Gut

Microbiome
in Health
Contents
INTRODUCTION

COLONIC MICROBIOME

LOCATION OF COLONIES OF MICROBIOME

FUNCTIONS OF THE GUT MICROBIOTA

PROTECTIVE ROLE OF GUT MICROBIOTA

GUT MICROBIOTA EFFECT ON BONE, BRAIN

THE GUT MICROBIOME AND VARIOUS INTESTINAL AND EXTRAINTESTINAL

DISEASES

SCFA S AND MICROBIOME

INTRODUCTION
Gut microbiota is a complex community of microorganisms that
live in the digestive tracts of humans and animals, including
insects.
In people, the gut microbiota has the biggest quantities of
microorganisms, and the greatest number of species compared
to other parts of the body.

They consist of thousands of microorganisms including bacteria,

viruses, and some eukaryotes that colonize digestive tract just
after birth
Defects in gut microbiota are linked to various diseases,
such as obesity, diabetes, and cancer, impacting
immunity, energy, lipid, and glucose metabolism.

Oral and saliva microbiomes contain millions of microbes,

but their persistence in the gut is hindered by stomach
acidity, bile acid production, digestive enzymes, and
antimicrobial proteins.
The intestinal microbiota consists of more than 1500 species .
Bacteroidetes and Firmicutes followed by Proteobacteria,
Fusobacteria, Tenericutes, Actinobacteria and Verrucomicrobia
were the most dominant phyla
make up to 90% of the total microbial population in humans
.
factors that can change the gut microbiota composition and
function include host genetics, diet, age, mode of birth and
antibiotics
COLONIC MICROBIOME
The colonic microbiome - dominated by anaerobic
bacteria, including Firmicutes, Bacteroidetes,
Actinobacteria, Proteobacteria, and Verruco microbia
Highly modifiable by diet and drugs and is found in the
lower gut, where climax communities of up to 100 billion
cells per gram reside for up to a few days.
100 million microbes per gram, forming personalized
communities with day and night rhythms
microbial content reflects food intake and processing.
Colonizing Streptococcus and Lactobacillus spp. express
efficient transport systems, competing with the host for
sugar uptake and use.
The microbial composition varies across the digestive
tract.
In the stomach and small digestive tract, only few
species of bacteria are present
The colon contains a densely-populated microbial
ecosystem with up to 1012 cells for every gram of
intestinal substance.
As a result of their abundance in the digestive tract,
bacterial species make up to 60% of the feces dry mass.
Most of the bacteria are anaerobes, except in the
cecum where high densities of aerobic microbes are
recorded.
The most dominant bacterial phyla in the human gut are:
Firmicutes, Bacteroidetes,Actinobacteria, and
Proteobacteria
Most recorded bacterial genera are Bacteroides,
Clostridium, Peptococcus, Bifidobacterium,
Eubacterium,Ruminococcus, Faecalibacterium and
Peptostreptococcus.
Location of colonies of
microbiome
The duodenal microbiota has higher compositional
dynamics related to pH compared to the jejunum and is
responsible for sugar, protein, and lipid digestion and
absorption.
The proximal ileum has a large mucus layer
Mostly colonized by anaerobes, including Bacteroidia,
Ruminococcaceae, and Lachnospiraceae..
FUNCTIONS OF GUT MICROBIOTA
The microbiota is responsible for metabolizing dietary elements.

Metabolizes indigestible carbohydrates like cellulose, hemicelluloses,

resistant starch, pectin, oligosaccharides and lignin into short chain
fatty acids (SCFAs) such as acetic, propionic and butyric acids.

These metabolic products are mainly produced by Firmicutes, and

Bacteroidetes .
 Essential role in vitamin synthesis such as biotin,
thiamine, cobalamin,riboflavin, nicotine and pantothenic
acids.
Gut microbiota can synthesize neurochemicals, such as
GABA, which affects central nervous and peripheral
systems.
It also generates carbohydrates, amino acids, amines,
phenols, indoles, and phenylacetic acid.
Gut microbiota also contribute to bile acid, cholesterol,
and conjugated fatty acids synthesis
Protective role of gut microbiota
The microbiota plays a protective role by occupying
intestinal surfaces and preventing pathogenic
microorganism invasion.
Its metabolic capacities include breaking down non-
digestible compounds through anaerobic fermentation,
producing short chain fatty acids (SCFAs).
These SCFAs are essential for intestinal epithelial cells
and strengthen the mucosal barrier, improving human
health.
SCFAs have anti-inflammatory and chemo-preventive
properties, making them tumor suppressors.
Propionate and butyrate have anti-carcinogenic effects,
and their properties reduce histone deacetylase activity
in colonocytes and immune cells.
Gut microbiota effect on bone growth
and development
The gut microbiota plays a crucial role in bone growth
and development through the regulation of nutrient
absorption, translocation of microbial products, and
immune system regulation.
Impacts bone growth and development through the
production of soluble calcium ions (SCFAs).
Enhance calcium absorption and other bone-related
minerals, resulting in calcium hydroxyapatite deposits in
teeth and bones, providing strength to tissues.
Acts as a significant immunoregulator of osteoclast-
osteoblast mediated bone remodeling processes
They include:
Lactobacillus acidophilus, Lactobacillus plantarum,
Lactobacillus rhamnosus GG, Lactobacillus reuteri,
Lactobacillus paracasei and Bacillus clausii
Microbiota and the gut–brain axis
◦ The gut brain microbiota axis is a bidirectional communication
system connecting gut microbes to the brain and vice versa.

It coordinates gut functions and connects the emotional centers

of the brain with peripheral intestinal functions and mechanisms
like enteric reflex, intestinal permeability, immune activation, and
enteroendocrine signaling.
Gut microbiota's circular SCFAs affect brain barrier integrity,
limiting entry of undesirable metabolites, affecting blood-brain
barrier integrity.
THE GUT MICROBIOME AND VARIOUS INTESTINAL
AND EXTRAINTESTINAL DISEASES

The gut microbiome is linked to various gastrointestinal

disorders, including IBDs, coeliac disease, IBS, colorectal
cancer, chronic liver diseases, and pancreatic disorders.
IBDs have deviating gut microbiome composition, with
facultative anaerobes outgrowing in active inflammation
and metabolite disturbances.
IBS is also linked to changes in gut microbiome and
metabolites, particularly in purine metabolism
.

Longitudinal analysis in infants at risk for coeliac disease showed

increased microbial species and metabolites, while anti-inflammatory
strains were decreased.
Chronic rheumatoid arthritis (CRC) is linked to disturbed gut
microbiome, with bacteria like Fusobacterium nucleatum, Escherichia
coli, and Bacteroides fragilis implicated.
Chronic liver diseases, particularly advanced liver cirrhosis, have
microbial aberrations, and pancreatic adenocarcinoma is linked to
impaired gut microbiome composition.
Obesity Linkage
The gut microbiome has been extensively investigated in
obesity and obesity-related disorders like type 2 diabetes
and non-alcoholic fatty liver disease (NAFLD).
Studies have linked altered gut microbiomes to obesity,
with microbial variations strongly correlated with insulin
resistance and glucose regulation.
NAFLD, the most common chronic liver disease in the
Western world, is characterized by a bloom in certain
Enterobacteriaceae and a decrease in F. prausnitzii.
GUT MICROBES AND METABOLIC
DISORDERS: MOLECULAR FACTORS
The gut bacterial community regulates metabolic
disorders through the production of diverse metabolites
and interactions with host cells' receptors.
These metabolites, ranging from small molecules to large
macromolecules, are essential for bacterial integrity and
are influenced by microbial composition and diet.
The abundance and availability of these metabolites are
influenced by various factors.
MOLECULES PRODUCED BY GUT BACTERIA
Short chain fatty acids and impact on
host health: molecular mechanisms
In normal conditions, less than 5 g/day of fat and simple
carbohydrates and proteins reach the colon.

Gut microbes metabolize non-digestible carbohydrates

into SCFAs, which regulate various metabolic pathways in
the gut and distant areas, impacting health and affecting
various organs.
A diet rich in fermentable dietary fibres, such as
prebiotics, can reduce body weight gain, fat mass
development, insulin resistance, and energy intake.

Prebiotics modulate the gut microbiota, leading to higher

endogenous production and secretion of gut peptides
like GLP-1, GLP-2, and peptide YY.
These effects are not limited to one type of fermentable
carbohydrates, as microbial fermentation of resistant
starches or arabinoxylans into SCFAs also leads to
increased plasma GLP-1 and PYY levels.

The chemical structure of fermentable fibers is directly

related to the SCFA production profile, with some
bacteria producing butyrate from amino acids or plant
compounds.
SCFAs stimulate gut peptide secretion by acting on G-
protein-coupled receptors in enteroendocrine L-cells,
specifically in the ileum and colon.

These receptors, GPR43 and GPR41, are expressed in

various tissues and cell types.
SCFAs, such as butyrate, play a crucial role in maintaining
the gut barrier and influencing the microbial
environment.
It helps control anaerobic conditions by activating
mitochondrial β-oxidation and PPARγ, which limit oxygen
diffusion and reduce NO production.
This helps maintain anaerobic conditions and prevents
the proliferation of pathogenic facultative anaerobes.
Severe intestinal inflammation, including IBD, cancer,
obesity, and diabetes, increases Enterobacteriaceae
abundance, but decreased abundance of bacteria
producing SCFAs, like propionate and butyrate, in
humans.
Lipopolyscaccharides/Pathogen-
associated molecular patterns
The gut barrier is a complex system protecting the host
from microbial invaders and harmful stimuli.
Pathogen-associated molecular patterns (PAMPs), such
as bacterial LPS, are potent activators of the
inflammatory response. These endotoxins can elicit an
inflammatory response with small amounts.
LPS and other PAMPs are activated by specific pattern
recognition receptors (PRRs) that sense microorganisms
and infectious agents and signal a defensive response.
There are four major subfamilies of PRRs: toll-like
receptors (TLRs), LRR-containing receptors, RIG-1-like
receptors, and C-type lectin receptors.
TLRs mediate responses to distinct microbial components
derived from pathogens, such as bacterial lipoproteins and
bacterial LPS.
TLRs are widely distributed in immune cells and body cells,
triggering antigen presenting cell activation and signaling cascades
to fend off microbial invaders or repair damaged tissue.
Excessive activation of TLRs can disrupt immune homeostasis,
leading to increased risk of inflammatory diseases and autoimmune
disorders.
This is particularly evident in metabolic endo toxaemia, where high-
fat diet and weight gain are associated with higher gut permeability
and systemic elevation in circulating plasma LPS.
LPS from different bacteria impact gut-barrier function,
inflammation, glucose absorption, and host metabolism.
Metabolic endo toxaemia levels affect host metabolism
based on gut microbiota composition.
Disruption of PRRs expression leads to inflammation-
promoting microbiota alterations, such as TLR5
deficiency.
TLR activation relies on MyD88 protein, an essential
adaptor protein for all TLRs.

Deletion of MyD88 in the intestines partially protects

against diet-induced obesity, diabetes, and inflammation.
METABOLISM OF BILEACIDS
Primary bile acids (BAs) are amphipathic molecules
synthesised in the liver from cholesterol and are
released into the small intestine for digestion and
absorption.
BAs also serve an endocrine function as signaling
molecules, modulating epithelial cell proliferation, gene
expression, lipid, glucose, and energy metabolism by
activating several receptors.
Primary beta-amylases (BAs) can be modified by gut microbes along
the intestinal tract, leading to the formation of secondary BAs like
deoxycholic acid, lithocholic acid, and urso deoxycholic acid.

These bacterial metabolism changes the bioavailability and

bioactivities of BAs, impacting their metabolic responses

.BAs are considered microbiota-derived signaling metabolites due

to their signaling capacities.
Key bacteria and their specific
molecules
Unique host signaling molecules has been found in
potentially symbiotic gut bacteria, such as
immunomodulatory polysaccharides and sphingolipids
Produced by Bacteroides spp and muropeptides formed
by Enterococcus
Example: Probiotics - L. acidophilus , L. rhamnosus GG,
and Bifidobacterium spp.ClpB, an antigen-mimetic of
alpha-melanocyte stimulating hormone( increases satiety
via increased plasma GLP-1 and PYY production.)
Newly identified molecules, impact on
health and their targets
Enterosynes- newly identified molecules from gut
microbiota
Defined as molecules originating from the gut which
have the capacity to modulate duodenal contraction by
targeting the enteric nervous system (ENS).
Enterosynes can be chemically diverse and related to
hormones, bioactive peptides/lipids, nutrients,
microbiota and immune factors'.
 Examples: Fructoselysine, an advanced glycation end
product (AGE), trimethylamine N-oxide (TMAO) and
imidazole propionate (IMP).
AGEs are Maillard reaction products formed in our foods
by thermal processing when free amino groups of
proteins and amino acids react with reducing
carbohydrates, forming compounds that are poorly
bioavailable.
TMAO is a metabolite produced by gut bacteria, such as
Proteobacteria, that convert quaternary amines like
betaine, choline, and L-carnitine into acetaldehyde and
trimethylamine (TMA).

These metabolites are associated with atherosclerosis,

cardiovascular risks, and the formation of atherosclerotic
plaques.
IMP is produced from histidine by intestinal bacteria that
impaired insulin signaling and glucose tolerance.
Streptococcus mutans and Eggerthella lenta, have been
identified as IMP producers
Thus confirming the involvement of intestinal bacteria in
generating undesired compounds and discovering new
anaerobes that may detoxify and convert these
compounds into beneficial signaling products.
SHORT CHAIN FATTY ACIDS
Short-chain fatty acids (SCFAs) are the main end
products of the metabolism of bacteria attached to
surfaces of the intestinal lumen.
SCFAs include: acetic acid (C2: 0), propionic acid (C3: 0),
butyric acid(C4: 0), valeric acid (C5: 0) and caproic acid
(C6: 0).
SCFAs provide about 10% of the caloric requirement in
humans [4], affecting inter alia, brown adipose tissue,
mitochondrial functions in the liver and appetite control
[1].
Fermentation of carbohydrates (polysaccharides and
oligosaccharides) in the proximal part of the colon by
saccharolytic bacteria leads to:
the linear production of short-chain fatty acids (n-
SCFAs),
H2 and CO2, while the fermentation of amino acids or
proteins is associated with branched SCFAs (BSCFAs), H2,
CO2, CH4, phenols and amines production.
 Acetic Acid
Acetic acid is the most abundant SCFA in the human colon
and accounts for over 50–60% of SCFAs content.
Acetic acid production is mediated by homoacetogenic
bacteria or gastrointestinal acetogens capable of
producing acetate from H2 and CO2.
Acetic acid is the main substrate in the synthesis of
cholesterol.
PROPIONIC ACID
The main producer of propionic acid is bacteria of the
genus Bacteroides, Fimicutes and Lachnospiraceae.
The clinical effect of propionic acid on the lipid
metabolism manifests itself in the form of a reduction in
cholesterol concentrations and a reduction in fat
storage; it also has anti-cancer and anti-inflammatory
activity.
PREGNANCY
Changes in the Intestinal Microbiota during Pregnancy
Dietary fiber provided with the diet plays a key role in
shaping the human microbiome.
The adult human gut is colonized by at least 1800 genera
and approximately 15–36,000 species of bacteria.
Pregnancy has been shown to influence the composition
of the maternal gut microbiome, which differs in the first
and third trimester of gestation .
During the first trimester of pregnancy, the composition
of the gut microbes is similar to that of healthy, non-
pregnant women.
From the first to the third trimester, the composition of
the intestinal microflora changes significantly .
The intestinal microflora in women in the third trimester
of pregnancy show higher proportions of phylum
Proteobacteria strains associated with inflammation
.Between the first to the third trimester, the number of
Bifidobacteria, Proteobacteria and lactic acid-producing
bacteria increases, while the number of butyrate-
producing bacteria is decreased .
The persistence of microbiotainduced changes in the
composition of various factors (dysbiosis) may be
associated with detrimental long-term effects, leading to
diseases such as obesity, enteritis, diabetes and
metabolic syndrome in the host organism and offspring .
It is possible that human intestinal microflora play a role
in the regulation of nutrient metabolism, and dysbiosis
may be associated with an increased acquisition of
energy resources .
Pregnancy leads to gut microbiome changes in women
with diet-induced obesity, resulting in inflammatory
processes, altered levels of soluble fatty acids (SCFAs),
and metabolic actions.
Acetic acid is the dominant SCFA in pregnant women and
their infants, with the highest concentrations observed
in three-month-olds.
Increased maternal serum SCFAs may positively affect
weight gain, glucose metabolism, and metabolic
hormone levels.