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 Background
• Diet and lifestyle have a crucial influence on the health
status of humans
• Various metabolic syndromes represent diet-induced
diseases (one of the largest global health problems)
• A growing list of publications
– the gut microbiota, i.e., the community of microorganisms residing
in the GIT, as one of the major players involved in the development
of certain metabolic syndromes
• several studies :
– diet, and thus nutrient availability, modulates the composition and
activity of the gut microbiota

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• recent metagenomics-based studies :
– gut microbiota as an environmental factor influencing whole-body
metabolism by affecting not only energy balance but also immune
and gut barrier functions

• The human gut is considered a bioreactor with a huge

diversity of bacterial taxa, predominantly belonging to
the Firmicutes and Bacteroidetes phyla and shaped by
different environmental parameters.

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• Dysbioisis :
– Disruption of the state of homeostasis among members
of the gut microbiota  cause imbalances among
bacterial communities  residing in the intestine
– frequently associated with the development of a variety
of diseases ranging from localized gastroenterological
disorders to neurological, respiratory, metabolic,
hepatic, and cardiovascular illnesses

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 The etiology of obesity
• Obesity and overweight :
– abnormal or excessive fat accumulation, resulting from an amount
of ingested energy that is higher than the amount expended
– WHO : overweight  BMI between 25.0 and 29.9 kg/m2
obese  BMI greater or equal to 30.0 kg/m2
• The worldwide prevalence of obesity has doubled during
the last 30 years
• WHO : obesity as a current global epidemic
• In 2014, about 1.9 billion adults were deemed to be
overweight
• Childhood obesity has increased in infants and young
children
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• Etiology of obesity is multifactorial and environmental
 dietary, genetic, pathological, and lifestyle factors,
 individual contributions may not always be fully
understood.
• There is a strict correlation between diet, microbiota, and
obesity
• The gut microbiota has been shown to regulate energy
metabolism and fat storage, and is believed to be a driving
force in the development of metabolic disorders associated
with obesity

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 Obesity and diet
• Obesity and metabolic syndrome in general are influenced
by many physiological factors that are strongly associated
with diet and lifestyle, in addition to genetic and
environmental factors
• Before the development of agriculture and animal
husbandry, human diet was necessarily limited to wild
plants, berries, roots, and raw animal foods.
• The ongoing westernization, urbanization, and
mechanization processes have resulted in a population
with a sedentary lifestyle and a high fat content, high
energy-dense diet that replace the traditional diets that are
rich in complex carbohydrates and fibers
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• a diet in which fat represents more than 30% of its total
energy contributes to the development of obesity
• In a high fat diet (HFD) = typical western USA diet:
– carbohydrate (51.8%), fat (32.8%), and protein (15.4%)
– with high levels of refined sugars, refined vegetable oils, and salt

• The modified fatty acid composition of a western diet,

which is usually rich in saturated and trans fatty acids,
increases the risk of chronic vascular disease by elevating
(blood serum) concentrations of total and LDL-cholesterol

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• Diets low in potassium and high in sodium may lead to a
variety of chronic illnesses, including hypertension, stroke,
kidney stones, and cancers of the gastrointestinal tract
• Dietary fibers :
– reduce total and LDL-cholesterol by delaying gastric emptying,
which may reduce appetite and thus help to control caloric intake
– Eg. Inulin, resistant starch, and beta-glucans are important dietary
fibers, which have been well studied and shown to modulate gut
microbiota
– Inulin has been reported to regulate GI motility and appetite,
reduce fat mass accumulation, and affect adipose tissue
metabolism

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• Ingestion of resistant starch and beta-glucans causes a
satiating effect
• Sufficient fiber intake should amount to 25–30 g/day,
while in a typical western diet this is about 15 g/day

• The change from a traditional diet to a western diet may

alter the gut microbiota composition, thereby influencing
various aspects of human health because of the strong
correlation between diet and gut microbiota

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 Diet and microbiota

• The diet represents one of the most important factors that

determine gut microbiota composition
• The gut microbiota :
– now considered an organ, which regulates numerous physiological
pathways and affects different host functions

• A substantial portion of gut physiology, including the

modulation of gut motility, intestinal barrier homeostasis,
nutrient absorption, and fat distribution, is believed to be
influenced by the mutualistic relationship between
intestinal microorganisms and their human host.

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• David et al. :
– human gut microbiota is rapidly modified by dietary changes.
Different gut microbiota assemblies were shown to possess a
varying capacity to produce particular metabolites, including SCFA,
such as butyrate, phenolic acids, and branched-chain fatty acids
• Arumugam et al:
– introduced a number of distinct gut microbial profiles, called
enterotypes, which are currently believed to encompass three
different microbial patterns dominated by Prevotella, Bacteroides,
or Ruminococcus that are not restricted to a specific geographical
origin

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• Enterotypes : influenced by the diet followed by the host.
• individuals following a diet rich in protein and animal fat
are associated with the Bacteroides enterotype,
while Prevotella dominated individuals ingesting more
carbohydrates
• Only a limited number of well-balanced host-microbial
symbiotic states exist that may respond differently to diet
and drug intake

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• RS-based diet :
– provoke increased abundance of Ruminococcus bromii, as well as
uncultured Oscillabacter and Eubacteria rectale
• Inulin-based diet members belonging to
the Bifidobacterium genus and Atopobium group were
shown to undergo a significant increase in abundance,
while members of the Bacteroides/Prevotella groups
showed a reduction in relative numbers
• HFD :
– modification of the gut microbiota composition and a stimulation of
the bile acid secretion and increased fecal concentration of
secondary bile acids

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 Links between obesity and host genetics

• Host genetics has a direct influence on various metabolic

syndromes, such as diabetes and obesity.
• Several studies in mice as well as in humans have revealed
specific associations between host genotype and
microbiota composition
• Leptin, i.e., the so-called satiety hormone :
– plays different roles in human physiology by regulating appetite
and body weight, and insulin secretion
– Different studies have demonstrated that leptin genes (lep) and the
corresponding leptin receptor (LEPR) exert a specific effect on the
gut microbiota composition

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• apoA1
– Another gene that was shown to be involved in obesity as well as in
cardiovascular disease
– encodes for the Apoliprotein A1, and mutation of which increases
the development of these diseases/metabolic disorders
– polymorphism of the apoA1 gene has been correlated with a
different gut microbiota composition in mice, characterized by an
enrichment of Desulfovibrionaceae and a depletion of members of
the Bifidobacteriaceae family

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• Human phospholipase D1-encoding gene (pld1)
– The gene product of pld1 was shown to provoke glycerol
phospholipid hydrolysis with the concomitant production of
phosphatidic acid, which is an intracellular messenger implicated
in several cellular processes, including obesity
– SNPs of pld1 gene were associated with abundance levels of
genus Akkermansia muciniphila It has been proposed that a lower
abundance of A. muciniphila may induce the development of
obesity in mice [
• Existence of correlations between a polymorphism of PLD1
and this bacterial taxon may represent an example of how
host-associated genotype that is responsible for a specific
gut microbiota profile, ultimately influencing the
development of obesity.
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 Microbiota and obesity

• High number of different microbial phylotypes present in

healthy adult subjects, plays an important role in
maintaining immune homeostasis
• Differences in the gut microbiota between lean and obese
animals :
– microbiota, which is able to extract more energy from a given diet,
is typified by a reduced presence of taxa belonging to
the Bacteroidetes phylum and a proportional increase in members
of the Firmicutes phylum
– The alteration of the microbiota equilibrium
between Firmicutes and Bacteroidetes, with the increase of one
phylum with respect to the other, was shown to be associated with
a higher presence of enzymes for (complex) carbohydrate
degradation and fermentation [
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• a specific bacterial taxon was demonstrated to be
associated with obesity, i.e., Christensenellaceae spp., and
proposed as a novel microbial biomarker for obesity
– The member of this family was shown to reduce weight gain in
mice and to modulate the gut microbiota composition

• obesity is correlated with a microbiota exhibiting an

imbalanced Firmicutes/Bacteroidetes ratio, associated with
an increase in Actinobacteria phylum and a decrease
of Verrucomicrobia

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• recent clinical study (263 individuals : 134 obese, 38
overweight, 76 lean, and 15 anorexic)
– importance of a small number of microbial biomarkers that are
linked to obesity, encompassing Bacteroidetes, Firmicutes, M.
smithii, Escherichia coli, and various Lactobacillus species
• mycobiome of obese subjects :
– increased presence of the phylum Ascomycota, the
class Saccharomycetes, and the
families Dipodascaceae and Saccharomycetaceae,
– fungi belonging to class Tremellomycetes, as compared with non-
obese individuals
• Mucor racemosus and Mucor fuscus were more
represented in non-obese individuals compared to obese
– relative abundance of the Mucor genus increased after weight loss
in obese subjects in a manner analogous to Bacteroidetes

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 Early microbe contact and the risk of obesity

• The intestinal microbiota of neonates typically exhibits low

diversity and a relative dominance of the
phyla Proteobacteria and Actinobacteria

• Several factors, such as gestational age, diet (e.g., breast

milk vs. formula milk), sanitation, and antibiotic treatment
are thought to influence the gut microbiota development
and composition with the emergence and dominance of
members of the Firmicutes and Bacteroidetes and
reductions of other phyla, such
as Proteobacteria and Actinobacteria

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• one study : a child born from an obese mother possesses
different levels
of Faecalibacterium spp., Oscillabacter spp., Blautia spp.,
and Eubacterium spp. compared to a child born from a lean
mother

• the presence of a low concentration of Bacteroides spp. and

a high level of Lactobacillus spp. in the newborn during the
first 3 months of life may cause child obesity and
overweight

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• biodiversity of the infant gut microbiota is influenced not
only by the maternal health status, mode of delivery,
gestational age of the mother, and weight gain during
pregnancy but also by maternal BMI

• breast milk of obese mothers is characterized by a reduced

microbiota diversity and distinct microbiota composition
as compared to that from lean mothers, which was shown
to contain a higher abundance of Bifidobacterium and
lower counts of Staphylococcus

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• increased presence of Bifidobacteriumspp. during the early
stages of life may provide protection against overweight
and obesity

• Another factor that may influence the development of

pediatric obesity is exposure to antibiotics in early stages
of life

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 Probiotic bacteria and prebiotic in prevention
and treatment of obesity
• Modulation of gut microbiota through the use of prebiotics
and probiotics are claimed as possible strategies for the
prevention of weight gain in obese-prone subjects and a
non-invasive treatment for those individuals suffering
from severe obesity.
• probiotics are health-promoting microorganisms
– FAO/WHO : “live microorganisms that after ingestion confer health
benefits to the host maintaining the gut microbiota correct
equilibrium”
– a definition recently updated as follows: “live microorganisms that,
when administered in adequate amounts, confer a health benefit on
the host”
– Bifidobacterium and Lactobacillus
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• In a small number of cases
– the role of particular Lactobacillus species on the modification of
the body weight, both in animals and human beings, has been
assessed
– the resulting data are rather contradictory and variable depending
on the species as well as the strains involved
– probiotic therapy based on Lactobacillus rhamnosus, Lactobacillus
delbrueckii, and L. reuteri was shown to result in weight increase
perhaps because of their pro-inflammatory effects
– other Lactobacillus species, such as Lactobacillus
fermentum and Lactobacillus gasseri were associated with weight
loss.
– Lactobacillus sporogenes, showed no significant effects on weight

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• Bifidobacterium pseudocatenulatum, Bifidobacterium
longum, and Bifidobacterium adolescentis have been shown
to reduce body weight and blood serum levels (i.e., total
cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride,
glucose, leptin and lipase levels)

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 Preclinical and clinical studies based on
probiotic therapy
• mice receiving an HFD for 12 weeks combined with a
probiotic mixture encompassing both lactobacilli
(Lactobacillus paracasei CNCM I-4270, L. rhamnosus I-
3690) and bifidobacteria (Bifidobacterium
animalis subsp. lactisI-2494)
– All strains significantly attenuated HFD-induced weight gain,
improved glucose–insulin homeostasis, and reduced hepatic
steatosis

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• diet-induced obese C57BL/6J mice treated
with Lactobacillus curvatus HY7601 and Lactobacillus
plantarum KY1032 for 10 weeks
– reduced body weight gain and fat accumulation,
– lowered levels of plasma insulin, leptin, total-cholesterol, and liver
toxicity biomarkers.

• treatments with certain probiotic bacteria may counteract

diet-induced obesity and modulate genes associated with
metabolism and inflammation in the liver and adipose
tissue

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• L. rhamnosus GG can protect animals from HFD-induced
insulin resistance, as well as attenuate adiposity in the
liver and mesenteric adipose tissue

• A significant reduction of total body and visceral adipose

tissue weight, together with improvement in insulin
sensitivity was observed in Wistar rats following a short-
term treatment with probiotic mixtures containing a
concentrated biomass of 14 probiotic bacteria belonging to
the genera Bifidobacterium, Lactobacillus, Lactococcus,
and Propionibacterium

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• The effectiveness of probiotic therapy in the
control/reduction of body weight was evaluated not only
in animal experiments but also in human clinical trials. In
this context, a group of women with excess body weight or
obese phenotype (25< BMI <40) were enrolled for a
randomized, double-blind trial to receive a probiotic mix
based on L. acidophilus and L. casei, Lactococcus lactis, B.
bifidum, and Bifidobacterium lactis for 8 weeks.
Supplementation with a probiotic mix reduced abdominal
fat and increased antioxidant enzyme activity as compared
to dietary intervention alone

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• other microorganisms, sometimes referred to as the next
generation probiotics and belonging to A.
muciniphila, Pediococcus pentosaceus , Saccharomyces
boulardii, and Bacteroides uniformis have been evaluated
for their potential anti-obesity effects.
• A clinical trial involving a dietary intervention of 49
overweight and obese adults
– significant association between A. muciniphila abundance and
metabolic health
– subjects with higher gene richness and A. muciniphila abundance
exhibited the healthiest metabolic status, particularly in fasting
plasma glucose, plasma triglycerides, and body fat distribution

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• several preclinical and a small
number of clinical studies
involving different bacterial
strains have been performed,
showing that nearly all tested
strains elicited varying anti-
obese effects.

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 Preclinical and clinical studies using prebiotics

• Prebiotics are considered to exert anti-obesity activities

through the selective modulation of specific
microorganisms of the human gut microbiota. However,
the underlying molecular mechanisms driving this
response are far from being completely understood.
• Recently, the intervention with dietary inulin-type fructans
(ITF) in 30 obese women for 3 months (16 g/day) :
– modified the gut microbiota composition, without provoking any
significant change in host metabolism, and ultimately did not cause
a significant effect on body weight
• treatment with ITF, but not the placebo, led to an increase
in Bifidobacterium and Faecalibacterium prausnitzii
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• Prebiotic supplementation has been shown to influence
not only appetite perception and fat mass storage but also
host energy homeostasis.
• Prebiotics seem to mediate microbial SCFA production,
which has multiple roles in host homeostasis
• prebiotics that are able to preferably stimulate the
production of propionate and butyrate, as opposed to
acetate, are of particular interest, since acetate constitutes
a lipogenic and cholesterogenic substrate in the liver, while
the production of propionate may decrease the hepatic
lipogenic potential

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 Conclusions
• recent studies have also revealed the key role of the
microbiota in the incidence and severity of this metabolic
disorder. However, many details of the complex
relationship that exists between microbiota, diet, and host
remain to be unraveled
• There is an urgent need for dietary interventions that
provide unambiguous proof of the effectiveness of various
dietary supplements (prebiotics and/or probiotics) with
regards to modulation of the gut microbiota composition
and/or metabolic activity to ultimately improve human
health in the context of obesity

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