Trends in Food Science & Technology 57 (2016) 201e212

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Trends in Food Science & Technology

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and-technology

Impact of dietary fiber and fat on gut microbiota re-modeling and

metabolic health
ez a, *, Eva M. Go
Alfonso Benítez-Pa  mez Del Pulgar a, Louise Kjølbæk b,
Lena Kirchner Brahe b, Arne Astrup b, LesliHingstrup Larsen b, Yolanda Sanz a
a
Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology (IATA-CSIC), 46980, Paterna, Valencia, Spain
b
Department of Nutrition, Exercise and Sports (NEXS), Faculty of Science, University of Copenhagen, 1958 Frederiksberg, Denmark

a b s t r a c t
Keywords: Background: Scientific evidence suggests that diet plays a role in obesity and its comorbidities, partly via
Gut microbiota its interactions with the individual's gut microbiota. Likewise, the individual's microbiota influences the
Microbiome
efficacy of dietary interventions to reduce body weight. However, we require a better understanding of
Fiber
Fat
the key components of the gut microbiota that are responsive to specific diets and of their effects on
Diet-related diseases energy balance in order to use this information in practice.
Obesity Scope and approach: This review provides an up-to-date description of the influence of dietary fibers and
fat on gut microbiota and the mechanisms presumably mediating their effects on metabolic health. We
also discuss the main knowledge gaps and the need to gain greater understanding of the role of diet-
microbe interactions in obesity and the associated comorbidities.
Key findings and conclusions: Dietary fibers are major drivers of gut microbiota composition and function,
stimulating the dominance of bacteria able to utilize these substrates as energy source, although effects
vary depending on both the type of fiber and the individual's microbiota. However, the key bacteria and
the primary and secondary metabolic pathways mediating specific fiber-induced effects on the metabolic
phenotype remain unclear, and this information is necessary to personalize fiber-based interventions.
The literature also shows that gut microbiota contributes to the adverse consequences of high-fat diets
on the metabolic phenotype; however, little is known about the effects of dietary fat type. Further
progress is expected from translational approaches integrating controlled dietary intervention human
trials, combining functional omics technologies and physiological/clinical endpoints, and mechanistic
studies in experimental models. This will ultimately help us to progress towards establishing informed
microbiome-based dietary recommendations and interventions, which can contribute to tackling the
obesity epidemic and its comorbidities.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction continuously growing in low- and mid-income countries, particu-

larly in urban settings (World Health Organization, 2015). Obesity is
Obesity has reached pandemic dimensions affecting a vast a result of an unbalance between energy intake and expenditure, to
number of people worldwide. In 2014, approximately 39% of adults which over-nutrition and a sedentary lifestyle are major contribu-
(1.9 billion) were overweight and 13% of these (600 million) were tors (Coppinger, Jeanes, Dabinett, Vogele, & Reeves, 2010). Obesity
obese. Moreover, 42 million children under the age of 5 were re- is associated with a state of chronic low-grade inflammation, which
ported as overweight or obese in 2013 (World Health Organization, partly explains the insulin resistance phenotype observed in many
2015). It is well known that obesity is not only associated with obese individuals. In turn, insulin resistance is a component of the
populations in high-income countries, but the prevalence is metabolic syndrome that often precedes the development of type 2
diabetes (T2D) and cardiovascular disease (CVD) (Jia, DeMarco, &
Sowers, 2016). This metabolic inflammation is characterized by
infiltration of macrophages and lymphocytes in peripheral tissues.
* Corresponding author. Av. Catedratic Agustin Escardino, 7, 46980, Paterna,
Valencia, Spain.
This is accompanied by an increased production of pro-
E-mail address: [email protected] (A. Benítez-Pa
ez). inflammatory cytokines, adipokines, acute-phase proteins and

http://dx.doi.org/10.1016/j.tifs.2016.11.001
0924-2244/© 2016 Elsevier Ltd. All rights reserved.
202 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa

other immune mediators as a consequence of the activation of as dietary fibers that modify the composition and/or metabolic
several signaling pathways, including the nuclear factor kappa B activity of gut microbiota, thereby conferring a benefit to the host
(NFkB)/Inhibitor of thek kinase (IKK), c-jun N-terminal kinase (Gibson, 2004; Gibson, Probert, Loo, Rastall, & Roberfroid, 2004).
(JNK), protein kinase R (PKR) and the Toll-Like receptors (TLRs) According to this definition, a wide variety of food ingredients can
(Gregor & Hotamisligil, 2011). Adipose tissue from obese in- be classified as prebiotics such as GOS, FOS and longer inulin-
dividuals is considered to be the main contributor to obesity- derived fructans, xylo-oligosaccharides (XOS) and arabinoxylan
related metabolic inflammation, with the highest accumulation of oligosaccharides (AXOS); however this is based mainly on their
infiltrating macrophages and tissue concentrations of cytokines, impact on gut microbiota rather than on robust evidence of their
with similar events occurring in the liver and central nervous sys- effects on health-related endpoints (Hutkins et al., 2016). Dietary
tem, contributing to systemic insulin resistance (Johnson & Olefsky, fiber is not digested by human enzymes and thus it reaches prox-
2013). imal colonic regions, where it constitutes the main energy source
In the last decade, an increasing number of studies have re- for obligate anaerobic bacteria, whose fermentative activity leads to
ported that obesity is associated with alterations in gut microbiota the generation of organic acids (lactic, succinic acid) and short-
structure, suggesting that specific microbial taxa could be chain fatty acids (SCFA) (acetate, propionate and butyrate).
contributing factors to the obesity epidemic, although results are Consequently, the quantity and quality of fiber is considered to be
not fully consistent across human observational studies (Sanz, one of the main dietary determinants of gut microbiota composi-
Rastmanesh, & Agostoni, 2013). Animal studies have provided in- tion and function (Scott, Gratz, Sheridan, Flint, & Duncan, 2013).
formation about the mechanisms by which gut microbiota could The current recommendations on dietary fiber intake (25 g per day
play a role in obesity, including contribution to nutrient digestion for adults) are based on their well-known role in regulating bowel
and absorption and to regulation of immune and neuro-endocrine habits (frequency of defecation), including native chicory inulin
functions (Moya-Perez, Neef, & Sanz, 2015). Experimental models considered to be prebiotic (Hutkins et al., 2016). In addition, there is
have also demonstrated that gut microbiota can transmit the evidence for a role of dietary fiber and some prebiotics (inulin and
obesity-associated metabolic phenotype of its original human host oligofructose) in the reduction of dietary glycemic responses and
when transferred to a germ-free recipient, providing a first evi- glycemic load, with favorable effects on metabolic risk factors.
dence of causality (Turnbaugh et al., 2006). Furthermore, a unique Furthermore, consumption of fiber-rich diets with fiber intake
fecal transplantation study in humans has also demonstrated that above recommendations is associated with a reduced risk of cor-
the transference of feces from a lean donor into subjects with onary heart disease and type 2 diabetes as well as improved weight
metabolic syndrome beneficially influence glucose metabolism, maintenance (Bes-Rastrollo, Martinez-Gonzalez, Sanchez-Villegas,
confirming the causal role of gut microbiota (Vrieze et al., 2010). de la Fuente Arrillaga, & Martinez, 2006; EFSA NDA Panel, 2010; Liu
Nonetheless, the role of gut microbiota in obesity seems largely et al., 2000; Ludwig et al., 1999; Ye, Chacko, Chou, Kugizaki, & Liu,
dependent on diet-microbe interactions due to the fact that diet is a 2012). Dietary fiber is thought to positively influence metabolic
major modifiable factor influencing gut microbiota composition health through multiple mechanisms, although effects cannot be
and function (De Filippis et al., 2015; Flint, Duncan, Scott, & Louis, generalized as they vary depending on the type of fiber. The
2015). Indeed, experimental models revealed that such in- mechanisms of action include direct effects related to its physico-
teractions contribute to obesity, for example, by increasing lipid chemical and structural properties (e.g. indigestibility, viscosity,
absorption or aggravating adipose tissue inflammation indepen- etc.) and indirect effects mediated by the individual's gut micro-
dently of adiposity in the context of diets rich in saturated lipids biota. For example, compared to digestible carbohydrates, insoluble
(Caesar, Tremaroli, Kovatcheva-Datchary, Cani, & Backhed, 2015; and soluble fibers reach distal portion of colon with no major
Semova et al., 2012). Furthermore, dietary reprogramming of degradation by human enzymes leading to a significant reduction
microbiota ameliorates development of metabolic dysfunction in postprandial glycemic responses due to their slower digestion
despite susceptible genotypes (Ussar et al., 2015). Nevertheless, our (EFSA, 2014). Consequently, consumption of fiber improves the
understanding of how diet-microbe interactions influence energy glucose metabolism as a whole, which have direct impact on satiety
balance, eating behavior and obesity in humans is still insufficient and tip the balance towards oxidation instead storage metabolism
to transform this information into practical solutions to tackle (reviewed in (Koh-Banerjee & Rimm, 2003)). Moreover, dietary fi-
obesity-associated disorders. ber is considered to be very useful for weight loss/maintenance
This review discusses the most recent data regarding the po- aims given its low energetics estimated to be ~1.91 kcal/g (8 kJ/g) in
tential role of dietary fiber and fat in remodeling gut microbiota comparison with other macronutrients as digestible carbohydrates,
composition and function and, thereby, in programming metabolic (~4.06 kcal/g), proteins (~4.06 kcal/g), and fat (~8.84 kcal/g)
health. It also addresses the main limitations that must be over- (Menezes et al., 2016). Soluble viscous fibers may also exert bene-
come to progress our understanding of the microbiome's role in the ficial metabolic effects by their ability to form gels that delay gastric
chain of events causing obesity. Only on gaining a better under- emptying, inhibit nutrient absorption and bile acid (BA) binding;
standing of the above, will we be able to speed up the translation of altogether this may contribute to a decreased postprandial glyce-
this information into informed microbiome-based dietary in- mic response and a reduction in body cholesterol stores due to
terventions and recommendations. increased synthesis of new BAs from cholesterol in the liver
(Dikeman & Fahey, 2006). In addition, dietary fiber is thought to
2. Impact of dietary fiber on human physiology mediate other effects (e.g. satiety and anti-inflammatory effects)
through activation of the fermentative activity of gut bacteria, and
2.1. Dietary fiber: role in metabolic health and as main fuel for gut the generation of potentially beneficial metabolites (e.g. SCFAs), as
microbiota explained in greater detail in section 3.

Dietary fiber is generally defined as non-digestible carbohy- 2.2. Evidence of the influence of dietary fiber on gut microbiota
drates plus lignin, which include structurally different components from observational studies
including non-starch polysaccharides, resistant oligosaccharides
(e.g. fructo-oligosaccharides [FOS], galacto-oligosaccharides [GOS]) The role of non-digestible carbohydrates in the gut microbiota is
and resistant starch (EFSA NDA Panel, 2010). Prebiotics are defined well exemplified by the differences in the infant's gut microbiota
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A. Benítez-Pa 203

between breast-fed and formula-fed infants and between infant could have altered the host-microbiota partnership and micro-
formula supplemented or not with oligosaccharides, which mainly biome functionality, with an adverse long-term impact on health
stimulate the growth of bifidobacteria (Closa-Monasterolo et al., that could be transmitted from generation to generation
2013; Hascoet et al., 2011). These effects have also been well- (Sonnenburg et al., 2016). Notwithstanding, evidence from sys-
established by comparing the gut microbiota of individuals from tematic studies in humans is required to confirm this hypothesis.
different geographical regions that consume rural diets (Africa and
South America) rich in dietary fiber or Western diets (Europe and 2.3. Evidence for the influence of dietary fiber on gut microbiota
North America) rich in animal protein and fat (De Filippo et al., from intervention studies
2010; Yatsunenko et al., 2012). A comparison of the microbiota
between European and African children, consuming a fiber-rich A summary is given in Table 1 of recent representative human
diet, showed that the latter have reduced abundance of Firmi- dietary interventions investigating how most common types of
cutes and increased abundance of Bacteroidetes, particularly the dietary fibers contribute to remodeling the gut microbiota. The
Prevotella and Xylanibacter genera, known to have genes specialized responsiveness and effects of dietary fibers may differ depending
in cellulose and xylan utilization, with parallel increased fecal on the individual's gut microbiota profile (Korpela et al., 2014),
concentrations of SCFAs. In contrast, Enterobacteriaceae species suggesting the need to work towards defining more specific and
(Proteobacteria) were reduced in African compared with European personalized dietary interventions and recommendations.
children (De Filippo et al., 2010). Another large study including
healthy children and adults also revealed important differences in 2.3.1. Effects of wholegrain (WG)-rich foods
bacterial communities and functional gene repertoires between US Wholegrain cereals are composed of starch-rich endosperm,
subjects from metropolitan areas and those from countries with a germ, and bran with high plant-fiber content. During harvesting
rural lifestyle (Amazonas of Venezuela and Malawi), finding the and food processing, these components must preserve their rela-
genus Prevotella to be abundant in humans with a diet rich in corn tive proportions as in the intact kernel (HEALTHGRAIN Consortium
and cassava and in US children not following a full western diet - http://www.healthgrain.org). Rice, wheat, maize, oats, and barley
(Yatsunenko et al., 2012). A more recent study comparing African are the main whole grains consumed worldwide and some of them
Americans and rural South Africans, found that animal protein and have been proven to reduce the risk of certain diet-related diseases
fat intake was 2e3 times higher in Americans whereas carbohy- such as obesity and CVD. A controlled cross-over study showed a
drate and fiber (mainly resistant starch) intake was higher in Af- bifidogenic effect upon consumption of 48 g/day maize-based WG
ricans. The same authors also reported diet-associated microbiota breakfast cereals during 21 days (Carvalho-Wells et al., 2010). This
and metabolite changes that were related to colon cancer risk. effect was observed exclusively for the intervention period and not
While the American microbiota was dominated by Bacteroides, the sustained after completion of the WG diet, strongly indicating that
African microbiota was dominated by Prevotella and higher levels of WG fiber is predominantly used by Bifidobacterium spp. (Carvalho-
starch degraders, carbohydrate fermenters, and butyrate pro- Wells et al., 2010). Similar results were obtained by Costabile and
ducers. Moreover, the American microbiota had higher levels of coworkers who reported increased bifidobacteria and lactobacilli in
potentially pathogenic Proteobacteria (Escherichia and Acineto- feces after daily consumption of WG wheat breakfast cereals (48 g/
bacter) and BA deconjugators (Ou et al., 2013). A recent Dutch day) in comparison with non-WG cereal (Costabile et al., 2008).
population-based metagenomic study involving 1135 subjects has More recent results have shown that a four-week dietary inter-
associated higher diversity, functional microbiome richness and vention with 60 g/day WG barley flakes in healthy adults induced a
abundance of Bacteroidetes with higher intake of fruits and vege- significant increase in the genus Blautia and a less pronounced
tables (source of dietary fiber), higher concentrations of high- increase in the abundance of the genera Roseburia, Bifidobacterium
density lipoprotein (HDL) and lower concentrations of fecal chro- and Dialister (Martinez et al., 2013). Additionally, this study showed
mogranin A (Zhernakova et al., 2016). The total amount of carbo- that WG barley, brown rice and specially the combination of WG
hydrates in the diet was also positively associated with barley and brown rice reduced plasma interleukin-6 (IL-6) and
Bifidobacterium but negatively associated with Lactobacillus and postprandial glucose. Interestingly, Eubacterium rectale was signif-
microbiome diversity (Zhernakova et al., 2016). All in all, these icantly more abundant in volunteers showing improvements in
observational studies reveal that long-term consumption of fiber- postprandial blood glucose and insulin response, whereas abun-
rich diets promotes the dominance of fiber-degraders of the dance of Dialister species was associated with the highest im-
phylum Bacteroidetes and Actinobacteria (Bifidobacterium spp.) provements in IL-6 levels (Martinez et al., 2013).
and, more consistently, of Prevotella spp. and reductions in Pro-
teobacteria; nevertheless, Bacteroides spp. seem to be adapted to 2.3.2. Resistant starch (RS)
both fiber-rich diets and diets rich in animal protein and fat, Starch is the major component of the plant-derived foods and
probably due to their versatile metabolic capabilities. Notwith- comprises an important part of the human diet. The starch is
standing, these observational data only provide associations but referred as resistant when it cannot be hydrolyzed by digestive
not causal relationships between specific dietary habits and the enzymes of the human GIT. The RS can be classified into several
predominance of specific bacterial taxa, which limits their value in types (RS1 to RS5) according to the physical or chemical reasons to
practice. Furthermore, other relevant environmental factors such as be indigestible. The RS1 is contained inside whole grains and is
hygiene, geography, and ethnicity that could be involved in the physically inaccessible for digestion; the RS2 is also native starch
respective gut microbiota profile observed are not well assessed. but remains indigestible by its compact structure; the RS3, also
A recent experimental study in animal models also suggests that known as retrograde starch, is obtained by slow re-crystallization
the lack of dietary fiber leads to a substantial loss in gut microbiota prior to heat disruption on water; the RS4 is the chemically
diversity, which influences the ability of gut bacteria to be trans- modified starch by cross-linking or esterification; and the RS5 is a
ferred from parents to offspring. It also revealed that simply mixture of starch with lipids with high stability (Ma & Boye, 2016).
restoring fiber consumption was not enough to reverse these ef- Early studies about the RS impact on gut microbiota indicated that
fects since some bacterial groups failed to return to their previous administration of controlled diet including 22 g/day RS induces
levels (Sonnenburg et al., 2016). These results have led to hypoth- changes in gut microbiota mainly in the clostridia cluster including
esize that long-term dietary changes in industrialized countries members of the Ruminococcus genus (Abell, Cooke, Bennett,
204 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa

Table 1
Summary of dietary fiber interventional studies with gut microbiota assessments in humans.

Fiber Study design Subjects Time Gender Population Effects on gut microbiotaa Reference

Maize-derived DB, R, PC, CO 32 3 weeks Females (21) European ↑Bifidobacterium (Carvalho-Wells et al., 2010)
WG cereal Males (11) UK
WG wheat cereal DB, R, PC, CO 31 3 weeks Females (16) European ↑Bifidobacterium, Lactobacillus (Costabile et al., 2008)
Males (15) UK
WG barley R, CO 28 4 weeks Females (17) USA ↑Blautia,Bifidobacterium, Roseburia, (Martinez et al., 2013)
Males (11) Dialister
4Dialister- plasma IL-6levels
4Eubacterium- plasmaglucose/
insulin
Inulin DB, R, PC, CO 32 4 weeks Females European ↑Bifidobacterium (Petry et al., 2012)
Switzerland
Inulin (Agave) DB, R, PC, CO 29 3 weeks NA USA ↑Bifidobacterium (Holscher et al., 2015)
↓Desulfovibrio
4Faecalibacterium - fecal butyrate
Inulin/FOS DB, R, PC 31 8 weeks Females European ↑Bifidobacterium, Lactobacillus (Garcia-Peris et al., 2012)
Spain
Inulin-type fructans DB, R, PC 30 12weeks Females European ↑Bifidobacterium, (Salazar et al., 2015)
Belgium Faecalibacteriumprausnitzii
↓Bacteroides, Propionibacterium
4Bifidobacterium - plasma LPS
levels
4Faecalibacterium - plasma LPS
levels
4Bacteroides - Fat mass
Inulin/Oligofructose DB, R, PC 22 12 days (mean) Females (9) European ↓Faecalibacterium, Bacteroides, (Majid et al., 2014)
Males (13) UK Prevotella
Inulin/Oligofructose DB, PC 30 12 weeks Females (44) European ↑Bifidobacterium, (Dewulf et al., 2013)
Belgium Faecalibacteriumprausnitzii
Inulin/Oligofructose DB, R, PC 252 16weeks Females (123) European ↑Bifidobacterium (Closa-Monasterolo et al., 2013)
Males (129) Spain
B-GOS DB, R, PC, CO 45 6 weeks Females (29) European ↑Bifidobacterium (Vulevic et al., 2013)
Males (16) UK ↓Clostridium histolyticum,
Desulfovibrio, Bacteroides
GOS DB, R, PC, CO 31 3 weeks Females European ↑Bifidobacterium (Whisner et al., 2013)
The Netherlands
GOS DB, R, PC 163 >16 weeks NA European ↑Bifidobacterium (Giovannini et al., 2014)
Italy
XOS R, PC 22 3 weeks Females (7) Taiwan ↑Bifidobacterium (Chung et al., 2007)
Males (15)
AXOS R, PC, CO 20 3 weeks Females (14) European ↑Bifidobacterium (Cloetens et al., 2010)
Males (6) Belgium
AXOS DB, R, PC, CO 63 3 weeks Females (30) European ↑Bifidobacterium (Francois et al., 2012)
Males (33) Belgium
AXOS DB, R, PC, CO 65 3 weeks Females (35) USA ↑Bifidobacterium (Maki et al., 2012)
Males (30)
RS3 R, CO 14 3 weeks NA European ↑Ruminococcusbromii, (Walker et al., 2011)
Scotland Eubacteriumrectale
RS2, RS4 DB, CO 10 3 weeks Females (5) USA ↑Bifidobacterium adolescentis, (Martinez et al., 2010)
Males (5) Eubacteriumrectale,
Ruminococcusbromii,
Parabacteroides distasonis
↓Faecalibacteriumprautsnitzii,
Doreaformicigenerans
RS R, CO 46 4 weeks Females (30) Australia ↑Ruminococcusbromii (Abell et al., 2008)
Males (16)
a
Gut microbiota changes expressed in terms of abundance. ↑ indicates higher proportions of a determined bacterial genus after intervention, and ↓ indicates the inverse
effect. 4 indicates direct correlations among bacterial abundance and metabolic parameters studied, being negative or positive, respectively. DB ¼ Double-blind; Single-
Blind ¼ SB; R ¼ randomized; PC ¼ Placebo-controlled; CO ¼ Cross-over; NA ¼ No information was explicitly available for gender distribution into the intervention groups.

Conlon, & McOrist, 2008). Interventions with 50e60 g/day RS3 with metabolic syndrome and help to control waist circumference
increased the abundance of several Ruminococcus spp. and espe- and fat mass in non metabolic syndrome individuals (Nichenametla
cially Ruminococcus bromii and Eubacterium rectale (Walker et al., et al., 2014). These beneficial effects of RS on metabolic aspects are
2011). Similar results were obtained when 33 g/day RS2 or RS4 thought to be at least partially mediated by the microbiota induced
were administrated in baked crackers to volunteers during 3 weeks. changes but direct evidence still has to be provided.
In this case, increased proportions of Bifidobacterium adolescentis
and Parabacteroides distasonis were found to be induced particu- 2.3.3. Inulin and FOS
larly by RS4 intake, whereas increased proportions of Ruminococcus Inulin and FOS, also called oligofructose or oligofructans, are
bromii and Eubacterium rectale were induced by RS2 consumption types of fructo-polysaccharides that consist of several b-linked D-
(Martinez, Kim, Duffy, Schlegel, & Walter, 2010). In addition, RS fructosyl residues with a D-glucose group at end of the extended
intake of has been found to improve lipid metabolism in individuals saccharide chain. These differ in the polymerization degree, which
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A. Benítez-Pa 205

may range from 2 to 60 fructose units. FOS are usually produced by its prebiotic potential (reviewed in (Riviere, Selak, Lantin, Leroy, &
degradation of inulin obtained primarily from artichoke and De Vuyst, 2016)), other AX-degrading bacteria in the human colon
chicory plants. These are used in the food industry as sweeteners, belong to the genera Roseburia and Bacteroides and include the
texture modifiers and fibers. A number of intervention studies have butyrate producing Roseburia intestinalis (Chassard, Goumy, Leclerc,
shown that the effects of inulin and FOS on gut microbiota Del'homme, & Bernalier-Donadille, 2007). These data are of interest
composition can be associated with modifications on health related since a higher relative abundance of butyrate-producing bacteria
outcomes or subrogated biomarkers (Table 1). In adults and infants, and Bacteroides spp. has been reported in healthy individuals
it is generally reported that inulin and FOS intake increases the compared to patients with T2D or pre-diabetic subjects in some
number of bifidobacteria, sometimes associated with changes in studies (reviewed in (Sanz, Olivares, Moya-Perez, & Agostoni,
metabolic products (e.g. lactate) (Closa-Monasterolo et al., 2013; 2015)). Human intervention trials have also shown increased fecal
Garcia-Peris et al., 2012; Petry, Egli, Chassard, Lacroix, & Hurrell, abundance of Bifidobacterium spp. following intake of 4 g/day XOS
2012). In some studies, inulin or FOS-induced microbiota changes during three weeks (Chung, Hsu, Ko, & Chan, 2007) and from 2.14 to
have also been correlated with indicators of metabolic health. For 10 g/day AXOS (Cloetens et al., 2010; Francois et al., 2012; Maki
example, a three-month double-blind placebo-controlled inter- et al., 2012). Furthermore, a higher abundance of this genus has
vention with a mixture of inulin/oligofructose or maltodextrin (8 g been reported in normal weight subjects compared to obese and
twice daily in powder to be dissolved in warm drinks) in obese T2D subjects in some observational studies (Schwiertz et al., 2010;
women, showed increased abundances of Bifidobacterium spp. and Wu et al., 2010).
Faecalibacterium prausnitzii, which correlated to reduced serum LPS
(lipopolysaccharide) levels. Additionally, the researchers observed 3. Microbiome components involved in the utilization of
reductions of Bacteroides intestinalis, Bacteroides vulgatus and Pro- dietary fiber
pionibacterium spp., which correlated to modest changes in fat
mass. Additionally, they found reductions in plasma LPS, fecal ac- Dietary intake of fibers may lead to enrichment and altered
etate and propionate concentrations, and fasting insulinemia expression of microbial genes which encode proteins/enzymes of
(Dewulf et al., 2013; Salazar et al., 2015). A recent study has eval- metabolic pathways involved in the utilization of dietary fiber and
uated the role of agave inulin showing a dose-dependent bifido- the production of potentially beneficial metabolites (e.g. SCFAs). It
genic effect. The consumption of 5 or 7.5 g/day agave inulin in is necessary to identify and characterize these pathways in order to
chocolate chews, primarily promoted the presence of understand the components of the microbiota and the microbiome
B. adolescentis, B. breve, B. longum, and B. pseudolongum (Holscher that may underlie health effects associated with dietary fiber
et al., 2015). Positive correlations were also detected between intake. Members of the phyla Bacteroidetes and Firmicutes are
fecal butyrate concentrations and the dose of fiber, and between specialized in the utilization of complex carbohydrates and are the
fecal butyrate concentration and Faecalibacterium abundance. main producers of SCFAs. Butyrate and propionate are the two most
These effects could be explained by cross-feeding interactions thoroughly investigated SCFAs in terms of their potential role in
disclosed between bifidobacteria and Faecalibacterium (Moens, metabolic health. The production of these SCFAs may require the
Weckx, & De Vuyst, 2016). Interestingly, a depletion of Desulfovi- participation of different bacterial genera and species via cross-
brio species was also identified as a consequence of agave inulin feeding mechanisms. For example, Bacteroides thetaiotaomicron
consumption (Holscher et al., 2015), which could be of clinical can directly produce propionate and acetate, which then can be
relevance because increased Desulfovibrio species have been related used by Eubacterium halli to produce butyrate (Mahowald et al.,
to obesity and the associated endotoxemia (Xiao et al., 2014; Zhang- 2009). Similar cross-feeding mechanisms have been described be-
Sun, Augusto, Zhao, & Caroff, 2015; Zhang et al., 2009). tween some Bifidobacterium spp. and Faecalibacterium prausnitzii
leading to increased butyrate production (Rios-Covian, Gueimonde,
2.3.4. GOS Duncan, Flint, & de los Reyes-Gavilan, 2015). Fig. 1 shows the
GOS are mainly produced through transgalactosylation re- pathways identified for bacterial production of butyrate by
actions mediated by b-galactosidases using lactose or derivatives as genomic and metagenomic analysis of the human gut microbiota
substrate. GOS are often used to supplement infant formula due to (Mahowald et al., 2009; Reichardt et al., 2014; Vital, Howe, & Tiedje,
their chemical and structural resemblance to human milk oligo- 2014). A conventional genetic signature to explore both the
saccharides. In infant formula, GOS have been shown to exert a enrichment and variability of butyrate producers is via analyzing
bifidogenic effect (Giovannini et al., 2014). In adults, the six-week the butyryl-CoA:acetate CoA-transferase gene (BCoAT gene)
administration of 5.5 g/day GOS powder mixture dissolved in wa- encoding the respective enzyme responsible for the last step in
ter to subjects with metabolic syndrome has been shown to reduce butyrate production. Quantitative approaches indicate BCoAT gene
levels of Clostridium histolyticum, Desulfovibrio spp. and Bacteroides enrichment in gut microbiota from individuals with a high intake of
spp.(Vulevic, Juric, Tzortzis, & Gibson, 2013). These changes were plant fiber, which is indicative of increased colonic butyrate pro-
accompanied by increases in Bifidobacterium spp. and reductions in duction (Hippe et al., 2011; Louis, Young, Holtrop, & Flint, 2010;
inflammatory markers, including fecal calprotectin and plasma C- Remely et al., 2014; Vital, Gao, Rizzo, Harrison, & Tiedje, 2015).
reactive protein (CRP) and in some metabolic parameters (e.g. Additionally to genes encoding enzymes of pathways respon-
plasma insulin, total cholesterol and triglycerides in males). sible for SCFA production, the detection of other genes involved in
the uptake and degradation of complex polysaccharides could be
2.3.5. Xylans and arabinoxylans useful to define the active bacteria and their mode of action in
Arabinoxylans (AX) from cereals are cell wall components that response to fiber intake. Pioneer studies regarding characterization
constitute a major part of the dietary fiber fraction of cereal grains of proteins involved in the utilization of complex carbohydrates by
and thus, an important fiber source in the diet (McCleary, 2003). anaerobe gut bacteria have revealed the essential role of poly-
Enzymatic hydrolysis of AX either in the production of processed peptides encoded by Sus genes, extensively studied in
foods or by bacteria in the colon yields arabinoxylan oligosaccha- B. thetaiotaomicron (Reeves, Wang, & Salyers, 1997). The Sus
rides (AXOS) and xylooligosaccharides (XOS), both of which are products were originally described as outer membrane proteins
proposed to be prebiotic fibers (Broekaert et al., 2011). Additionally able to bind complex starch. Notwithstanding, the genetic context
to the well known bifidogenic effect of AX, a fact in which is based of their encoding genes has enabled the inclusion of glycoside
206 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa

Lysine Acetyl-CoA Glutarate

KamA Thl

ß-Lysine Acetoacetyl-CoA 2-Oxoglutarate

KamD, E Hbd L2Hgdh

2-Hydroxyglutarate
3,5-Diaminohexanoate 3-Hydroxybutanoyl-CoA
Gct 4-Aminobutyrate
/Succinate
Kdd 2-Hydroxy-
Glutaryl-CoA
Cro
3-Keto-5-aminohexanoate HgCoAd Succinate-semialdehyd

Acetoacetate
Glutaconyl-CoA Ab
Kce Gcd
Kal 4-Hydroxybutyrate
3-aminobutyryl-CoA Crotonoyl-CoA
Isom Abfd
Vinyl- 4-Hydrox
Bcd-(αß) AceƟl-CoA butyryl-CoA

Butyryl-CoA 4Hbt
Ptb
Acetate
Ato But
Butyryl-phosphate

Buk Butyrate
Fig. 1. The bacterial butyrate synthesis pathways (adapted from (Vital et al., 2014)). Vital and coworkers have reconstructed four different pathways for butyrate synthesis through
and an extensive metagenomic approach. Protein names and major substrates are shown across the different biosynthetic pathways. Genes/proteins responsible of the last step of
butyrate production, and frequently used as biomarkers for gut microbiota studies, are highlighted in red. They are known as: 4Hbt, butyryl-CoA:4-hydroxybutyrate CoA trans-
ferase; But, butyryl-CoA:acetate CoA transferase; Ato, butyryl-CoA:acetoacetate CoA transferase (a, b subunits); and Buk, butyrate kinase.

hydrolases (GH) enzymes in the Sus repertoire of proteins, which studies performed in Flint's lab with Ruminoccocus bromii in which
collectively work to produce small oligosaccharides that are more this bacteria was observed to present a specialized extracellular
easily imported by bacteria. Consequently, Sus genes have become polypeptide complex, known as amylosome (Ze et al., 2015). It was
useful to detect different polysaccharide utilization loci (PULs) in also found to be an indispensable member of the human gut
other Bacteroides species by comparative genomics approaches, microbiota, having a direct effect on energy recovery from a central
allowing them to be studied in response to a wide variety of component of diet, i.e., RS (Ze, Duncan, Louis, & Flint, 2012).
complex polysaccharides (reviewed in (White, Lamed, Bayer, & However, Bifidobacterium (Actinobacteria) species are also well-
Flint, 2014)). Nowadays, research on carbohydrate utilization by gut known fiber fermenters. Although Bifidobacteria have fewer GHs
bacteria is conceived as a cornerstone to understand their physi- encoded in their genomes than Bacteroidetes, they also exhibit a
ology and potential interactions and bidirectional communication great versatility for the uptake and catabolism of oligosaccharides.
with the host in health and disease. In this regard, the Carbohydrate This versatility is well exemplified in genome-wide expression
Active Enzymes (CAZy) database (http://www.cazy.org/) is one of analyses, which have disclosed a wide variety of genes appearing to
the most complete repositories describing the families of respond specifically to different carbon sources (Andersen et al.,
structurally-related catalytic and carbohydrate-binding functional 2013; O'Connell et al., 2013). In this context, we have recently
domains of enzymes that bind, degrade, modify or create glycosidic described the genome response of B. pseudocatenulatum CECT 7765,
bonds (Lombard, Golaconda Ramulu, Drula, Coutinho, & Henrissat, a strain isolated from breast-fed babies, during utilization of
2013). Hierarchical classification of CAZy comprises 4 main families lactulose-derived oligosaccharides. An exhaustive inventory of GH
such as the Glycoside Hydrolase (GH, with 135 subfamilies reported enzymes present in the genome of this species have a set of open
at Nov 2016), the Glycosyltransferase (GT, with 101 subfamilies), reading frames (ORFs) that seem to control the uptake and degra-
the Polysaccharide Lyase (PL, with 24 subfamilies), and the Carbo- dation of this digestion-resistant oligosaccharide (Benitez-Paez,
hydrate Esterase (CE, with 16 subfamilies) family. All GH reported Moreno, Sanz, & Sanz, 2016).
are classified according to the functional modules they contain, Although GHs and related proteins appear to be the key traits to
with the aim to determine sites of action (exo or endo-acting en- infer versatility of gut microbes for utilization of polysaccharides
zymes) or type of cleavage (a- or b-glycosilases). Members of the and their contribution to the production of fermentation end-
phyla Bacteroidetes and Firmicutes are characterized by encoding products such as SCFAs, little is known about the effects of fiber
the largest set of GH in their genomes, thus exhibiting a remarkable fermentation on secondary metabolic pathways and the generation
versatility for the utilization of different polysaccharides as carbon of other nutrients (e.g. amino acids and vitamins) and bioactive
source (White et al., 2014). These features convert species of such compounds. Some in vitro studies have reported that oligosaccha-
bacterial phyla into key players for degradation of complex poly- ride fermentation also increases amino acid synthesis (Benitez-
saccharides in the human colon. Proof of this can be found in the Paez et al., 2016; Sulek et al., 2014). In particular, our study
 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa 207

revealed that the utilization of GOS by B. pseudocatenulatum CECT may also interact with peroxisome proliferator-activated receptor
7765, using bacteria cultures, increased the production and extra- (PPAR) g, thereby inhibiting pro-inflammatory signal transduction
cellular accumulation of branched-chain amino acids such as pathways (e.g. nuclear factor-kappa B [NF-kB]) leading to reduction
leucine (Benitez-Paez et al., 2016). Additional studies are, however, of downstream cytokine/chemokine production (IL-6, IL-8, and
needed to understand the effects of the interplay between dietary MCP-1) in intestinal epithelial cells and metabolic tissues (e.g. ad-
fiber and amino acid metabolism in the large intestine and fully ipose tissue) (Mastrofrancesco et al., 2014). Activation of PPARg also
understand the metabolites resulting from the activity of the gut seems to be crucial in orchestrating Treg accumulation and function
microbiota and their potential consequences on health beyond the in the adipose tissue, which play an important role in preventing
well-known SCFAs. inflammation and insulin resistance (Cipolletta, Cohen,
Spiegelman, Benoist, & Mathis, 2015). Butyrate as well as other
4. Effects of dietary fiber on metabolic health mediated by SCFAs, protects against the liver inflammation process associated
gut microbiota with steatosis by inhibiting the NF-kB activation and down-
regulating expression of TLR4 receptor (Mattace Raso et al., 2013).
There is a wealth of human intervention studies with dietary The molecular mechanisms underlying SCFA modulation of NF-kB
fibers, but only a few of them have assessed the relationship be- activity have recently been disclosed as related to JNK and p38
tween microbiota-induced changes and endpoints related to kinases, which control NF-kB activity (Haghikia et al., 2015).
physiological functions and metabolism. Further studies are also However, we cannot discard additional mechanisms to control NF-
needed that directly assess the effects of fiber-induced microbiota kB function involving acetylation/deacetylation of histones and the
changes on metabolic outcomes, for example via fecal trans- RelA (p65) monomer itself (Davie, 2003; Glozak, Sengupta, Zhang,
plantation or via inoculation of specific bacterial consortia from & Seto, 2005).
humans into animal models. Consequently, there is still a large
degree of uncertainty about to what extent the effects attributed to 4.2. Enteroendocrine secretion and appetite
dietary fibers on metabolic health are mediated by gut microbiota
in humans, and which are the key species involved. Nonetheless, In obese animals fed inulin-type fructans, there is an increase in
considerable mechanistic data are available from other animal plasma anorexigenic peptides (peptide YY and glucagon-like pep-
study approaches, as summarized below. tide - GLP-1) and a decrease in the orexigenic peptide ghrelin,
which increases satiety (reviewed in (Delzenne et al., 2013)). In
4.1. Gut barrier integrity, metabolic endotoxemia and inflammation addition, supplementation with fructans in HFD-fed mice modu-
lates neuronal activation within the arcuate nucleus, which can
Obesity and particularly the intake of a high-fat diet (HFD) are help to control food intake (Anastasovska et al., 2012). These effects
thought to lead to a leaky gut and metabolic endotoxemia on anorexigenic peptide secretion could be mediated by in-
(increased serum LPS levels) in animal models and to some extent teractions of SCFAs with G-protein receptors such as FFAR2 (GPR41)
in humans. This is assumed contributing to the low-grade chronic and FFAR3 (GPR43), which could explain induction of satiety and
inflammation leading to metabolic dysfunction and disease increased insulin sensitivity (Blaut, 2014). Also in humans, prebiotic
(metabolic syndrome and T2D). In fact, LPS is a potently inflam- interventions with fructans have led to increases in anorexigenic
matory bacterial antigen linked to common metabolic diseases peptides and/or decreases in orexigenic (ghrelin) peptides (Cani,
(Conlon & Bird, 2015). LPS is an endotoxin consisting of three parts; Joly, Horsmans, & Delzenne, 2006; Cani et al., 2009; Parnell &
lipid A, the oligosaccharide core and the O-antigen, with the lipid A Reimer, 2009; Verhoef, Meyer, & Westerterp, 2011), but effects on
causing endotoxicity. LPS is normally present in the human gut satiety have not always been consistent (Peters, Boers, Haddeman,
(1 g) and under normal conditions it does not cause negative Melnikov, & Qvyjt, 2009).
health effects. In healthy humans the normal/low plasma concen-
tration of LPS is 1e200 pg/ml, but increased levels have been found 4.3. Adiposity, lipid and glucose metabolism
in subjects with obesity and diabetes (Erridge, Attina, Spickett, &
Webb, 2007; Moreira, Texeira, Ferreira, Peluzio Mdo, & Alfenas Reduced adiposity in rodents due to dietary supplementation
Rde, 2012). LPS binds to TLR4 via CD14 on, for example, the mem- with inulin-type fructans or AX has also been attributed to the role
brane surface of immune cells leading to activation of genes that of SCFAs in modulating PPARg expression via interaction with the
codify pro-inflammatory cytokines (e.g. TNF-a and IL-6) involved in G-protein coupled receptor protein FFAR3 (Delzenne, Neyrinck,
metabolic inflammation. Experimental models of obesity have Backhed, & Cani, 2011). Interestingly, den Besten and co-workers
shown prebiotic-induced increases in bifidobacteria and Akker- found that SCFAs decrease PPARg expression, thus promoting ac-
mansia spp. associated with reduced endotoxemia and systemic tivity of the uncoupling protein 2 (UCP2) and, thereby, stimulating
inflammation (Cani et al., 2007; Schneeberger et al., 2015). These oxidative metabolism in liver and adipose tissue, insulin sensitivity
effects can be partly explained by the ability of those bacteria to and weight loss (den Besten et al., 2015). Studies with inulin-type
ferment glycans leading to SCFA production and promoting local fructans have also shown they can decrease hepatic accumulation
decrease of pH, which may modulate gut microbiota composition of triglycerides and/or cholesterol in liver tissue. These effects have
and inhibit the growth of enterobacteria, which may be a source of been associated with a decrease in sterol-response-element-
LPS (Delzenne, Neyrinck, & Cani, 2013; Everard et al., 2013). This binding protein-dependent cholesterogenesis, lipogenesis, or
effect could also be related to the role of SCFAs in strengthening the changes in PPARa-driven fatty acid oxidation (reviewed in
gut barrier function, which also reduces LPS translocation via (Delzenne et al., 2013)). The majority of studies show prebiotic
different mechanisms, including modulation of expression and administration also leads to improved fasting or postprandial gly-
localization of tight-junction proteins, induction of endocrine cemia due to the very low digestion rates of prebiotics compared
peptide production (GLP-2) and modification of the intestinal levels with digestible carbohydrates (for review see (Roberfroid et al.,
of endocannabinoids (Everard et al., 2013). 2010)). In addition, SCFA-stimulation of GLP-1 secretion can also
SCFAs also play an anti-inflammatory role by regulating the size mediate an improvement in glucose metabolism, reducing obesity-
and function of the colonic regulatory T cells (Treg), specifically related hepatic insulin resistance.
inducing Foxp3þIL-10eproducing Tregs (Smith et al., 2013). SCFAs In humans, intervention studies with fructans have reported
208 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa

modest effects on body weight and fat mass in obese adults, but Animal studies have revealed different mechanisms by which
simultaneous changes in microbiota were not considered to have HFDcould exert adverse effects, partly mediated by the microbiota,
any correlation (Genta et al., 2009; Parnell & Reimer, 2009). on the host metabolic phenotype. For example, diets rich in satu-
Nevertheless, there are also reports of a lack of effect on body rated fat may contribute to inflammation, a hallmark of metabolic
weight in obese children (Liber & Szajewska, 2014). On the other dysfunction leading to metabolic syndrome and T2D, by promoting
hand, a rapid improvement in glucose tolerance has been observed the expansion of pathobionts, reducing the proportion of protective
for individuals consuming WG barley the night prior to analysis. bacteria, and promoting a leaky gut that in turn facilitates the
These results were thought to be caused by the high amount of translocation of bacterial products (e.g. LPS) causing immune
soluble dietary fiber and resistant starch contained in barley ker- activation (Caesar et al., 2015; Delzenne et al., 2011; Devkota et al.,
nels, which facilitated bacterial fermentation in the colon overnight 2012). In a recent study, HFD-induced microbiota changes were
and produced significantly higher levels of SCFAs. This was indi- correlated with obesity-related inflammatory and metabolic bio-
rectly measured from breath H2 excretion (Nilsson, Granfeldt, markers (Schneeberger et al., 2015). Akkermansia muciniphila was
Ostman, Preston, & Bjorck, 2006). Moreover, recent results of this the species showing the clearest inverse associations with inflam-
dietary intervention model indicate that the fiber-associated matory markers in the adipose tissue and also with biochemical/
improvement of glucose metabolism is also associated with an hormonal parameters in circulation (i.e., insulin, glucose, tri-
increase in Prevotella spp. (Kovatcheva-Datchary et al., 2015). glycerides and leptin).
However, as the majority of the dietary fat is absorbed in the
5. Impact of dietary fat on gut microbiota and associated small intestine and does not serve as an energy source for gut
metabolic endpoints microbes, the effect of fat on gut microbiota must be partly medi-
ated by indirect mechanisms. Increased fat intake also leads to in-
Globally, an increase in dietary fat content is usually paralleled creases in fat quantities and of BAs reaching the colon, and
with a decrease in carbohydrates, including dietary fiber content, particularly the concentration and composition of BAs modulates
thus making it difficult to attribute the observed changes, at the gut microbiota exerting antimicrobial effects (Islam et al., 2011;
physiology or gut microbiota levels, exclusively to one of the Ridlon, Kang, Hylemon, & Bajaj, 2014). Primary BAs (e.g. cholic acid
macronutrients whose proportion is being increased. Conse- [CA] and chenodeoxycholic acid [CDCA] in humans and beta-
quently, a decreased abundance of butyrate-producing bacteria and muricholic acid [b-MCA] in mice) are sterol compounds synthe-
lower fecal SCFA excretion following a HFD is most likely caused by sized from cholesterol in the liver, conjugated with taurine and
a decrease in dietary carbohydrate intake. Therefore, major con- glycine, and then secreted into the small intestine to emulsify lipids
clusions derived from future animal or human studies including to facilitate their digestion and absorption. The majority of BAs are
HFD interventions must be addressed carefully in order to consider reabsorbed (enterohepatic recycling), but as increased fat intake
confounding effects regarding the proportions and energetics or leads to increased BA secretion, theoretically more BAs will escape
other macronutrients administrated. enterohepatic recycling, and hence reach the large intestine. During
the transit to the large intestine, primary BAs undergo deconjuga-
5.1. Evidence from animal studies tion, oxidation of hydroxyl groups at C-3, C-7, andC-12, and 7a/b-
dehydroxylation reactions mediated by intestinal bacterial en-
The role of gut microbiota in HFD-induced obesity was sug- zymes, yielding secondary BAs such as deoxycholic acid (DCA),
gested through animal experiments involving germ-free mice fed a lithocholic acid (LCA), and b-muri-deoxycholicacid. Bacterial bile
HFD, which were protected from obesity compared to conven- salt hydrolases (BSH), e.g. produced by Clostridium spp, catalyze the
tionally raised mice (Rabot et al., 2010), thus highlighting the role of first reaction on secondary BAs and this is a step necessary for the
microbiota in HFD-induced obesity. Furthermore, a study in mice subsequent7a/b-dehydroxylation (Degirolamo, Rainaldi, Bovenga,
by Hildebrandt and coworkers showed that changes in the gut Murzilli, & Moschetta, 2014). Overall, the amount and composi-
microbiota composition were caused by dietary fat content rather tion of BAs are strongly influenced by gut microbiota and vice versa,
than the degree of obesity, suggesting that fat directly impacts on and BA biotransformation has important biological consequences
microbiota regardless of the metabolic phenotype (Hildebrandt due to their role in dietary lipid absorption and as signaling mol-
et al., 2009). Gut microbiota transferred to germ-free mice from ecules, modulating cholesterol and triglyceride metabolism and
conventionally raised mice resulted in weight gain and a higher glucose and energy homeostasis (Degirolamo et al., 2014; Staels &
relative abundance of Firmicutes and a lower abundance of Bac- Prawitt, 2013). Secondary BAs have strong antimicrobial activity
teroidetes when mice were fed a HFD compared to a low-fat chow (e.g. damage of the bacterial cell membrane by interaction with
diet from 16 weeks of age (Turnbaugh, Backhed, Fulton, & Gordon, phospholipids) due to their amphipathic properties. For example,
2008). Although differences established at phylum level are of DCA has 10 times the bactericidal activity of CA (Islam et al., 2011),
limited value since each phylum comprise many different species therefore an increase in the proportion of secondary BAs following
which may potentially play many different functions, a common HFD very likely affects the microbiota composition. A rat study,
trait for HFD-feding seems to be that it increases the Firmicu- evaluating the effect of adding CA at different doses compared with
tes:Bacteroidetes ratio (de Wit et al., 2012; Hildebrandt et al., 2009; controls (no CA added), demonstrated adose-dependent increase of
Lam et al., 2012; Turnbaugh et al., 2008), although there is not fecal BA and DCA (Islam et al., 2011). Furthermore, a dose-
complete consistency across studies (Lecomte et al., 2015); this dependent decrease in fecal SCFA concentration was observed
would also be due to experimental and environmental differences. along with a reduction in total bacterial count and an increase in
A recent 16-week study in mice fed a HFD reports that the abun- Firmicutes at the expense of primarily Bacteroidetes.
dance of Akkermansia muciniphila was progressively and drastically Dietary saturated fat compared to poly-unsaturated fatty acids
decreased while other groups including Bifidobacterium spp. and (PUFAs) was also reported to favor taurine conjugation of hepatic
Lactobacillus spp. showed a transient decrease. In contrast the BAs, which caused an expansion of d-Proteobacteria-type patho-
abundance of Roseburia spp. and Bilophila wadsworthia increased bionts, in particularly B. wadsworthia which is a sulfite-reducing
after 12 and 16 weeks upon HFD, respectively (Schneeberger et al., bacterium exerting a cytotoxic effect on epithelial cells and acti-
2015). Interesting, B. wadsworthia have been linked to insulin vating Th1-type inflammatory response (Devkota et al., 2012).
resistance and inflammation in humans (Brahe et al., 2015). Studies in rodent models of HFD-induced obesity have also
 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa 209

shown that saturated fat reduces the mucus layer, which acts as the the production of acetate, propionate and butyrate (O'Keefe et al.,
first barrier separating the immune system from microbial and 2015). Similarly, Duncan and coworkers observed a higher abun-
antigen interactions that may activate an inflammatory response. dance of Roseburia and Eubacterium and higher fecal excretion of
This effect was parallel to a reduction in the abundance of Akker- butyrate in humans following a moderate fat diet compared to
mansia spp., while administration of this bacterium reversed it, high-fat intake, with these changes in the gut microbiota and
increasing mucus layer thickness, and thus suggesting a derived metabolites being positively correlated with carbohydrate
microbiota-mediated effect (Everard et al., 2013). Other animal intake (Duncan et al., 2007).
studies have reported correlations between HFD-induced changes O'Keefe and coworkers also measured BA excretion and
in the microbiota and alterations in the expression of tight observed that the high-fat diet of Americans was associated with
junction-related proteins, and in gut permeability. In mice a HFD increased expression of microbial genes coding for the enzyme
has been shown to reduce the expression of the tight-junction- related to converting primary BAs to secondary BAs, whereas a
related protein zonula occludens (ZO)-1 mRNA (Cani, Delzenne, dietary switch to a lower-fat diet reduced the abundance of these
Amar, & Burcelin, 2008) associated leading to increased gut bacteria. Furthermore, excretion of the secondary BAs LCA and DCA
permeability measured by transepithelial resistance (Lam et al., was increased by the HFD. Also short-term consumption of diets
2012). Additionally, decreased transepithelial resistance (i.e. composed entirely of animal (rich in fat and protein) or plant
increased gut permeability) was associated a drop in the abundance products (rich in fiber) can rapidly alter gut microbial composition
of Lactobacillus spp. and augmented abundance of Oscillibacter spp. (David et al., 2014). An animal-based diet increased the abundance
(Lam et al., 2012). of bile-tolerant microorganisms, including Alistipes, Bilophila, and
Animal studies also show that when a HFD is supplemented Bacteroides species. By contrast this diet decreased the abundance
with either prebiotics (Cani et al., 2007; Everard et al., 2013; Serino of Firmicutes, including genus and species specialized in the utili-
et al., 2012) or antibiotics (Cani, Bibiloni, et al., 2008) the HFD- zation of polysaccharides (Roseburia, Eubacterium rectale, and
induced alterations in gut microbiota and metabolism are Ruminococcus bromii). Furthermore, the animal-based diet
partially reversed, indicating that gut microbiota partly mediate the increased the abundance of B. wadsworthia and secondary BAs.
consequences of HF feeding. These findings support the observations in rodent models
A few studies have investigated the effects of different dietary comparing diets rich in PUFA or saturated fat (D. L. Gibson et al.,
fatty acids (Lam et al., 2012; Lappi et al., 2013; Simoes et al., 2013). 2015; Schneeberger et al., 2015), suggesting similar mechanisms
In mice, it has been shown that n-6 high fat diets do not increase of action and similar metabolic effects.
insulin resistance, intestinal permeability and fat accumulation to The relationship between PUFAs and the microbiota are even
the same degree as saturated fatty acid diets, which is possibly due less well understood. A recent study in women with obesity and
to a lower increase in H2S-producing bacteria (Lam et al., 2012). metabolic syndrome who consumed inulin-type fructans for 3
Likewise, lower decreases in Bacteroidetes have been found under months reported that PUFA-derived metabolites were associated
diets rich in n-3 or n-6, compared to diets rich in saturated fatty with Bifidobacterium spp., Eubacterium ventriosum, and Lactoba-
acids (T. Liu, Hougen, Vollmer, & Hiebert, 2012). cillus spp., and negatively correlated with serum cholesterol (Druart
et al., 2014). However, another human intervention study found
5.2. Evidence from human studies that supplementation with n-3 fatty acids (180 mg EPA and 120 mg
DHA) for 6 weeks did not induce changes in the gut microbiota
Only a few human intervention studies have investigated the although it decreased insulin resistance and CRP (Rajkumar et al.,
effects of HFD compared to low-fat diets (LFD) or the type of fat 2014). Unfortunately, amelioration of these metabolic parameters
(saturated fat versus PUFAs) in relation to changes in gut microbiota could not be directly associated with one specific fatty acid since
and the metabolic consequences. As found in animal studies, total only a mixture was tested. Therefore, further studies are needed to
bacterial counts decrease in humans who consume a HFD (35e38 E gain greater understanding of how the quality of dietary fat in-
%), compared to a LFD (23e27 E%) over 24 weeks (Fava et al., 2013). fluences gut microbiota composition and function, and potential
Moreover, low/moderate-fat intake appears to induce a higher mediated effects on metabolism in humans.
abundance of Bacteroides spp. and/or Bifidobacterium spp.,
compared to high-fat intake in human intervention trials 6. Concluding remarks
(Brinkworth, Noakes, Clifton, & Bird, 2009; Fava et al., 2013). An
energy-restricted HFD (58 E%), compared with an isocaloric Fiber is an instrumental dietary component that can be used to
moderate-fat diet (28 E %) was shown to increase the total number remodel gut microbiota composition and function to potentiate the
of anaerobes in the moderate-fat group, but not in the high-fat beneficial effects of healthy diets on body weight management and
group, but the ratio between anaerobe:aerobe remained un- metabolism. However, efforts are still needed to identify the
changed in each group (Brinkworth et al., 2009). Additionally, a optimal functional partnership between key bacterial species and
study comparing high-fat and moderate-fat ad libitum diets (66 E% types of fibers, considering the specificities of the individual's
vs. 35 E%) over 4 weeks did not report any effect on the gut microbiota. Fermentation of dietary fiber generates SCFAs, which
microbiota in terms of total bacterial count; however, the meth- presumably articulate beneficial effects in the context of obesity;
odology used to study microbiota abundance was based on a yet many other secondary metabolic products resulting from diet-
limited number of species (Duncan et al., 2007). microbe interactions have yet to be discovered. Gut microbiota
As stated above, an increase in the intake of dietary fat is usually appears to contribute to the adverse consequences of high-fat diets
at expenses of a decrease in that of simple or complex carbohy- on the metabolic phenotype, aggravating the associated low-grade
drates, making it difficult to attribute the observed effect exclu- inflammation and increasing energy absorption; however, further
sively to one of the macronutrients. O'Keefe and coworkers studies are needed to understand the potential effects of the quality
(O'Keefe et al., 2015) compared the effects on gut microbiota in a of dietary fat on the gut microbiota and secondary metabolic pro-
cross-over study with a 2-week diet period administering either cess, such as those involving bile acids and their signaling roles.
African- or American-food. The switch from a rural African to an Additional efforts must be conducted to identify the specific com-
American-diet (52% fat, 21% carbohydrate, 27% protein, and 12% ponents of the gut microbiota, at species and strain level, influ-
fiber) decreased the abundance of butyrate-producing bacteria and enced by different types of dietary fibers and fats and to understand
210 ez et al. / Trends in Food Science & Technology 57 (2016) 201e212
A. Benítez-Pa

their roles and mechanisms of action in humans to facilitate the use Characterization of the xylan-degrading microbial community from human
faeces. FEMS Microbiology Ecology, 61, 121e131.
of this information in nutritional practice. This ambitious goal is
Chung, Y. C., Hsu, C. K., Ko, C. Y., & Chan, Y. C. (2007). Dietary intake of xylooligo-
expected to be accomplished by developing translational research saccharides improves the intestinal microbiota, fecal moisture, an pH value in
approaches that integrate controlled dietary interventions in the elderly. Nutrition Research, 27, 756e761.
humans, combining functional omics technologies and physiolog- Cipolletta, D., Cohen, P., Spiegelman, B. M., Benoist, C., & Mathis, D. (2015).
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ical/clinical endpoints, and mechanistic studies in experimental cells in visceral adipose tissue: Age, diet, and PPARgamma effects. Proceedings of
models colonized with specific dietary-driven human microbiotas. the National Academy of Sciences of the United States of America, 112, 482e487.
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et al. (2010). Tolerance of arabinoxylan-oligosaccharides and their prebiotic
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Zaragoza-Jordana, M., et al. (2013). Safety and efficacy of inulin and oligo-
Framework Program under the grant agreement no 613979 fructose supplementation in infant formula: Results from a randomized clinical
(MyNewGut) and by FUNDACION MAPFRE under grant 00 Hernando trial. Clinical Nutrition, 32, 918e927.
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