the first two
weeks post-weaning, a piglet’s digestive system is immature and incapable of digesting
and absorbing all nutrients. Overeating can result in excessive undigested nutrients in the
gut, which can subsequently provide a substrate for the proliferation of potential harmful
bacteria. In this review, the post-weaning period is classified into two physiological phases:
an acute phase (from weaning to 5–7 days post-weaning) and a maturation phase (from
5–7 days post-weaning onwards) [138]. This review focusses on feed formulation and
feed-processing strategies aimed at supporting the gut health of weaned piglets. These
strategies are subsequently combined into nutritional strategies in relation to the acute and
maturation phases of weaned piglets.

5. Post-Weaning Nutritional Strategies during the Acute Phase

During the acute phase, piglets experience short-term anorexia, with energy intake
not being restored to pre-weaning levels until two weeks post-weaning [139]. Combined
with the stress of weaning, low feed intake results in impaired gastric barrier and function,
intestinal inflammation and histological changes in the small intestine (e.g., villi atrophy),
thereby reducing the activity of brush-border enzymes. These changes lead to impairments
in the gut mucosal integrity of piglets, thereby increasing the risk of inflammation, resulting
in the accumulation of undigested nutrients in the large intestine and an overgrowth of
harmful bacteria. The changes ultimately increase the piglets’ susceptibility to enteric
bacterial infections [21]. It is therefore important to stimulate feed intake in newly weaned
piglets (e.g., by using a transition diet or the same diet that was used in the pre-weaning
period). Other nutritional strategies aimed at increasing feed intake post-weaning (e.g., the
inclusion of highly palatable ingredients in the post-weaning diet) have been reviewed
by others [140,141]. To promote gut health in weaned piglets, a wide range of nutritional
interventions have been investigated and reviewed, with several functional ingredients
and feed additives receiving the most attention [142–145]. In the following sub-sections,
the nutritional strategies for the acute phase are discussed in relation to their effect on
gut health and functionality (i.e., stomach functioning, stomach retention and digestion
kinetics, and the health and function of the small and large intestine).

5.1. Nutritional Strategies to Support Stomach Functioning

In order to keep piglets healthy, it is important to establish a good gastric barrier and
function. The stomach secretes hydrochloric acid (HCl) and enzymes to break down carbohy-
drates, protein and fats. The secretion of HCl reduces gastric pH and serves two purposes:
(1) to facilitate protein digestion and (2) to create a natural barrier. The enzyme pepsinogen
that is released is converted into pepsin within an acidic environment, after which protein
hydrolysis occurs at pH values of 2.0 to 3.0 [146], while pepsin is inactivated at pH values
greater than 5.5 [147]. The ability of the stomach to digest nutrients effectively is dependent
on gastric pH and gastric emptying rate, diet composition, meal size and the amount of
gastric secretions produced [147]. Young piglets produce only low amounts of HCl, how-
ever, resulting in a high stomach pH and, consequently, impaired nutrient digestion [148].
Combined with the infrequent but relatively large amounts of solid feed intake per meal
during the immediate post-weaning period [149], impaired nutrient digestion may result
in an elevated and variable stomach pH in newly weaned piglets (Figure 2). High stomach
pH values increase the amount of undigested protein that enters the intestinal tract, in
addition to increasing the risk of post-weaning diarrhoea [69] and possibly impairing the
gastric barrier function [150].
 trient digestion may result in an elevated and variable stomach pH in newly weaned pig‐
lets (Figure 2). High stomach pH values increase the amount of undigested protein that
Animals 2021, 11, 402 16[69]
enters the intestinal tract, in addition to increasing the risk of post‐weaning diarrhoea of 36
and possibly impairing the gastric barrier function [150].

8.00
7.00
6.00

pH digesta
5.00
4.00
3.00
2.00
1.00
Stomach pH Ileum pH

Boxplots
Figure2.2.Box
Figure plotsrepresenting
representingindividual
individualvariation
variationinindigesta
digestapHpHofof the
the stomach
stomach andand
thethe ileum
ileum 4
4 h after the piglet’s last meal. Piglets were ± 47 days of age (3 weeks post-weaning).
h after the piglet’s last meal. Piglets were ± 47 days of age (3 weeks post‐weaning). Average stomach Average
stomach
pH pH (SD
was 4.04 was=4.04 (SDand
0.991) = 0.991) andileal
average average ileal7.03
pH was pH (SD
was=7.03 (SDThe
0.323). = 0.323). The data represent
data represent 213 indi‐
vidual piglets that were fed one of 31 experimental diets containing protein‐rich feedstuffsfeedstuffs
213 individual piglets that were fed one of 31 experimental diets containing protein-rich (6–8 pig‐
lets/experimental treatment; treatment;
(6–8 piglets/experimental between 2017 and 2020
between at Schothorst
2017 and 2020 at Feed ResearchFeed
Schothorst B.V., Research
Lelystad, The
B.V.,
Netherlands).
Lelystad, TheThe pH of the stomach
Netherlands). The pHwas measured
of the stomach inwas
the stomach
measured content
in theafter thorough
stomach mixing.
content after
Ileal digesta
thorough were taken
mixing. from thewere
Ileal digesta last taken
2 m offrom
the small intestine
the last 2 m of and mixedintestine
the small before measuring
and mixedthe pH
before
value.
measuring the pH value.

ItItisiswell
wellknown
knownthat thatthe
thebuffer
buffercapacity
capacityof ofthe
thediet
dietcan
canmodulate
modulategastric
gastricpH pH(Figure
(Figure3)3)
and the amount of HCl that is needed to acidify the stomach content
and the amount of HCl that is needed to acidify the stomach content [147]. The buffer capacity [147]. The buffer
capacity of feed ingredients
of feed ingredients can be according
can be defined defined according
to “acid to “acid capacity”
binding binding capacity” (ABC),is
(ABC), which
which
defined is as
defined as the
the ability ofability
a feed of a feed ingredient
ingredient to resist ato resist in
change a change
pH value.in pH
Thevalue.
ABC The ABC
is usually
ismeasured
usually measured as the milliequivalents
as the milliequivalents (meq) of acid (meq) of acid
or base or base
needed to needed
change the to change
pH of thethefeed
pH
of the feed ingredient to the pH end‐titration (usually at pH 4) [151].
ingredient to the pH end-titration (usually at pH 4) [151]. Feed ingredients with a high Feed ingredients with
aABC-4
high ABC‐4 valueacid-binding
value (i.e., (i.e., acid‐binding
capacity capacity
at pH 4) athave
pH 4)a have a stronger
stronger effect oneffect on neutral‐
neutralising the
ising
pH inthe thepH in the stomach
stomach than do feedthaningredients
do feed ingredients
with a low with
ABC-4a low ABC‐4
value. Thevalue.
ABC-4The ABC‐4
value of a
value
diet isofapparently
a diet is apparently
dependentdependent
on the contenton the content
of crude of crude
protein, ashprotein, ash and
and minerals minerals
[151]. Other
[151].
factors Other
thatfactors
might that
playmight
a roleplay a role
as well as wellwater-holding
include include water‐holding
capacity,capacity,
intrinsicintrinsic
osmotic
pressurepressure
osmotic [152], the particle
[152], size ofsize
the particle the ofdiet
the[147]
diet and
[147]the
andconcentration
the concentration of aspartic and
of aspartic
glutamic
and glutamic acid.acid.
AminoAminoacidsacids
(e.g., (e.g.,
glutamic acid and
glutamic aspartic
acid acid) have
and aspartic acid)a relatively low pKa
have a relatively
(dissociation
low constant)constant)
pKa (dissociation value (4.25 and(4.25
value 3.67 and
respectively; [153]), suggesting
3.67 respectively; that they that
[153]), suggesting may
contribute
they to the ability
may contribute to theof ability
proteinoftoprotein
resist atopH change.
resist a pHThe role of
change. Thefeedstuffs, minerals
role of feedstuffs,
and organic
minerals andacids on acids
organic stomach pH is described
on stomach in the following
pH is described paragraphs.
in the following paragraphs.

5.1.1. The Role of Feedstuffs and Minerals

(A) 400 (B) 6.00
In general, feedstuffs such as fish meal, milk by-products and vegetable proteins (e.g.,
ABC‐4 value complete diet,

350 R2 = 0.513 5.00soybean meal) are known for their high buffer
pH stomach content

rapeseed meal, sunflower seed meal and

300 p = 0.001
capacity (ABC-4 value of >400 meq/kg),4.00 whilst cereals (e.g., wheat, barley and maize) have
250
a low buffer capacity (ABC-4 value of <150 meq/kg; [151]). It could even be suggested
meq/kg

200 3.00
that the calcium (Ca) content of starter diets should be limited for a short period (e.g., two
150 weeks), due to its effect on stomach pH 2.00
(high buffer capacity), thereby favouring stomach
100 functioning without limiting the mineral1.00 requirements for bone formation [151,154]. Given
50 that the amount of Ca required for growth is considered less than the amount required
0 0.00
for bone ash, González-Vega et al. [155] suggest that a standardised total tract digestible
0.00 1.00(STTD)
2.00 Ca3.00 4.00 of
content 5.00 might be sufficient toUnaffected
6.00
0.48% maximisediet
bone Low ABC‐4 value
ash content in piglets. The
pH stomach content diet
buffer capacity of feedstuffs and minerals should, therefore, be taken into consideration in
the formulation of newly weaned piglet diets.
 [151]. Other factors that might play a role as well include water‐holding capacity, intrinsic
osmotic pressure [152], the particle size of the diet [147] and the concentration of aspartic
and glutamic acid. Amino acids (e.g., glutamic acid and aspartic acid) have a relatively
low pKa (dissociation constant) value (4.25 and 3.67 respectively; [153]), suggesting that
Animals 2021, 11, 402 17 of 36
they may contribute to the ability of protein to resist a pH change. The role of feedstuffs,
minerals and organic acids on stomach pH is described in the following paragraphs.

(A) 400 (B) 6.00

ABC‐4 value complete diet,

350 R2 = 0.513 5.00

pH stomach content
300 p = 0.001
4.00
250
meq/kg

200 3.00
150 2.00
100
1.00
50
0 0.00
0.00 1.00 2.00 3.00 4.00 5.00 6.00 Unaffected diet Low ABC‐4 value
pH stomach content diet

Figure 3. Relationship between the acid-binding capacity (ABC)-4 value of the complete diet and stomach pH. (A)
shows the correlation between the ABC-4 value of the complete diet and stomach pH. The data represent the ABC-4
value of 31 experimental diets containing protein-rich feedstuffs (6–8 piglets/experimental treatment) (between 2017 and
2019; Schothorst Feed Research B.V., Lelystad, The Netherlands). The ABC-4 value was measured in meq/kg using the
methodology described by Lawlor et al. [151]. Each dot represents the average stomach pH per dietary treatment. (B)
shows the effect of acidifying the complete diet on individual stomach pH. The experimental diets contained one of three
different protein-rich feedstuffs that are known for their high (i.e., fish meal), intermediate (i.e., Hi-Pro Soybean Meal) and
low ABC-4 value (i.e., maize gluten). The values displayed in (B) represent the stomach pH from all protein-rich feedstuffs
together. The low ABC-4 diets were acidified by replacing limestone with calcium formate (either completely or partially)
and adding citric acid. The unaffected diets did not contain organic acids. The average ABC-4 values of the unaffected diet
were 308 meq/kg (SD = 26), with a value of 243 meq/kg (SD = 95) for the low ABC-4 diets. The average stomach pH of the
unaffected diet was 4.22 (SD = 0.997), with a value of 3.57 (SD = 1.075) for the low ABC-4 diet.

5.1.2. The Role of Organic Acids and Their Interaction with Feed Ingredients
The addition of organic acids to piglet diets can lower the buffer capacity of the diet.
Organic acids that can be added to the feed or water can act through (1) their direct bacte-
riostatic/bactericidal effects and by (2) decreasing stomach pH, thereby improving the onset
of protein digestion and reducing the survival of pathogens [156]. Organic acids may also
have other modes of action (e.g., as an energy source) along other segments of the digestive
tract, as described in previous reviews [157,158]. It should be noted that organic acids
can differ in their anti-bacterial properties and their capacity to reduce stomach pH, in
which factors including molecular weight, pKa , chain length and buffer capacity play an
important role [159]. Furthermore, the use of a blend of organic acids is preferable to the
use of a single acid, as together they have a wider range of anti-bacterial properties [158].
For example, one organic acid may result in the fast reduction in the stomach pH, whilst
another may undissociate more quickly at that pH and enter the pathogenic cell wall [160].
It is also important to consider that, due to their pungent odour, some organic acids can
have a negative effect on diet palatability when included in high concentrations [159].
The relative success of diet acidification with organic acids on piglet performance,
health and nutrient digestibility is also dependent in large part on other feed ingredi-
ents [156,161]. This is often overlooked, and it is therefore highlighted briefly in the current
review. For example, in diets containing high amounts of milk products, the acidification
of the diet with organic acids is less effective. This can be explained by the high lactic
acid concentration in the stomach as a result of the fermentation of lactose from milk,
which masks the effectiveness of organic acids [161]. Organic acids can be expected to be
more effective in diets containing less-digestible feedstuffs (e.g., plant proteins) [156,161].
The effectiveness of the organic acids is also affected by the inclusion rate and particle
size of minerals. It is well known that calcium carbonate (provided by limestone) can
increase the digesta pH in the proximal part of the gastro-intestinal tract, due to its high
acid-binding capacity. Both the inclusion rate and particle size of limestone can increase
the surface area, thereby resulting in a faster Ca solubility and release, and thus in a higher
buffer capacity of the gastric content [162]. In addition, ZnO has a high buffer capacity [151]
 Animals 2021, 11, x 19 of 37

digesta pH in the proximal part of the gastro‐intestinal tract, due to its high acid‐binding
Animals 2021, 11, 402 capacity. Both the inclusion rate and particle size of limestone can increase the surface 18 of 36
area, thereby resulting in a faster Ca solubility and release, and thus in a higher buffer
capacity of the gastric content [162]. In addition, ZnO has a high buffer capacity [151] and,
under conditions in which ZnO can still be added in high amounts to the diet, it can coun‐
and,
teractunder conditions in
the effectiveness ofwhich
organic ZnO can still be added in high amounts to the diet, it can
acids.
counteract
In summary, knowing the ABC‐4acids.
the effectiveness of organic value of each feed ingredient in the diet (e.g.,
In summary,
feedstuff, premix, knowing the ABC-4
and additives) value
can help of each
to select feed ingredient
ingredients insuitable
that are the dietfor
(e.g., feed-
young
stuff, premix, and additives) can help to select ingredients that are suitable
piglets, and it can help to explain the buffer capacity of the complete diet. Although the for young
piglets,
reductionand
initthe
canABC‐4
help to explain
value thediet
of the buffer capacitytooflower
is assumed the complete
stomach diet. Although
pH, and although the
reduction
the ABC‐4invalue
the ABC-4 value ofbeing
is increasingly the diet
usedis assumed
in practisetoaslower stomach parameter
an important pH, and although
in diet
the ABC-4 value is increasingly being used in practise as an important parameter in diet
formulations, scientific research is lacking with regard to the evaluation of the optimal
formulations,
ABC‐4 (or pH)scientific research is
value of complete lacking
piglet diets.with regard to the evaluation of the optimal
ABC-4 (or pH) value of complete piglet diets.
5.2. Factors that Prolong Stomach Retention, Promote Gut Health and Modulate Digestion
5.2. Factors that Prolong Stomach Retention, Promote Gut Health and Modulate Digestion
Kinetics along
Kinetics along the
the Small
Small Intestine
Intestine
The gastric-passage
The gastric‐passage rate rate is
is determined
determined by bymultiple
multiplefactors,
factors,including
includingmeal
mealsize,
size,stom‐
stom-
ach mobility and the fraction of the liquids or solids in the stomach, as the liquidfraction
ach mobility and the fraction of the liquids or solids in the stomach, as the liquid fraction
passes more
passes more rapidly
rapidly than
than the
the solid
solid fraction
fraction [163].
[163]. Prolonged
Prolongedretention
retentionof ofstomach
stomachcontent
content
can be
can be beneficial
beneficial forfor newly
newly weaned
weaned piglets,
piglets, at
at least
least to
to some
some extent.
extent.ForForexample,
example,ititcan can
improve protein hydrolysis in the stomach, thereby resulting in greater
improve protein hydrolysis in the stomach, thereby resulting in greater protein digestibility protein digestibil‐
ity along
along the the
smallsmall intestine
intestine [164].
[164]. Furthermore,
Furthermore, the the amount
amount of substrate
of substrate andand fermentation
fermentation end-
end‐products (e.g., SCFA) arriving at the end of the ileum
products (e.g., SCFA) arriving at the end of the ileum can also prolong stomach can also prolong stomach re‐
retention
by stimulating the feedback mechanism of hypothalamic satiety signals (Figure 4). 4).
tention by stimulating the feedback mechanism of hypothalamic satiety signals (Figure
Nutritional strategies
Nutritional strategies that
that can
can prolong
prolongstomach
stomachretention
retentioninclude
includecoarseness
coarsenessororstruc‐
struc-
ture and various physiochemical characteristics (e.g., viscosity,
ture and various physiochemical characteristics (e.g., viscosity, water-binding capacitywater‐binding capacityand
and water‐holding
water-holding capacity)
capacity) of the of feedstuff
the feedstuff
and and
diet.diet. Furthermore,
Furthermore, these
these dietary
dietary factors
factors can
can affect the nutrient‐digestion kinetics along the small intestinal segments
affect the nutrient-digestion kinetics along the small intestinal segments and improve gut and improve
gut health
health [165].
[165]. Although
Although thisthis is an
is an interestingaspect,
interesting aspect,fewfewstudies
studies have
have been
been conducted
conducted
in weaned piglets [164,166]. Current knowledge about nutritional strategiestotoprolong
in weaned piglets [164,166]. Current knowledge about nutritional strategies prolong
stomach retention
stomach retention andand modulate
modulate digestion
digestion kinetics
kinetics along
alongthe thesmall
smallintestine
intestineininpiglets
pigletsare are
outlined in
outlined in the
the following
following paragraphs.
paragraphs.

Figure4.4. Interactions
Figure Interactions between
between thethe
passage rate rate
passage of digesta and feed
of digesta andintake.
feed AA = amino
intake. AAacids, CCK acids,
= amino = cholecystokinin, GLP‐
CCK = cholecys-
1 = glucagon‐like peptide 1, GIP = glucose‐dependent insulinotropic polypeptide, HCl = hydrochloric acid, PYY =
tokinin, GLP-1 = glucagon-like peptide 1, GIP = glucose-dependent insulinotropic polypeptide, HCl = hydrochloric acid,peptide
YY, SCFA = short‐chain fatty acids. The figure is adapted from Giger‐Reverdin et al. [152] and Lee et al. [167].
PYY = peptide YY, SCFA = short-chain fatty acids. The figure is adapted from Giger-Reverdin et al. [152] and Lee et al. [167].

5.2.1. The Role of Particle Size or Feed Structure

Particle size is measured by passing the feedstuff or whole diet through a series of
sieves. Different grinding technologies (e.g., roller mill and hammer mill) result in different
Animals 2021, 11, 402 19 of 36

particle-size distributions. The hammer mill yields finer particles, while the roller mill
yields coarser particles, but a more uniform particle size distribution [168,169]. Both
fine grinding and pelleting can reduce particle size and improve nutrient digestibility by
increasing the surface area for the digestive enzymes. At the same time, however, fine
particles can lead to dust and undesired gut problems, including stomach ulcers [170],
Streptococcus suis (S. suis) colonisation in the stomach [150] and Salmonella typhimurium
colonisation in the ileum [171]. It is therefore important to have enough structure in the
diet by adding coarse particles, in order to ensure good stomach functioning and a gradual
transition of particles from the stomach to the gut. As coarse grinding reduces nutrient
digestibility, structure may be created by ingredients with low energy values (e.g., wheat
bran or wheat straw). It has been demonstrated that feeding piglets coarse rather than
finely ground wheat bran (4% inclusion level) during the first two weeks post-weaning is
effective in reducing E. coli adhesion to the ileal mucosa and in reducing the severity of
diarrhoea after an enterotoxigenic E. coli challenge [172].
Although studies in weaned piglets on the effectiveness of coarse particles in the diet
are limited, studies involving growing pigs have consistently shown beneficial effects. In
a study by Hedemann et al. [171], grower pigs (33 kg of body weight) fed a coarse diet,
either mash or pelleted (80.1% of the particles were <1000 µm, 15.6% were between 1000
and 2000 µm, 2.1% were between 2000 and 3500 µm, and 2.3% were >3500 µm), exhibited
a higher relative empty stomach weight (+7%) than did pigs fed a fine diet (93.6% of
the particles were <1000 µm, 6.4% were between 1000 and 2000 µm, 0.0% were between
1000 and 2000 µm, and 0.0% were >3500 µm). Another study, using pigs in the same
body-weight class, reports that the pH of the stomach content in the fundus gastric region
of pigs that were fed either a coarsely ground diet (geometric mean diameter 671 µm) or a
finely ground diet (geometric mean diameter 217 µm) was lower for the coarsely ground
diet (pH of 2.5) than for the finely ground diet (pH of 5.0) [150]. If fibre-rich by-products
(e.g., wheat bran) are not available, or if they are contaminated with undesired compounds
(e.g., mycotoxins), structure can be added to the diet by coarsely grinding a portion (e.g.,
5%) of the cereals (e.g., barley).
In addition to the particle size of the feedstuff and/or diet, the structure of feedstuffs
may influence gastric emptying rate, as well as digestion kinetics. This has been suggested
by Bornhorst et al. [173], who found that the effects of brown rice (which has a higher fibre
content and more structure than white rice) were more beneficial than those of white rice on
the gastric emptying rate and acidification of the stomach content. More specifically, pigs
(20.9 kg of body weight) receiving the brown-rice diet had a slower gastric emptying rate
and nutrient transit from the stomach to the small and large intestines than did those that
were fed the white-rice diet. This resulted in a lower distal stomach pH for the brown-rice
treatment group after ingestion of the meals. The authors suggest that this may have been
a result of physical resistance in the stomach due to the accumulation of bran layers from
the brown rice [173].
Taken together, these findings suggest that, for young piglets at increased risk of
post-weaning disorders, bringing structure to the diet through the use of fibre-rich cereal
by-products or the introduction of some cereals in coarse-ground form may support
stomach acidification, improve nutrient digestion and reduce the risk of gastro-intestinal
infections. Additional research is needed in order to identify the best feed structure (e.g.,
particles >1.5 mm in pelleted diets) for weaned piglets for optimising gastric function, gut
health and nutrient digestibility.

5.2.2. The Role of Heat Treatment

Most pig diets are pelleted or otherwise treated with heat. The conditions of the production
process may alter animal health and performance. Extrusion and expansion are “short-time,
high-temperature” processes, and are based on a combination of high temperature, mois-
ture, high pressure and shear forces. Expansion is less intensive than extrusion. Intensive
feed-production processes may alter the chemical composition of a specific feedstuff or
 Most pig diets are pelleted or otherwise treated with heat. The conditions of the pro‐
duction process may alter animal health and performance. Extrusion and expansion are
“short‐time, high‐temperature” processes, and are based on a combination of high tem‐
perature, moisture, high pressure and shear forces. Expansion is less intensive than extru‐
Animals 2021, 11, 402 20 of 36
sion. Intensive feed‐production processes may alter the chemical composition of a specific
feedstuff or a complete diet [174]. Structures of carbohydrate and protein molecules may
be altered during processing. Extrusion can increase starch gelatinisation and increase the
a complete
solubility of NSP.diet [174].
The Structures
increase in theofproportion
carbohydrate of and protein
soluble NSP molecules maydiet
could affect be altered
viscosity
during processing. Extrusion can increase starch gelatinisation and increase
and water‐holding capacity, which could subsequently prolong gastric retention time (as the solubility
of NSP. The increase in the proportion of soluble NSP could affect diet viscosity and water-
discussed in greater detail below). In addition, extrusion may also improve protein diges‐
holding capacity, which could subsequently prolong gastric retention time (as discussed
tion: (1) through the denaturation of proteins, which makes them more accessible to pro‐
in greater detail below). In addition, extrusion may also improve protein digestion: (1)
teolytic enzymes,
through or by (2) making
the denaturation protein
of proteins, more
which accessible
makes them moreby breaking
accessibledown the bonds
to proteolytic
between starchorand
enzymes, proteins
by (2) makingthat are more
protein normally present
accessible in cereals
by breaking [175].
down the bonds between
Excessively high processing
starch and proteins temperatures
that are normally present incan reduce
cereals protein digestibility, however,
[175].
due to Maillard reactions.
Excessively Furthermore,
high processing cereal sources
temperatures can reduce differ in terms
protein of starch‐granule
digestibility, however,
due to Maillard reactions. Furthermore, cereal sources differ in terms of
size, amylose‐to‐amylopectin ratios and degree of crystallinity [176]. These differences in‐ starch-granule
size,
fluence theamylose-to-amylopectin
potential effects of feed ratios and degree
processing (e.g.,ofextrusion)
crystallinity
on[176].
starchThese differencesand
gelatinisation
influence the potential effects of feed processing (e.g., extrusion) on starch
diet viscosity. For example, the heat treatment (e.g., pelleting at different temperatures or gelatinisation
and diet viscosity. For example, the heat treatment (e.g., pelleting at different temperatures
expanding followed by pelleting) of diets based on wheat and barley has been shown to
or expanding followed by pelleting) of diets based on wheat and barley has been shown
increase viscosity,
to increase thus thus
viscosity, yielding thethe
yielding highest
highestdiet
dietviscosity
viscosity at themaximum
at the maximum temperature
temperature
(Figure 5). No such effect was observed for the maize‐based
(Figure 5). No such effect was observed for the maize-based diet. diet.

2000
70 ℃
90 ℃
1500 120 ℃
Viscosity, cP

1000

500

0
Maize Wheat Barley
Figure 5. Differences in the viscosity of diets based on wheat, barley and maize under different
Figure 5. Differences in the viscosity of diets based on wheat, barley and maize under different heat‐
heat-processing conditions. The data were collected at Schothorst Feed Research B.V. (Lelystad, The
processing conditions. The data were collected at Schothorst Feed Research B.V. (Lelystad, The
Netherlands). The respective diets consisted of 60% maize, 60% wheat or 60% barley, and they were
Netherlands). The respective diets consisted of 60% maize, 60% wheat or 60% barley, and they were
pelleted at 70 ◦ C, pelleted at 90 ◦ C or expander pelleted at 120 ◦ C. Viscosity was measured after
pelleted at 70 °C, pelleted at 90 °C or expander pelleted at 120 °C. Viscosity was measured after 15
15 min according to the method developed by Bedford and Classen [177].
min according to the method developed by Bedford and Classen [177].
The effect of heat treatment of barley on viscosity was confirmed by an in vivo study
The effect
(using of heatconducted
extrusion) treatmentby of Rodrigues
barley on viscosity
et al. [166]was confirmed
in weaned by an
piglets. In in
thatvivo study
study,
extruded barley resulted in increased viscosity of digesta at the proximal
(using extrusion) conducted by Rodrigues et al. [166] in weaned piglets. In that study, small intestine
(frombarley
extruded 1.95 toresulted
5.09 centipoise (cps)) and
in increased distal ileum
viscosity (from at
of digesta 3.14 to proximal
the 6.56 cps), as compared
small intestine
to raw barley. No such effect was observed for rice [166]. Recent studies
(from 1.95 to 5.09 centipoise (cps)) and distal ileum (from 3.14 to 6.56 cps), as compared [166,178] have to
generated new insight into the effect of extrusion on the kinetics of starch digestion in
raw barley. No such effect was observed for rice [166]. Recent studies [166,178] have gen‐
pigs. In general, the starch digestion appears to be faster for extruded cereals than it is for
erated new insight into the effect of extrusion on the kinetics of starch digestion in pigs.
ground cereals, as measured along the small intestine (Table 4). Further investigation is
In general,
needed the
withstarch
regard digestion appears
to the potentially to be effects
beneficial faster offor extruded
large particlescereals than
in coarsely it is for
ground
ground cereals,
cereals as measured
(as discussed above),along the small intestine
heat-processed cereals or (Table 4). Further
a combination investigation
thereof on gastric is
needed with and
retention regard to the
digestion potentially
kinetics in weanedbeneficial
piglets. effects of large particles in coarsely
ground cereals (as discussed above), heat‐processed cereals or a combination thereof on
gastric retention and digestion kinetics in weaned piglets.
Animals 2021, 11, 402 21 of 36

Table 4. Starch-digestibility kinetics along the small intestine 1 .

Location along the SI

Feedstuff Body Weight (kg) Reference
SI 1 SI 2 SI 3 SI 4
Ground barley 33 34 54 86 94 [178] 2
Extruded barley 33 53 64 94 98 [178] 2
Ground maize 33 21 60 80 84 [178] 2
Extruded maize 33 53 78 94 98 [178] 2
Rice, raw 12 - 85.3 - 97.1 [166] 3
Rice, extruded 12 - 83.1 - 99.0 [166] 3
Barley, raw 12 - 80.0 - 96.2 [166] 3
Barley, extruded 12 - 88.5 - 98.3 [166] 3
1 Digestibility coefficients are calculated at the dietary level. 2 Small intestine (SI) 4 is the last 1.5 m of the small
intestine, with the rest of the small intestine divided into three parts of equal length (SI 1, SI 2 and SI 3, from
proximal to distal SI). 3 The small intestine (SI) was divided into two sections, corresponding to the proximal
two-thirds of the SI (SI 2) and the distal one-third of the SI (SI 4).

5.2.3. The Role of Physicochemical Characteristics

Feed ingredients have a variety of physicochemical properties, including viscosity and
hydration (i.e., water-holding capacity and water-binding capacity). Soluble (fermentable)
fibres are believed to increase the viscosity and water-holding capacity (WHC) of the digesta
content of the stomach and small intestine [179]. Studies on the effect of soluble (usually
fermentable) and insoluble (usually inert) fibre on stomach retention and passage rate have
yielded inconsistent results. For example, Fledderus et al. [164] report a 10% reduction in
the gastric-emptying rate due to the addition of 1% dietary carboxymethylcellulose, along
with a nearly seven-fold increase in diet viscosity for piglets at 3 weeks post-weaning. Gas-
tric protein hydrolysis and ileal crude protein digestibility increased as well. The authors
further report that supplementation with both guar gum and cellulose (i.e., insoluble fibres)
increased the gastric passage rate and the viscosity of the ileal digesta, although only guar
gum increased the total tract-retention time [180]. Another study suggests a linear increase
in digesta viscosity with increasing intake of soluble fibre [179], although an increase in
viscosity in the small intestine could increase the risk for E. coli proliferation [181].
Both WHC and water-binding capacity (WBC) are defined as the capacity to retain
water. The difference is that WBC is defined after centrifugation, whereas WHC is not.
Fibre sources that are rich in pectin (e.g., pea cotyledon and sugar beet pulp) have exhibited
greater WBC (7.6 and 8.7 kg/kg dry matter) than have been observed for hull fractions
(3.7 kg/kg dry matter) [182,183]. Water-binding capacity has been suggested to have a
negative influence on feed intake when included at extreme levels in the diet [184]. Insoluble
fibres have been suggested to stimulate feed intake by increasing the gastric passage rate. If
the WBC content or viscosity of the stomach digesta is too high, however, feed intake will be
depressed by gastric distension [185]. In one study, Ndou et al. [186] explore the role that
the WHC of bulk feed plays in predicting the feed intake of piglets weighing 18 kg. The
authors report that a WHC of >4.5 g water/g dry matter resulted in lower feed intake,
due to prolonged stomach retention. In general, a certain level of diet viscosity and WHC
is beneficial for prolonging gastric retention time, although excessive levels can reduce
feed intake.

5.3. The Role of Main Nutrients in Supporting the Health and Function of the
Gastro-Intestinal Tract
5.3.1. The Role of Crude Protein Level, Quality and Functional Amino Acids
Diets for weaned piglets have traditionally been quite luxurious and rich in energy
and crude protein (CP), in order to compensate for the low feed intake that occurs during
the immediate post-weaning phase. At the same time, however, high CP levels are known
to be a major risk factor for post-weaning diarrhoea in weaned piglets [142,187,188]. The
fermentation of undigested CP in the end of the small intestine and the colon may lead to
the proliferation of pathogenic bacteria. In addition, fermentation creates harmful products
Animals 2021, 11, 402 22 of 36

for the intestine (e.g., biogenic amines, ammonia and other toxins), which can result in
diarrhoea. Meanwhile, the excess of amino acids (AA) cause energy to be deaminated and
excreted as urea through urine [171]. For these reasons, the CP levels of piglet diets should
be lowered at least during the first two weeks post-weaning.
The selected CP sources in post-weaning piglet diets should be easily digestible and
have minimal impact on stomach pH, and the amount of CP that may be attached to fibre
parts should be limited. The literature on interactions between fibre and protein fermentation
has been reviewed by Jha and Berrocoso [189]. In short, given the limited fermentation
capacity of weaned piglets, excessive levels of fermentable fibres can increase microbial
protein in the large intestine. In addition, protein is generally digested and absorbed in the
small intestine, whereas fibre is fermented by microbiota in the large intestine. If too much
CP is attached to fibre, this will reduce CP digestion and absorption in the small intestine,
possibly increasing the risk of post-weaning diarrhoea.
Another factor that should be considered is the rate of digestion for CP-rich sources.
In a study by Montoya et al. [190], the rate of digested protein entering the small intestine
strongly predicted the disappearance of AA in the small intestine. The digestion and
absorption of protein occur primarily in the first half of the small intestine, while poorly
digestible proteins entering the small intestine are digested and absorbed throughout the
entire small intestine. Chen [191] reports differences in CP digestibility along the small
intestine in pigs. The results suggest that dried plasma protein is highly digestible, since
CP digestibility was 59% in the proximal small intestine, as compared to soybean meal,
which yielded poor CP digestion (26%) in the proximal small intestine. Similar digestibility
coefficients were reached only at the end of the ileum (74% for soybean meal) compared
with 76% at 34 of the small intestine for dried plasma protein. These results suggest that,
when determining the digestibility of a CP-rich source, the distal ileum might not represent
what actually happens in the piglet. Future digestibility research should focus more on the
kinetics of CP digestibility, instead of considering only the distal ileum.
Another factor that could influence the digestibility of CP-rich feedstuffs is the grind-
ing diameter, with fine grinding increasing the surface area for the digestive enzymes.
Although results with respect to particle-size reduction and digestibility in CP ingredi-
ents have been inconsistent, some authors suggest that fine grinding improves nutrient
digestibility and the feed-conversion ratio, while others do not [192–194]. In addition, the
effectivity of fine grinding for a given ingredient may be dependent on the structure of
the complete diet. As mentioned earlier, coarser diets influence stomach function (e.g.,
by increasing stomach retention) and can improve gut morphology [171]. It is therefore
plausible to speculate that longer retention time due to the combination of a coarser diet
and fine-ground protein sources would result in an additive effect with respect to protein
hydrolysis in the stomach and digestion in the small intestine. For example, the expected
effects of a coarse diet on gastric pH, solid gastric content and nutrient flow from the
stomach to the small intestine may help to improve the digestion and absorption of fine
CP-rich feedstuffs.
In order to avoid AA deficiencies, it is important to keep AA in balance when reducing
the CP content, since some AA become limiting. Piglets need AA in order to deposit protein
and renew the turnover of the body protein [195]. Lysine is typically the first limiting AA
for pigs fed with cereal-based diets, and its major function is to maintain body-protein
synthesis [196]. At the same time, however, other essential and semi-essential AA may be
utilised in post-weaning piglet diets, given their role in promoting intestinal development
and health (e.g., improving intestinal morphology, increasing the proliferation of epithelial
cells, and maintaining intestinal mucosal integrity). Examples include glutamine, threonine
and tryptophan (reviewed by Mou et al. [197]).

5.3.2. The Role of Dietary Fibres

The inclusion of dietary fibre in post-weaning diets has been controversial, as fibre
can reduce feed intake and nutrient digestibility, thus increasing the risk of proliferation
Animals 2021, 11, 402 23 of 36

of pathogenic bacteria in the gastro-intestinal tract. These controversial results are partly
due to the lack of information regarding the functional effects of dietary fibre, including
the modification of the physicochemical characteristics of the digesta or the fermentation
characteristics of various feedstuffs. The beneficial effects of fibre in weaned piglets have
been intensively reviewed by Molist et al. [198] and by Flis et al. [199]. In addition to
the aforementioned influence of physicochemical properties on stomach retention and
gut viscosity, it could also be interesting to rank fibre according to its fermentation char-
acteristics: (1) inert fibre (ICHO), consisting of carbohydrates that are not digested and
fermented in the gastro-intestinal tract of piglets; (2) fermentable fibre (FCHO), consisting
of carbohydrates that are not digested, but are fermented in the large intestine of piglets.
The main ingredients that are generally used as sources of ICHO are wheat bran, oat hulls,
sunflower hulls and wheat straw. The main sources of FCHO are sugar beet pulp, citrus
pulp, chicory pulp and inulin.
In a review article, Flis et al. [199] conclude that the use of different sources of inert
fibre to dilute diets during the immediate post-weaning period increases feed intake by
between 4% and 54%, as compared to a control diet low in inert fibre. The same authors
also report that the supplementation of post-weaning diets with different sources of FCHO
reduces feed intake by between 7% and 28%, as compared to a control diet low in inert
fibre [199]. Similar results are reported by Montagne et al. [200] in a study on interactions
between fibre fermentability in the diet and the sanitary conditions of the farm with regard
to the growth and health status of weaned pigs. In this study, piglets fed with a high level
of FCHO (6% sugar beet pulp and 2% soybean hulls/kg) and allocated in rooms with high
infection pressure exhibited lower feed intake during the first two weeks post-weaning,
as well as a higher incidence of diarrhoea than did piglets from the other experimental
groups. The authors conclude that the inclusion of ingredients with FCHO immediately
post-weaning imposes an additional risk factor for piglet health and growth, especially
under poor sanitary conditions. In contrast, Gerritsen et al. [201] observed that diluting
the diet with 12% ICHO during the first two weeks post-weaning resulted in higher feed
intake, stomach weight and amylase activity of the brush-border enzymes in the ileum,
as compared to piglets fed with the control diet (low in ICHO). Moreover, the inclusion
of ICHO resulted in lower E. coli counts in the ileum and colon digesta. The inclusion of
fibre sources rich in ICHO in post-weaning diets can therefore be used to dilute the dietary
energy level and to increase feed intake and the passage rate of the intestinal content, while
reducing the proliferation of pathogenic bacteria in the small intestine. Based on the ICHO
and FCHO levels used by Gerritsen et al. [201], it could be speculated that the ratio of
FCHO to ICHO during the immediate post-weaning period should be <1.
In conclusion, with regard to dietary fibre, it is advisable to include moderate levels of
ICHO in the diet in order to: (1) dilute the diet and avoid diarrhoea due to the accumulation
of undigested nutrients; (2) to help piglets to increase stomach capacity and restore the
activity of brush-border enzymes.

5.3.3. The Role of Fat

Another important dietary factor during the immediate post-weaning period is the
fat source used. In addition to its necessity as an energy source, fat enhances the quality
of pellets. While many studies have examined the role of dietary fibre and CP content in
the post-weaning piglet diet, the role of fat in piglet nutrition has received only limited
attention. This gap in knowledge is surprising, given that the ability of piglets to digest fat is
impaired during the immediate post-weaning period, especially in case of diarrhoea [202].
The fat source used in post-weaning piglet diets should therefore be easily digestible. Fat
digestion requires the emulsion of conjugated bile acids with fats, followed by the transport
and absorption of the fat micelle. The digestibility of dietary fat is directly related to the
ability to form micelles, which is associated with the length and double bonds of specific
fatty acids. For example, in contrast to long-chain fatty acids, SCFA can easily form micelles,
in addition to diffusing directly into enterocytes [203]. It is therefore not surprising that
Animals 2021, 11, 402 24 of 36

shorter chain length is associated with better fat digestibility [203]. In addition, unsaturated
fatty acids are regarded as being more easily digestible than are saturated fatty acids.
The ratio of unsaturated fatty acids to saturated fatty acids (i.e., the “US ratio”) should,
therefore, be considered in order to ensure proper digestion of the fat used in post-weaning
piglet diets. A higher US ratio is required for young piglets than for older pigs [203].
Medium-chain fatty acids (e.g., coconut fatty acids, palm kernel oil), which contain
6–12 carbon atoms, are also regarded as a readily available energy source, as they are
easily digestible (i.e., they can be absorbed intact into the intestinal epithelial enterocytes).
They may also have certain antimicrobial [204] and immunomodulatory effects, in ad-
dition to providing a good source of energy for gastro-intestinal cells (as reviewed by
Jackman et al. [205]). It has been suggested that MCFAs disrupt the phospholipid mem-
brane of bacteria and that they can have a bacteriostatic (inhibiting the growth of bacteria)
or bactericidal (directly killing bacteria) effect, especially for Gram-positive bacteria and
lipid bilayer viruses [205]. It is nevertheless important to consider the fact that different
MCFAs can target different pathogens, with varying effectivity [205], with MCFA being the
preferred fat source in post-weaning piglet diets.
Omega-3 fatty acids (ω-3) are regarded as immune-modulating nutrients, due to
their anti-inflammatory properties. It has been suggested that ω-3 could play a role in
attenuating the intestinal inflammation that is normally observed at weaning, with the
ratio ω-6:ω-3 being an important parameter to consider. For example, lower plasma con-
centrations of tumour necrosis factor-α (TNF-α), the principle mediator of inflammation,
were found for piglets fed with a diet supplemented with ω-3 fatty acids, as compared
to piglets fed with the control diet [206]. Similarly, Huber et al. [207] replaced maize oil
with fish oil at 1.25%, 2.5% and 5% in order to achieve ω-6:ω-3 ratios of 5:1, 3:1 and 1:1,
respectively. They report that the acute phase protein (APP) haptoglobin decreased with
increasing fish-oil supplementation after challenging weaned piglets with ovalbumin and
lipopolysaccharide (LPS). This indirectly suggests reduced production of pro-inflammatory
cytokines, and thereby reduced production of APP (e.g., haptoglobin) by the liver [207].
Moreover, Shin et al. [208] report that reducing the ω-6:ω-3 ratio to 4:1 post-weaning sup-
pressed the inflammatory response, as evidenced in lower IL-1β and PGE2 levels, amongst
other indicators. Future diet formulations should therefore devote greater attention to
optimising the ω-6:ω-3 ratio for piglet diets during the acute post-weaning phase.

6. Post-Weaning Nutritional Strategies during the Maturation Phase

During the maturation phase, gut integrity and function are restored, due to higher
feed intake and strengthened digestion, absorption and fermentation capacity, as reviewed
by [209–211]. In this phase, it is important to maintain piglet health while improving
growth and preparing for the growing–finishing phase. Similar to the acute phase, it
remains important to have structure in the diet and a low ABC during the maturation
phase, in order to support a good gastric barrier, thereby promoting digestibility and gut
health. There are also several differences between the nutritional approaches needed in the
acute and maturation phases. As mentioned before, during the maturation phase, piglets
recover their feed intake as their gastro-intestinal tracts mature. For example, nutrient
digestibility increases with age, with the protein digestibility of wheat-protein-based
diets increasing over time from 47% (Day 7), to 70% (Day 14), 76% (Day 21) and 78%
(Day 28) [212]. During the maturation phase, diets can be formulated to focus on increasing
lysine intake while maintaining a balanced AA profile to improve piglet performance. This
can be achieved by increasing the ratio of standardised ileal digestible (SID) lysine to energy
in the piglet diet. Testing a range of SID lysine levels from 10.3 to 15.1 g/kg in piglets
with body weights of 7–16 kg, the SID lysine requirement for growth ranged from 12.9
to 13.4 g/kg, using linear and quadratic broken lines, respectively, equivalent to 16.8 g of
SID per kg of gain [213]. For piglets of 10–25 kg, Kendall et al. [214] identify a requirement
of 19 g SID lysine per kg of gain. In another study (Table 5), growth performance and
feed efficiency exhibited a clear positive response to increases in the level of SID lysine.
Animals 2021, 11, 402 25 of 36

For the reasons discussed above, however, this high level of SID lysine should ideally be
achieved by using synthetic AA, rather than by increasing the CP content of the diet. It
should be noted that restrictions relating to the levels of Cu and Zn in piglet diets can have
detrimental effects on piglet performance. As reported by Bikker et al. [215], decreasing Cu
from 170 to 100 mg between 28 and 40 days post-weaning could result in a reduction of
approximately 600 g in body weight at the end of the post-weaning period (25.2 vs. 24.6 kg
body weight at the age of 68 days). These results highlight the importance of increasing
the SID Lys/NE in the last 3–4 weeks of the post-weaning period in order to counteract
this loss in performance.

Table 5. The effect of standardised ileal digestible (SID) lysine concentration on post-weaning
growth performance 1 .

Low Medium High Very High LSD 2 p-Value

Day 0–14
ADG (g/d) 219 ab 203 a 240 b 250 b 32.81 0.033
ADFI (g/d) 298 276 305 288 30.46 0.228
FCR 1.37 c 1.37 bc 1.27 b 1.16 a 0.097 <0.001
Faecal score 3 5.7 5.7 5.6 5.7 0.531 0.873
Day 14–28
ADG (g/d) 473 a 524 ab 525 ab 572 b 54.42 0.013
ADFI (g/d) 754 782 758 747 56.30 0.578
FCR 1.59 c 1.49 b 1.45 b 1.31 a 0.075 <0.001
Faecal score 3 6.1 5.6 5.6 5.9 0.603 0.315
a–c Different superscripts within a row indicate significant differences between dietary treatments (p < 0.05). 1 The
trial was performed in 2013 at Schothorst Feed Research B.V. (Lelystad, The Netherlands). In all, 144 piglets
were used in this experiment with 6 pens (for purposes of replication) per treatment and 6 piglets (3 boars and
3 gilts) per pen. The average body weight at the start of the trial was 8.0 kg, with an average weaning age of
25.3 days. The SID lysine content and SID Lys/NE ratio of the diet on Days 0–14 post-weaning were 9.90 g/kg
and 1.04 for the low lysine treatment, 11.1 g/kg and 1.17 for the medium lysine treatment, 12.1 g/kg and 1.27
for the high-lysine treatment, and 13.3 g/kg and 1.40 for the very-high-lysine treatment. The SID lysine content
and SID Lys/NE ratios of the diet on Days 14–28 post-weaning were 9.00 g/kg and 0.97 for the low-lysine
treatment, 10.1 g/kg and 1.09 for the medium-lysine treatment, 11.1 g/kg and 1.20 for the high-lysine treatment
and 12.2 g/kg and 1.32 for the very-high-lysine treatment. The diets were fed ad libitum. ADG = average daily
gain, ADFI = average daily feed intake, FCR = feed-conversion ratio 2 LSD is the least significant difference at
α < 0.05. 3 Faecal score was registered on a scale of 1–10 (1 = liquid faeces, 6 = optimal faeces, 10 = hard dry faeces)
and measured twice weekly at the pen level. Faecal scores were averaged by experimental period (i.e., Days 0–14
and Days 14–28 post-weaning).

During the maturation phase, piglets also have an increased fermentation capacity, and
they are able to generate energy from the absorption of SCFA [216]. This allows nutritionists
to increase FCHO levels in this phase. In a recent review, Jha and Berrocoso [189] indicate
that feeds with high contents of FCHO (e.g., citrus pulp and sugar beet pulp) are more
effective as fibre sources for reducing nitrogen loss in manure for piglets heavier than 15 kg
of body weight, as compared with ICHO. These results suggest that the ratio of FCHO to
ICHO should be >1.5 during the maturation phase. Hermes et al. [217] report decreased
faecal E. coli counts (7.77 vs. 6.86 log10 of CFU/g of faeces) and increased ratio of lactobacilli
to enterobacteria (0.76 vs. 1.37) in the faeces of pigs receiving diets supplemented with a
combination of 4% wheat bran and 2% sugar beet pulp/kg, as compared to a low-fibre diet.
The authors attribute the beneficial effects of the high-fibre diet to changes in the microbial
profile within the gastro-intestinal tract, due to the increased production of SCFA from the
fermentation of dietary pectins. Overeating should also be avoided during the maturation
phase, as it could increase the risk of pathogenic bacterial infections (e.g., S. suis) [69]. As
reported by Correa-Fiz et al. [218], supplementation of post-weaning diets with MCFA
and a supplement containing MCFA and natural plant extracts (with anti-inflammatory
properties) reduced clinical signs (e.g., meningitis) associated with S. suis on Day 43 post-
weaning. Considering that most S. suis infections occur around 3 weeks post-weaning, it
might be beneficial to supply MCFA for its antibacterial effects, in addition to supplying
long-chain fatty acids (e.g., vegetable oils) as energy sources. Compared to the acute phase,
Animals 2021, 11, 402 26 of 36

the US ratio of the diet can be reduced during the maturation phase, as piglets are expected
to have greater fat-digestibility capacity [219].
Taken together, in response to the physiological changes that piglets undergo during
Animals 2021, 11, x 28 of 38
the acute and maturation phases, several post-weaning nutritional strategies for piglets
have been formulated, as summarised in Scheme 1.

Scheme
Scheme 1. 1.Summary
Summaryof
of physiological
physiological changes
changesand nutritional
and strategies
nutritional for weaned
strategies pigletspiglets
for weaned duringduring
the acute
the(Week
acute1 (Week
post‐ 1
weaning) and
post-weaning) maturation
and (from
maturation Week
(from 1 to 1Weeks
Week 5–6 post‐weaning)
to Weeks phases.
5–6 post-weaning) phases.

7.7.Conclusions
Conclusions
Asdemonstrated
As demonstrated by by this
this review
review of of the
therelevant
relevantliterature,
literature,early‐life
early-lifenutritional
nutritional strat‐
strate-
egies
gies cancan modulate
modulate gutgut health,
health, andand thereby
thereby piglet
piglet performance,
performance, in both
in both the the
short short
and and
longer
longer
term. term.that
Given Given
thethat the critical
critical periodperiod
for gutfor gut (microbiota
(microbiota and immune)
and immune) development
development occurs
occurs before weaning, further research is needed in order to identify
before weaning, further research is needed in order to identify how functional ingredientshow functional in‐
gredients in supplemental milk and creep feed can be used to prepare
in supplemental milk and creep feed can be used to prepare piglets for weaning. The find-piglets for weaning.
Thefrom
ings findings
thisfrom thishighlight
review review highlight
a lack ofainformation
lack of information
regardingregarding the effects
the effects of pre‐
of pre-weaning
weaning nutritional strategies on post‐weaning gut health and performance.
nutritional strategies on post-weaning gut health and performance. In addition, the com- In addition,
the composition
position of and interaction
of and interaction between between
pre-weaning pre‐weaning and post‐weaning
and post-weaning diets appar‐
diets apparently play a
ently play a very important role in their potential to support piglet gut health and perfor‐
very important role in their potential to support piglet gut health and performance around
mance around weaning. It is therefore crucial to adopt a structured approach to nutri‐
weaning. It is therefore crucial to adopt a structured approach to nutritional strategies
tional strategies from the first days after birth to the first weeks post‐weaning, in order to
from the first days after birth to the first weeks post-weaning, in order to reduce gastro-
reduce gastro‐intestinal problems in piglets, thereby decreasing the associated morbidity,
intestinal problems in piglets, thereby decreasing the associated morbidity, mortality and
mortality and antimicrobial use. In the first days of life, the goal of dietary modulation is
antimicrobial use. In the first days of life, the goal of dietary modulation is to increase
to increase the survival of piglets. In the weeks following birth, early‐life nutritional pro‐
the survival of piglets. In the weeks following birth, early-life nutritional programming
gramming should focus on stimulating gut development and maturation. As weaning ap‐
should focus on stimulating gut development and maturation. As weaning approaches,
proaches, the focus should shift to stimulating the intake of solid feed, in order to prepare
the focus should
piglets for weaning,shift
asto stimulating
well the intake
as to preventing of solid and
undereating feed,overeating,
in order toandprepare piglets
the associ‐
for weaning, as well as to preventing undereating and overeating,
ated post‐weaning growth dip and gastro‐intestinal dysbiosis. Given that weaning is and the associated
post-weaning
highly stressful growth dip and
for piglets, gastro-intestinal
nutritional dysbiosis.
strategies should firstGiven
target that weaning
gut health andisfunc‐
highly
stressful for piglets, nutritional strategies should first target gut health
tionality. The results reported in the current review can be combined to formulate a com‐ and functionality.
The results reported
prehensive in the current
dietary approach review can
that supports be combined
stomach function andto formulate
optimisesathecomprehensive
kinetics of
nutrient digestion along the small intestine, in order to minimise undigested substrate and
the risk of over‐proliferation of bacteria at the end of the small intestine. Optimising this
Animals 2021, 11, 402 27 of 36

dietary approach that supports stomach function and optimises the kinetics of nutrient
digestion along the small intestine, in order to minimise undigested substrate and the risk
of over-proliferation of bacteria at the end of the small intestine. Optimising this approach
for newly weaned piglets will require future research in order to enhance understanding
with regard to digestion kinetics occurring between nutrients in the gut and the role of feed
processing on the modulation of stomach functioning. From about one-week post-weaning
onwards, the focus of nutritional strategies can shift gradually towards promoting piglet
growth performance, in order to improve body weight at the end of the post-weaning
period and to prepare piglets for the growing period, while maintaining gut health. Current
pig production will continue to face challenges relating to gut health and performance
in piglets, particularly in light of expected further restrictions regarding Cu and Zn. This
emphasises the need to study the interplay between nutrition and gut health.

Author Contributions: Conceptualisation, all authors; writing—original draft preparation, A.M.S.H.,

A.M. and X.G.; writing—review, all authors; writing—editing, A.M.S.H. and A.M.; visualisation,
all authors; supervision and project administration, F.M. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The experiments at Schothorst Feed Research B.V. as referred
to in this review were conducted according to the guidelines of the Animal and Human Welfare
Codes/Laboratory practice codes in the Netherlands. The protocols were approved by the Ethics
Review Committee.
Conflicts of Interest: The authors declare no conflict of interest.

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