Microbiota Intestinal Obesidad y Diabetes

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Interactions Between Gut

Microbiota and Host
Metabolism Predisposing
to Obesity and Diabetes
Giovanni Musso,1 Roberto Gambino,2
and Maurizio Cassader2
1
Gradenigo Hospital, Turin, Italy; email: giovanni_musso@yahoo.it
Department of Internal Medicine, University of Turin, Italy
Annu. Rev. Med. 2011. 62:36180
Keywords
The Annual Review of Medicine is online at

med.annualreviews.org
microbiome, gut flora, endotoxin, energy homeostasis, TLR4
This articles doi:

10.1146/annurev-med-012510-175505
Abstract
c 2011 by Annual Reviews.

Copyright
All rights reserved
0066-4219/11/0218-0361$20.00
Novel, culture-independent, molecular and metagenomic techniques

have provided new insight into the complex interactions between the
mammalian host and gut microbial species. It is increasingly evident that
gut microbes may shape the host metabolic and immune network activity and ultimately influence the development of obesity and diabetes.
We discuss the evidence connecting gut microflora to obesity and to
type 1 and type 2 diabetes, and we present recent insights into potential
mechanisms underlying this relationship: increased nutrient absorption from the diet, prolonged intestinal transit time, altered bile acid
entero-hepatic cycle, increased cellular uptake of circulating triglycerides, enhanced de novo lipogenesis, reduced free fatty acid oxidation,
altered tissue composition of biologically active polyunsaturated fatty
acid, chronic low-grade inflammation triggered by the endotoxin tolllike receptor 4 axis, and altered intestinal barrier function.
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INTRODUCTION
Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

Recent research has disclosed a tight and coordinated connection between gut microbes
and host metabolism, energy utilization, and
storage. The gut microbial community comprises trillions of microorganisms, reaching a
cell number that is an order of magnitude
greater than all the eukaryotic cells of the
host. The collective genome of these microorganisms (the microbiome) exceeds the size
of the human nuclear genome by two orders
of magnitude, contributing a broad range of
biochemical and metabolic functions that the
host could not otherwise perform (1). Furthermore, unlike its hosts genome, the collective
genome of the microorganisms can dynamically change the configuration of its components to adapt to the needs of its individual
constituents, of the community as a whole, and
of the host, whose environment varies widely
in response to factors such as dietary nutrients,
illness, and antibiotic use. Dynamic changes in
microbial genomic and metabolic diversity are
the subject of metagenomics and metabolomics,
and the examples of obesity and diabetes illustrate the interactions between the mammalian
host and its dynamic symbionts. In this review, we discuss advances in understanding the
mechanisms of the interaction of gut microbiota with their host and how this interaction may predispose to obesity and associated
disorders.
ALTERED GUT MICROBIOTA

COMPOSITION IN ANIMAL
AND HUMAN OBESITY
The relationship between obesity and gut
microbiota composition was known as early
as three decades ago, when surgically induced
weight loss through bypass surgery or weight
gain through lesion of the ventromedial hypothalamic nucleus was associated with changes
in gut microbial ecology (2, 3). To survey the
intestinal microbiota, those studies utilized
culture-dependent methods, which detect no
more than 30% of the microbes harbored
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in the gut owing to intrinsic limitations: the

unknown growth requirements of the bacteria,
the selectivity of the culture media, the need
of several species for strict anaerobic growing
conditions, and the difficulty of simulating
the reciprocal interactions between different
microbial communities and between bacteria
and the host environment (4). However, in
recent years the ability to obtain a thorough
picture of gut microbial communities has been
consistently improved by the introduction of
molecular, culture-independent techniques
based on ribosomal 16S sequencing, including
fluorescent in situ hybridization (FISH),
fragment restriction length polymorphism
(RFLP) mapping, competitive and quantitative
PCR, denaturing (or temperature) gradient
gel electrophoresis (DGGE/TGGE), shotgun
sequencing DNA, and whole metagenomic
analyses (5). These techniques have revealed
that the great majority of mammalian gut
microbiota belong to three bacterial phyla: the
Gram-negative Bacteroidetes, and the Grampositive Actinobacteria and Firmicutes. Firmicutes
comprises >200 genera, including Lactobacillus,
Clostridium, Bacillus, and Mycoplasma.
Far from being a static ecosystem, the
identity and gene content of individual members of these phyla continually and rapidly
shift in response to changes in host adiposity
and nutrient intake. For example, genetically
obese leptin-deficient ob/ob mice harbor a
significantly higher percentage of Firmicutes,
and a 50% lower percentage of Bacteroidetes in
their distal gut, compared to their wild-type
littermates fed the same polysaccharide-rich
diet (6). Also, the development of obesity is
associated with an enrichment in Firmicutes at
the expense of Bacteroidetes in mice fed a highfat/high-sugar Western diet, as compared with
mice receiving a low-fat/high-polysaccharide
diet (7). Unlike the genetic ob/ob obesity, this
shift is not phylum-wide, with the expansion
of Firmicutes due to a bloom in a single clade
of the Firmicutesthe Mollicutes. Beside compositional changes, plasticity was evident at the
genome level, due to selection or horizontal
gene transfer: In obese mice, the microbiome

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showed an enrichment in genes coding for enzymes that enable the extraction of energy from
otherwise indigestible alimentary polysaccharides, including glycoside hydrolases,
phosphotransferases, -fructosidase, and other
transport proteins and fermentation enzymes.
Collectively, these data suggest the gut microflora in obese individuals have an increased
capacity to harvest energy from the host diet.
Consistent with animal models, the increase
in Firmicutes/Bacteroidetes ratio has also been observed in obese humans compared to lean controls. The increase was reversed by surgically
induced or diet-induced weight loss, the latter
irrespective of the type of diet (fat or carbohydrate restricted) (813). Type 2 diabetes seems
also to be associated with changes in gut microbial composition, regardless of body weight
(14, 15).
These human studies confirmed animal data
suggesting that gut microbiota composition is
associated with obesity, but they did not prove
causality between gut microbes and the development of obesity. The human studies were
cross-sectional and, unlike the animal studies,
did not control for confounders that may impact both microbiota composition and obesity,
such as diet composition. One study tried to
prospectively assess gut microbiota in infants
subsequently developing obesity (16), finding
that children who became overweight by age
seven had a lower proportion of Bifidobacteria
and higher levels of Staphylococcus aureus in their
infancy than children who remained lean. Unfortunately, factors such as dietary composition
and physical activity were not evaluated.
Despite omitting these confounders, these
studies suggest that understanding the factors modulating gut microbiota composition
may have etiologic, preventive, or therapeutic implications for adult metabolic disorders.
Studies in resistin-like molecule knockout
(RELM KO) mice, which are resistant to
high-fat-induced obesity, have demonstrated
the importance of diet and antibiotic use. When
RELM KO and RELM wild-type mice were
switched from a standard diet to a high-fat diet,
both groups underwent similar changes in gut
microbiota composition, indicating that effects of diet dominated over the obese phenotype (17). Antibiotics can also pervasively affect
gut microbiota composition: A five-day course
of orally administered ciprofloxacin decreased
substantially the diversity of the fecal microbial
community (18). Recovery of the community
was evident within four weeks, but some genera
did not reappear for up to six months after treatment. As a therapeutic application, ob/ob and
diet-induced obese mice treated with a combination of norfloxacin and ampicillin showed
marked changes in gut microbial species and
improved insulin sensitivity, fasting glycemia,
and oral glucose tolerance (19, 20).
In the following sections, we examine potential mechanisms whereby gut microbes can
affect host metabolism and energy storage,
thereby predisposing to obesity and diabetes.
MICROBE-HOST INTERACTIONS
IN CARBOHYDRATE
METABOLISM
Carbohydrates (CHO) are a crucial nutritional
component for mammals, as well as for their gut
microbiota. Mammals absorb simple sugars, including galactose and glucose, in the proximal
jejunum; they can hydrolyze disaccharides (sucrose, lactose, and maltose) to their constituent
monosaccharides and can also degrade starch to
monosaccharides but have a limited ability to
hydrolyze other polysaccharides (21). As a consequence, every day a bulk of undigested plant
polysaccharides (cellulose, xylan, and pectin)
and partially digested starch reaches the distal gut microbial community. By hosting a microbiota able to hydrolyze these carbohydrates,
mammals avoid the need to evolve the complex
enzymatic repertoire required to break down
the wide variety of linkages of these polysaccharides; the microbes gain access to abundant,
readily fermentable carbon sources otherwise
wasted by the host.
Microbial Degradation of Starch

The anaerobe Bacteroides, among the most
abundant genera in the distal human gut, can
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degrade and ferment a great variety of polysaccharides, including starch, xylan, and psyllium
hydrocolloid (21, 22). The starch utilization
system (sus) of B. thetaiotaomicron, a prominent
saccharolytic bacterium in the normal distal gut
a
susR
SusR
susA
susB
susC
susD
susE
susF
Promoter
Besides their capacity to hydrolyze starch, gut

microbes have developed the ability to degrade
Figure 1
Transcriptional
activator
Maltose (or larger
oligosaccharide)

Microbial Degradation of
Host-Derived Glycans
SusR
Starch
-amylase
(SusG)
Porin
Starch-binding
complex (SusCF)
Cytoplasm
Glucose
monomers
-amylase
(SusA)
-glucosidase
(SusB)
Periplasmic space
Bacteroides thetaiotaomicron
susG
microbiota, is the most extensively studied example of polysaccharide utilization (21, 23, 24,
33) (Figure 1a).
CsuF (chondroitin
sulfate/hyaluronate
binding protein)
Chondroitin
sulfate
Chondroitin
sulfate lyases
-glucuronidase
Cytoplasm
Monosaccharides
Periplasmic space
Bacteroides thetaiotaomicron
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Disaccharides
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(a) Model of Bacteroides thetaiotaomicron starch

utilization. Eight starch-utilization genes have been
identified. Seven genes (susAsusG) encode proteins
that mediate the initial utilization steps (23); susCF
are outer membrane proteins that interact to form a
complex that mediates binding of starch to the bacterial cell surface (21). Bound starch is then hydrolyzed
at 1,4 and 1,6 linkages by -amylases (encoded
by susA and susG) to yield smaller oligosaccharide
products, which are eventually broken down to
glucose monomers by an -glucosidase (susB) (24).
By binding starch to its outer membrane prior to
initiating hydrolysis, B. thetaiotaomicron can degrade
a large polymer into oligosaccharides small enough
to pass through outer membrane porins without
losing these digestion products to nearby competing
microbes (21). Importantly for the energy harvest
from the diet of both microbe and host (see text), this
system is highly inducible by target polysaccharides.
An eighth gene, susR, encodes a transcriptional
activator that responds to the presence of maltose or
larger oligosaccharides by increasing transcription
of susAsusG (21). Thus, the starch-degrading
complex of B. thetaiotaomicron is expressed only if
glucose oligomers are available in the gut ecosystem.
Redrawn with permission from Reference 21.
(b) Model of Bacteroides thetaiotaomicron chondroitin
sulfate/hyaluronate utilization. Like starch,
chrondroitin sulfate and hyaluronate are too large to
enter the cell through membrane porins. Therefore,
both are first bound to the bacterial outer membrane
by a csuF-encoded outer membrane protein,
and then degraded to disaccharides in the periplasm
by chondroitin lyases I and II. Finally, a cytoplasmic
-glucuronidase cleaves the disaccharides to yield
monosaccharides. The chondroitin sulfate and
hyaluronate-utilization pathways are biochemically
distinct, but, like the expression of the starchutilization pathway, the expression of their genetic
pathways is controlled by chuR and is induced only
in the presence of chondroitin sulfate or
hyaluronate, or their component disaccharides.
Redrawn with permission from Reference 21.

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numerous plant- and host-derived glycoconjugates (glycans) including cellulose, chondroitin

sulfate, hyaluronic acid, mucin, and heparin.
The chondroitin sulfate and hyaluronate degradation pathways of B. thetaiotaomicron have been
extensively studied and resemble those of the
starch-utilization system (Figure 1b) (25).
B. thetaiotaomicrons ability to utilize these
host glycans appears to be critical for its survival
in the intestinal ecosystem. The genetic deletion of chuR prevents the mutant strain from
successfully competing with a wild-type strain
in cocolonization studies of germ-free hosts
(26).
Mucins and glycosphingolipids can also be
degraded by secreted bacterial hydrolases (glycosidases). Mucins are high-molecular-weight,
heavily glycosylated glycoproteins produced by
goblet cells, which help maintain the integrity
of the mucosal barrier (21). Commensal bacteria are equipped with a number of enzymes for
breaking down and utilizing the oligosaccharide side chains of host mucins. As these chains
typically have very heterogeneous and complex
structures, with diverse monosaccharide components connected by a variety of glycosidic
linkages, mucin degradation often requires the
participation of several bacterial species, each
of which expresses part but not all the required
glycosidases. However, some Bacteroides and Bifidobacterium members can completely degrade
these side chains.
Glycosphingolipids have oligosaccharide
side chains bound to a lipid ceramide group.
Glycosphingolipids on shed intestinal epithelial
cells are progressively degraded in the intestinal lumen (21). In humans, there is evidence
of selection for bacteria that are able to hydrolyze the oligosaccharide chains of glycosphingolipids produced by the individual they colonize: Hoskins & Boulding found that the fecal
flora (mainly Bifidobacterium and Ruminococcus)
of adults with the histo-blood group A phenotype degrade A but not B antigens, whereas
the fecal flora of individuals with the histoblood group B phenotype degrade B but not
A (27). Host glycans are therefore a useful nutrient source for B. thetaiotaomicron and other
bacterial species, as they are constantly replenished due to epithelial cell turnover. Upon
degradation they are readily fermented to yield
carbon and energy; and competition for these
glycans is limited because they are degraded by
only some bacterial species (21).
Host Utilization of Gut

Microbe-Derived
Fermentation Products
Monosaccharides released from complexpolysaccharide breakdown are converted by
bacteria to pyruvate via glycolysis, yielding a net
production of adenosine triphosphate (ATP).
In the highly anaerobic distal gut lumen, further carbon and energy are extracted from pyruvate by microbial fermentation. To recover
part of the nutritional value of microbially degraded polysaccharides, mammals have developed mechanisms for absorbing and utilizing
products of bacterial fermentation. The major
end-products of bacterial fermentation in the
gut are short-chain fatty acids (SCFAs), specifically acetate, propionate, and butyrate. Highly
fermentable polysaccharides yield a high propionate:acetate ratio, whereas prevalent fiber intake increases the proportion of acetate (28).
In humans, the molar ratio of these three
SCFAs is 70:20:10, with an overall concentration of 70120 mM, depending on dietary composition (29). Conversion of pyruvate to any
of these SCFAs yields an additional molecule
of ATP. Even after microbial extraction of
ATP, SCFA production appears to represent
60%75% of the energy content of ingested
carbohydrate (30). Host recovery of SCFAs is
generally efficient and occurs both by passive
diffusion and via mono-carboxylic acid transporters (e.g., MCT1 in the case of butyrate and
lactate). Acetate, propionate, and butyrate are
each ultimately taken up by different organs and
have different metabolic fates. Butyrate is the
preferred source of energy for colonic epithelial
cells, where it is converted to ketone bodies or
oxidized to carbon dioxide (31). The colonic epithelium derives 60%70% of its energy needs
from butyrate, as suggested from studies on
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isolated colonocytes (30). Absorbed acetate and

propionate are delivered to hepatocytes, which
use most of the propionate for gluconeogenesis. Although acetate can be used for lipogenesis
in colonocytes, hepatocytes and adipocytes are
the principal sites for de novo lipogenesis, at
least in rodents, where 7% of the synthesized
glucose is derived from colonic propionate and
80% of colonic propionate is used for lipogenesis (28, 32). The relative levels of acetyl-CoA,
propionyl-CoA, and butyryl-CoA synthetases
in different tissues appear to determine which
tissue metabolizes which SCFA (32).
In humans, the exact amounts and types of
carbohydrate that reach the colon are unknown.
They probably approach 40 g/day in countries
with Westernized diets, whereas they may
reach 5060 g/day where diets are high in fruit
and vegetables. The fermentation of 5060 g of
carbohydrates yields 0.50.6 mol of SCFA, with
a total energy value of 140180 kcal (10%
of the maintenance caloric requirement). However, human diets vary widely in their amount
of fiber, and comparative studies demonstrated
this greatly affects the amount and type of SCFA
produced, as well as the composition of colonic
fermenting bacterial species. When obese subjects consumed diets with normal, reduced, or
dramatically reduced carbohydrate content, fecal concentrations of the three major SCFAs
decreased with reduced total carbohydrate intake, but in particular, the concentration of butyrate decreased from 17.7 to 4.4 mmol L1 . In
parallel, the proportion of the cluster XIVa subgroup Roseburia/Eubacterium rectale decreased
on average from 11.4% to 3.3% of total bacteria detected between the highest and lowest
carbohydrate intakes. This tends to confirm a
dominant role for this group of bacteria in the
formation of butyrate in the colon, while also
indicating that the Roseburia/E. rectale group is
particularly dependent on residual dietary carbohydrate to maintain its competitiveness in
the colon (33). In another study comparing the
effects of energy-restricted diets with different
carbohydrate and fiber contents in obese subjects, patients on low-carbohydrate diets had a
significant reduction in fecal output, defecation

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frequency, fecal excretion and concentrations

of butyrate, and counts of Bifidobacteria (34).
In addition to their nutritional value,
SCFAs have important effects on other aspects
of gut physiology. They lower the pH of the
proximal colon, which can markedly affect the
composition of the colonic microbiota. Changing the pH from 5.5 to 6.5 resulted in a much
less butyrogenic but more propiogenic fermentation, and this was shown to correlate with a
shift in the composition of the microbiota. At
pH 5.5, the butyrate-forming Roseburia/E. rectale group comprised 20% of total bacteria; at
pH 6.5, this group became undetectable. At pH
6.5, the fermentor community became dominated by Bacteroides, indicating that Bacteroides
species were able to outcompete most other
bacteria for the soluble carbohydrates supplied
at pH 6.5, whereas at the lower pH, other bacterial groups were able to compete for these
substrates (35, 36). The inhibition of another
group of Gram-negatives, the Enterobacteria, at
acidic pH is recognized as an important factor limiting the populations of certain enteric
pathogens. SCFAs (particularly butyrate) have
also been implicated in stimulating intestinal
blood flow and modulating gut motility and
epithelial proliferation and differentiation (see
below) (37, 38).
GUT MICROBIOTA MODULATES

BIOLOGICALLY ACTIVE FATTY
ACID COMPOSITION
Mounting evidence suggests bioactive isomers
of conjugated linoleic acid (CLA)mainly the
cis-9,trans-11 (c9,t11) CLAexert antidiabetogenic, antiobesogenic, antiatherogenetic,
hypocholesterolemic,
hypotriglyceridemic,
and immunomodulatory actions (39). Different
human gut microbial strains, and Bacteroidetes
to a higher extent than Firmicutes, have shown
both in vivo and in vitro the ability to synthesize
c9,t11 CLA through three possible pathways: a
direct isomerization, a hydration/dehydration
mechanism, or a hydrogen-abstraction mechanism involving a radical intermediate (4043).
Wall et al. tested the hypothesis that different

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microbial species inhabiting human gut might

modulate the fatty acid composition not only
in the intestine but also in tissues crucial
for host metabolism (44). They randomized
healthy and immunodeficient mice and pigs
to a linoleic acidenriched diet, supplemented
or not with Bifidobacterium breve, a well-known
c9,t11 CLA-producing human commensal.
After 8 weeks, the mean c9,t11 CLA content
of the liver and adipose tissue was 1.54 times
higher in animals fed B. breve than in unsupplemented animals. The animals receiving
B. breve also exhibited significantly higher adipose tissue concentrations of eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA),
two omega-3 (n-3) polyunsaturated fatty
acids with important anti-inflammatory and
lipid-lowering properties. These changes were
accompanied by a reduced secretion of proinflammatory cytokines, namely tumor necrosis
factor (TNF)-, interleukin (IL)-1, IL-6, and
IL-8, coupled with a higher anti-inflammatory
IL-10 secretion from splenocytes from animals
supplemented with B. breve.
Although B. breve did not significantly influence body weight in either mice or pigs,
this study showed for the first time that host
composition of biologically active fatty acids
can be positively influenced by the administration of a metabolically active commensal acting on a dietary substrate. The mechanism(s)
by which B. breve induced changes in host n3 fatty acid composition remains to be elucidated. B. breve administration might influence
fatty acid metabolism by using or assimilating
certain polyunsaturated fatty acids, such as linolenic acid, or it might modulate dietary fatty
acid uptake in the intestine. The observed differences could also result from the ability of
some commensals to upregulate !6-desaturase
activity in the liver, enhancing the synthesis of
arachidonic acid from linoleic acid (45).

BILE ACIDACTIVATED
METABOLIC PATHWAYS
Dietary fat is absorbed in the proximal
small intestine, following bile acidmediated
emulsification. Bile acids are amphipathic

molecules that are synthesized from cholesterol in the liver, mostly as the primary bile
acids cholic acid and chenodeoxycholic acid.
By deconjugation and dehydroxylation, intestinal bacteria can convert these acids into secondary bile acidsmainly deoxycholic acid and
lithocholic acid in humans, but also hyodeoxycholic acid and -muricholic acid in rodents.
This ultimately affects their hydrophobicity
and entero-hepatic cycle as well as their intestinal lipid solubilization and absorption (46).
Bacteroides intestinalis and secondarily Bacteroides
fragilis and Escherichia coli are potentially involved in the generation of secondary bile acids
in the colon (47).
Besides favoring dietary lipid absorption,
different bile acids exert several other metabolic
regulatory functions (48, 49). Primary bile acids
are ligands for the nuclear transcription factor farnesoid X receptor (FXR), which can suppress hepatic gluconeogenesis and lipogenesis,
enhance fatty acid oxidation and triglyceriderich lipoprotein clearance, and improve hepatic
and extrahepatic insulin sensitivity (29, 30, 50).
Bile acids can also act as chemical chaperones
to enhance protein folding, ameliorate endoplasmic reticulum stress, and promote thermogenesis through intracellular cAMP-dependent
thyroid hormone activation mediated by the enzyme type 2 iodothyronine deiodinase (DIO2)
(29, 30).
Martin et al. used high-resolution 1 H nuclear magnetic resonance (NMR) spectroscopy
and ultraperformance liquid chromatography
mass spectrometry to assess the impact of
perturbation in gut microbiota composition on
bile acid entero-hepatic cycle and host tissuespecific metabolic profiles (51, 52). They found
that, compared with conventional gut flora, the
colonization with human baby intestinal microflora (dominated by Clostridium, Bacteroides,
and Enterobacteria) was associated with a shift in
the bile acid pattern toward tauroconjugates
mainly tauro--muricholic acid (T--MCA)
and taurocholic acid (TCA)owing to a lower
deconjugation activity from the human baby
microbiota. These changes had a direct impact
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on emulsification and absorption of bile acids

and indirectly affected hepatic fatty acid storage and lipoperoxidation, resulting in higher
triglyceride and lower glutathione content
in the liver of mice harboring the human
Hepatic
portal vein
flora (Figure 2). In a subsequent experiment,

supplementation with probiotic Lactobacillus
spp. significantly impacted the tauroconjugated/unconjugated ratio of bile acids and
the metabolism of SCFAs, amino acids, and
VLDL
secretion
Liver
Fat deposition
TCA/CA
TMCA/MCA
Apolipoprotein
synthesis
Dietary
nutrients
and fats
Pancreas
Gall Bladder
and common
bile duct
Enterohepatic
recirculation
VLDL
synthesis
Cholesterol
synthesis
BA recycling

Fatty liver
GSH
Acetate/
propionate
Modulation of
endocrine functions
Small intestine
GSH
LDL
Nutrients
Bile pool
TMCA/MCA
TCA/CA
Glycerol
GPC
Processing
Emulsification
Absorption
SCFAs
Acetate
propionate
Fats
Gut microflora:
HBF
Large intestine
Calorie recovery
Fibers
Fermentation
Rectum
Coprophagy
Hepatic
vein
Figure 2
Microbemammalian metabolic interactions related to bile acid and lipid metabolism. The bacterial
reprocessing of the bile acid pool and regulation of bile acid metabolism by bacterial SCFAs affect
significantly the entero-hepatic recirculation and the systemic lipid metabolism, that is, emulsification,
absorption, and transport of dietary fats. The gut bacterialinduced regulation of entero-hepatic
recirculation also leads to a physiological regulation of oxidative stress (glutathione), reprocessing of fatty
acids (deposition, apoprotein and VLDL synthesis), and VLDL secretion from the liver, which result in
controlling the influx and efflux of fatty acids in the liver. BA, bile acids; CA, cholic acid;
GPC, glycerophosphorylcholine; GSH, glutathione; HBF, human baby flora; LDL, low-density
lipoproteins; MCA, -muricholic acid; SCFAs, short-chain fatty acids; TMCA, tauro--muricholic acid;
TCA, taurocholic acid; VLDL, very low-density lipoproteins. Redrawn from Reference 51.
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methylamines, resulting in decreased plasma

concentrations of very low-density lipoprotein
(VLDL) and low-density lipoprotein (LDL)
and enhanced glycolysis.
Using a similar approach, another group investigated the effect of gut microbiota on the
serum metabolome and the lipidomes of serum,
adipose tissue, and liver in mice. They compared conventionally raised mice (i.e., colonized with a normal gut microbiota since birth)
with germ-free mice (i.e., raised in the absence
of microorganisms), assessed both in fasting
conditions and after an oral fat load (53). They
found that the serum metabolome of the conventionally raised (CONV-R) mice was characterized by increased levels of pyruvic acid
and tricarboxylic acid metabolites (citric acid,
fumaric acid, and malic acid), consistent with
higher energy metabolism in the presence of
gut microbiota, whereas levels of cholesterol
and fatty acids were reduced. The microbiota
also modified a number of lipid species in the
serum, adipose tissue, and liver, with its greatest
effect on triglyceride and phosphatidylcholine
species. Following the oral fat bolus, intestinal
lipid absorption did not differ between groups;
this was attributed to the increased gut transit
time of CONV-R mice, compensating for relatively reduced absorption rates compared to
germ-free mice. Triglyceride storage in adipose
tissue and the liver after oral fat load was higher
in CONV-R than in germ-free mice, consistent with an increased uptake from circulating
lipoproteins (see below). Furthermore, the authors demonstrated a higher VLDL production
rate in CONV-R mice.

DIETARY CHOLINE
BIOAVAILABILITY
In the liver, phospholipids are required for
bile production and lipoprotein secretion, and
are essential for cellular membrane integrity
(51). The phosphatidylcholine pool, in particular, is made from choline via the cytidine5-diphosphocholine-choline pathway and is
critical for hepatic VLDL secretion. Dietary
choline deficiency can cause nonalcoholic fatty

liver disease (NAFLD) in humans under total parenteral nutrition and in mice under a
methionine-cholinedeficient diet (54). Dumas
et al. (55) tested the effects of switching from a
low-fat diet to a 40% high-fat diet on plasma
and urine metabolic 1 H NMR profiles in the
129S6 mouse (a model of insulin resistance,
NAFLD, impaired glucose tolerance, dyslipidemia, and obesity) and in the BALBc mouse,
which is resistant to these phenotypes. They
found that the development of the obese phenotype under the high-fat diet was associated with a specific metabotype, i.e., a conversion by gut microflora of dietary choline
to hepatotoxic methylamines (dimethylamine,
trimethylamine, and trimethylamine-N-oxide).
This conversion resulted in a reduction of
choline bioavailability for the synthesis of phosphatidylcholine in the liver, eventually mimicking a choline-deficient diet, with impaired
VLDL secretion and triglyceride accumulation
in the liver (37).
EVIDENCE CONNECTING
MICROBIOTA-REGULATED
ENERGY HARVEST FROM THE
DIET AND INCREASED HOST
FAT STORAGE
The first evidence that gut microbiota can increase energy harvest from the diet and regulate host energy homeostasis and fat storage
14-day conventionalization (i.e., transplantation in the gut) of adult germ-free C57BL/6
mice with a normal microbiota, similar to human gut flora (composed mainly of Bacteroides,
especially B. thetaiotaomicron, and Clostridium
genera), harvested from the cecum of conventionally raised animals produced a 60% increase in body fat, a twofold increase in hepatic
triglycerides and a marked increase in fasting
plasma glucose and insulin resistance, despite a
29% lower chow consumption and comparable
whole-body energy expenditure (56). Gut microbiota promoted intestinal monosaccharide
uptake and transfer to the portal circulation
through enhanced Glut1 expression in small
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intestine enterocytes and a twofold increased

density of capillaries underlying the small intestinal villus epithelium (57, 58). Increased carbohydrate flow to the liver and adipose tissue
stimulated de novo lipogenesis by enhancing
carbohydrate response element binding protein
(ChREBP)- and sterol response element binding protein 1 (SREBP-1)-mediated transcription of genes encoding two rate-limiting lipogenetic enzymes: acetyl-CoA carboxylase (Acc)-1
and fatty acid synthase (Fas).This eventually resulted in accumulation of hepatic and adipose
tissue triglycerides (56, 59) (Table 1).
To further assess the role of gut microbiota
in mediating diet-induced obesity, germ-free
or conventionalized mice were fed a Westernized high-fat/carbohydrate-rich diet (60).
Despite similar caloric intake, germ-free mice
gained significantly less weight and fat mass
than conventionalized mice and were protected
against Western dietinduced glucose intolerance and insulin resistance. In contrast to previous findings, germ-free and conventionalized
mice had a similar residual energy content in
their feces, suggesting a higher energy harvest
from the diet might not be the sole mechanism
enhancing fat storage in conventionalized mice.
Importantly, the trait of obesity was transmissible along with the gut microbiota, as transplantation of the microbiota from obese mice
to germ-free wild-type recipient mice caused a
greater increase in adiposity than that caused by
transplantation of a microbiota from conventionally raised lean wild-type littermate donors
that had been fed standard chow (61, 62).
Collectively, these experiments suggest that
gut microbiota may affect host fat storage and
energy homeostasis, with increased energy harvest from the diet being a relevant though not
sole mechanism connecting gut microbes to
obesity.

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MICROBIAL MODULATION OF
HOST ENERGY HOMEOSTASIS
AND METABOLISM
Following these key experiments, four other
molecular mechanisms potentially linking gut
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microflora to host metabolism and fat storage

have been proposed.
Suppression of Intestinal Secretion of

Fasting-Induced Adipose Factor (Fiaf )
Fasting-induced adipose factor (Fiaf ), also
named angiopoietin-like protein 4, is a 50kDa glycosylated protein produced by enterocytes, hepatocytes, skeletal myocytes, and
adipocytes in response to fasting, to peroxisome proliferator-activated receptor (PPAR) agonists, and to inflammatory prostaglandins
PGD2 and PGJ2 (63). Its main function is the
inhibition of adipose tissue lipoprotein lipase
(LPL) to limit adipocyte uptake of fatty acids
and triglyceride accumulation (64).
Backhed et al. found that conventionalization of germ-free mice suppressed intestinal
expression of Fiaf in differentiated villous epithelial cells in the ileum (56). In a separate experiment, conventionalization of Fiaf knockout
(KO) mice produced only a 10% increase in total body fat compared to the 55% fat gain observed in wild-type littermates, and germ-free
Fiaf KO mice fed a high-fat, high-carbohydrate
diet were not protected against diet-induced
obesity. Backhed et al. also found that Fiaf
might modulate fatty acid oxidation in skeletal
muscle through regulating expression of peroxisomal proliferator-activated receptor coactivator (PGC)-1, a nuclear coactivator of genes
encoding key enzymes involved in mitochondrial fatty acid oxidation, including carnitine
palmitoyl transferase-1 (Cpt1) and mediumchain acylCoA dehydrogenase. Therefore, Fiaf
may be a prominent mediator of microbial regulation of adipose tissue fat storage by modulating multiple steps of energy balance, including
energy harvest from the diet, energy storage as
triglyceride in liver and muscle, and energy expenditure as fatty acid oxidation.
Modulation of Adenosine
Monophosphate (AMP)-Activated
Protein Kinase (AMPK) Activity
Backhed et al. further analyzed mechanisms
underlying resistance of germ-free mice to
Western dietinduced obesity, finding a
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Table 1
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Mechanisms whereby gut microbiota may modulate host energy homeostasis, fat storage, and insulin sensitivity

Mechanism
Molecular mediators
Ultimate effects
Complex polysaccharide (starch,

glycans) degradation to
monosaccharides
Microbial transport proteins, glycoside

hydrolases, and fermentation enzymes
Increased CHO uptake from the diet
Increased glucose absorption
Increased Glut1 expression in small intestine

enterocytes
Increased CHO enterocyte absorption
Increased monosaccharide transfer to

portal circulation
Increased microbiota-driven density of

capillaries underlying the small intestinal
villus epithelium
Increased CHO portal flow to the liver
Enhanced de novo lipogenesis
ChREBP- and SREBP-1-mediated expression

of lipogenic enzymes
Increased liver and adipose tissue Tg

accumulation
Increased hydrolisis of circulating

Tg-rich lipoproteins
Reduced intestinal Fiaf secretion, leading to

increased adipose tissue LPL activity
Increased storage of circulating Tg in

adipose tissue
Reduced FFA oxidation
Reduced Fiaf-induced (PGC)-1 expression

of mitochondrial FFA oxidative enzymes
Reduced FFA oxidation in liver and

muscle
Reduced FFA oxidation
Reduced AMPK-induced expression of

mitochondrial FFA oxidative enzymes
Reduced FFA oxidation in liver and

muscle
Reduced intestinal transit time and

increased L-FABP enterocyte
expression
Increased Gpr41-mediated PYY secretion

induced by microbial production of SCFA
from dietary polysaccharides
Increased energy harvest from the diet
Modulation of host liver and adipose

tissue fatty acid composition
Increased linoleic acid conversion to c9,t11

CLA by gut microbiota, increased liver and
adipose tissue abundance of DHA and EPA
through unknown mechanisms
Altered tissue composition of

biologically active fatty acids
Modulation of bile acid enterohepatic

cycle through bacterial deconjugation
and dehydroxylation of primary bile
acids
Modulation of intestinal lipid absorption, and

hepatic and adipose tissue gluconeogenesis,
de novo lipogenesis, FFA oxidation, and
triglyceride-rich lipoprotein metabolism
through FXR activation and
cAMP-dependent thyroid hormone
activation
Modulation of bile acidregulated

energy homeostasis, glucose and lipid
metabolism in the liver and adipose
tissue
Reduction of choline bioavailability for

synthesis of phosphatidylcholine in
the liver
Microbial conversion of dietary choline to

hepatotoxic methylamines
Hepatic accumulation of toxic

methylamines; impaired hepatic VLDL
secretion, resulting in NAFLD
Production of LPS by gut microbiota
LPS-TLR4-mediated induction of
proinflammatory cytokines SOCS-1,
SOCS-3, IL-6, TNF-, MCP-1 in adipose
tissue, liver and macrophages
Systemic, hepatic, and adipose tissue

inflammation and insulin resistance
Regulation of GLP-2 secretion by

intestinal enteroendocrine L cells
Unknown signaling pathways linking gut

microbes to L cells
Modulation of intestinal barrier function
Abbreviations: AMPK, enzyme adenosine monophosphateactivated protein kinase; CHO, carbohydrates; ChREBP, carbohydrate response element
binding protein; cAMP, cyclic adenosine monophosphate; CLA, conjugated linoleic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;
FFA, free fatty acid; FXR, farnesoid X receptor; GLP, glucagon-like peptide; IL, interleukin; L-FABP, liver fatty acid binding protein; LPL, lipoprotein
lipase; LPS, lipopolysaccharide; MCP, monocyte chemoattractant protein; NAFLD, nonalcoholic fatty liver disease; PGC, peroxisomal
proliferator-activated receptor coactivator; PYY, peptide YY; SCFA, short-chain fatty acid; TLR4, toll-like receptor 4; SOCS, suppressor of cytokine
signaling; SREBP, sterol response element binding protein 1; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein.
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persistent activation of the enzyme adenosine

monophosphate (AMP)-activated protein
kinase (AMPK) in the liver and muscle of
germ-free mice (56). AMPK is a heterotrimeric
enzyme that is conserved from yeast to humans and functions as a fuel gauge that
monitors cellular energy status; it is activated by phosphorylation of Thr-172 in its
catalytic -subunit in response to metabolic
stresses that result in an increased intracellular
AMP/ATP ratio (65). AMPK in turn activates
ATP-generating catabolic pathways in the liver
and skeletal muscle: It enhances mitochondrial fatty acid oxidation by phosphorylating
Acc, thereby increasing Cpt1 activity, and
it reduces hepatic glycogen synthase activity
and glycogen stores, improving hepatic and
muscle insulin sensitivity. Hepatic and skeletal
muscle AMPK activity and related metabolic
pathways were suppressed in conventionalized
mice, suggesting gut microbiota suppresses
AMPK-modulated fatty acid oxidation through
unknown molecular mediators.

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Modulation of Gut Motility

and Nutrient Absorption by
Microbial-Derived SCFAs
Besides representing a source of energy for
host de novo lipogenesis, short-chain fatty acids
(SCFAs) also act as signaling molecules: propionate, acetate, and, to a lesser extent, butyrate,
are ligands for at least two G proteincoupled
receptors (GPCRs), Gpr41 and Gpr43 (38, 66).
Both GPCRs are abundantly expressed in the
distal small intestine, colon, and adipocytes
(28). Upon activation, they induce the secretion of peptide YY (PYY) and leptin. Leptin
is an adipocyte-secreted polypeptide hormone
with pleiotropic effects on appetite and energy
metabolism; PYY is a peptide secreted by intestinal enteroendocrine cells, which inhibits
gut motility, slows intestinal transit time, and
enhances enterocyte expression of liver fatty
acid binding protein (L-FABP), a peptide involved in intracellular free fatty acid (FFA)
trafficking, eventually promoting intestinal nutrient absorption (67).
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Samuel et al. (68) compared the effect of

Gpr41 functional deletion on host adiposity
and energy harvest from the diet in mice
raised in germ-free conditions, conventionalized, or colonized with two prevalent human
gut fermentative commensals, B. thetaiotaiomicron and M. smithii. Despite an increased intestinal SCFA production in the presence of
fermentative flora, both conventionally raised
Gpr41 KO and germ-free Gpr41 KO mice colonized with B. thetaiotaiomicron and M. smithii
were significantly leaner, with reduced hepatic
de novo lipogenesis and triglyceride content,
than wild-type littermates, whereas there were
no genotype-related differences in germ-free
mice. Gpr41 deficiency was associated with decreased PYY expression, faster intestinal transit rate, and reduced harvest of energy from
the diet. These results revealed a pivotal role
for Gpr41 in a microbiota-dependent metabolic
circuit that regulates the flow of calories between the diet and the host. Furthermore, as the
fermentative capacity varies greatly among bacterial species, interindividual differences in the
intestinal microbial composition may modulate
host energy metabolism and host adiposity. If
these findings are confirmed, the inhibition of
SCFA activation of Gpr41 may be a potential
therapeutic tool for modulating caloric extraction from the diet.
Modulation of Host Inflammatory

Response: The Concept of Chronic
Low-Grade Endotoxinemia
It is increasingly recognized that obesity is characterized by chronic activation of inflammatory
pathways and that inflammatory pathways in
obesity induce insulin resistance. Among
different inflammatory pathways, innate immunity, and particularly toll-like receptor
(TLR)-activated pathways, have received
much attention. TLRs are a highly conserved
group of pattern-recognition receptors that
function as pathogen sensors in vertebrate
and invertebrate species. Upon recognition of
specific signature molecules, termed pathogenassociated molecular patterns (PAMPs), they

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trigger a rapid innate immune system response

against invading pathogens. Besides their role
in the innate immune system, TLRs play a pivotal role in modulating inflammatory response
to numerous intestinally derived PAMPs in
healthy and disease states, including obesity
and alcoholic and nonalcoholic fatty liver disease. All 10 members of the human TLR family
are structurally characterized by a leucine-rich
repeat (LRR) domain in their extracellular
domain and a toll/IL-1 receptor (TIR) domain
in their intracellular domain. TLR4 is the
TLR best known for sensing lipopolysaccharide (LPS), a membrane component of
Gram-negative bacteria. Upon binding LPS
and its coreceptor CD14, TLR4 interacts with
intracellular adaptor proteins myeloid differentiation factor 88 (MyD88) and TIR-domain
containing adaptor inducing IFN- (TRIF)
to activate transcription factors nuclear factor
(NF)-B, AP-1, and interferon regulatory
factors. These pathways enhance transcription
of many proinflammatory molecules including
cytokines, chemokines, and other effectors of
the innate immune response, most of which
have also been implicated in the pathogenesis of
the low-grade inflammatory state of obesity, insulin resistance, and diabetes (69). Besides LPS,
other exogenous and endogenous molecules
are ligands for TLR4, including FFA and products from dying cells (hyaluronian fragments,
heparan sulfate fragments, and heat-shock proteins, collectively named damage-associated
molecular patternsDAMPs). Interactions
with such molecules further promote a
widespread inflammatory response in cells expressing TLR4: gut immune cells, adipocytes,
endothelial cells, tissue macrophages, hepatocytes, and hepatic Kupffer and stellate cells
(70, 71).
Recently, Cani et al. provided unequivocal
evidence that chronic inflammation induced by
low-grade endotoxinemia can induce obesity,
insulin resistance, and glucose intolerance (72).
They reported that a four-week high-fat diet
increased the proportion of LPS-expressing
bacteria in the gut and induced a two- to
three-fold elevation in plasma LPS, which the
authors termed metabolic endotoxemia to

differentiate it from the higher endotoxinemic
levels of sepsis. When metabolic endotoxemia
was induced by subcutaneous infusion of LPS,
whole-body, liver, and adipose tissue weight
and insulin resistance increased to a similar
extent as in mice on the high-fat diet. LPS
receptor CD14 KO mice were unresponsive
to LPS and resistant to the metabolic effects
of both high-fat diet and LPS infusion (72).
Consistent with these observations, antibiotic
treatment changed gut microbiota composition, reduced cecal and plasma levels of LPS,
and improved the obese phenotype in both
high-fat-fed and ob/ob mice (73).
These experiments in rodent models have
been recently replicated in humans. Mehta et al.
performed subcutaneous adipose biopsies and
measured plasma adipokines and parameters of
glucose homeostasis using the frequently sampled intravenous glucose tolerance (FSIGT)
test in 20 healthy humans, before and after a
60-h LPS infusion to reach plasma endotoxin
levels comparable to those of animal studies
(74). They found that endotoxemia induced a
35% decrease in systemic insulin sensitivity,
coupled with a suppression in adipose tissue
insulin receptor substrate-1, without affecting
pancreatic cell function, and significantly increased systemic and adipose tissue expression
of proinflammatory and insulin resistance
inducing cytokines, including suppressor of
cytokine signaling (SOCS)-1 and SOCS-3,
IL-6, TNF-, monocyte chemoattractant
protein (MCP)-1, and C-X-C motif ligand 10
(CXCL10). Increased plasma endotoxinemia
has been linked not only to obesity but also
to the pathogenesis of nonalcoholic fatty
liver disease (NAFLD) and nonalcoholic
steatohepatitis (NASH), often encountered in
obese and diabetic subjects. Plasma endotoxin
levels are increased in NAFLD patients and
are associated with an increased hepatic TLR4
expression (75, 76). The levels of lipopolysaccharide binding protein (LBP) closely correlate
with the histological severity of NAFLD and
with the increased hepatic TNF- expression (77), and the functional TLR4 deletion
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prevented the development of NASH in

mice on a methionine-choline-deficient diet
(78).
Although the mechanisms underlying the
increased systemic LPS levels in obesity are
poorly understood, nutrient composition appears to play a major role in determining the
proendotoxinemic and proinflammatory potential of the diet. In mice, a high-fat diet
induced a higher increase in plasma endotoxin than an isocaloric high-carbohydrate
diet (79). In healthy humans, a high-fat/highcarbohydrate meal induced a significant postprandial endotoxinemia, coupled with an increased mononuclear cell expression of TLR4,
SOCS-3, and NF-B binding activity. These
increases were totally absent after a meal rich
in fiber and fruit (80). Postprandial plasma endotoxin levels following a high-fat meal were
sufficient to activate cultured human aortic endothelial cells through the release of soluble
TNF- from monocytes (81).
Deopurkar et al. compared the effects of
isocaloric meals rich in glucose, saturated fat,
or orange juice on plasma endotoxin, oxidative markers, and inflammatory markers
in healthy subjects (82, 83). Expression of
NF-B, SOCS3, TNF-, and IL-1 increased
significantly following glucose and cream intake, whereas plasma LPS concentrations and
TLR4 expression increased only after saturated
fat intake. Orange juice did not affect any of
the indices and, when added to a high-fat/highcarbohydrate meal, it prevented postprandial
increase in plasma endotoxin, TLR4, SOCS3, and other inflammatory and oxidative markers (82, 83). Other observational human studies linked the intake of a high-fat diet to plasma
endotoxinemia (79).
Mechanisms regulating intestinal barrier integrity may also modulate the extent of endotoxinemia (8487). Glucagon-like peptide
(GLP)-2, a 33-amino-acid peptide with established intestinotrophic functions, which is cosecreted with GLP-1 by enteroendocrine L cells,
appears to be a key modulator of gut barrier
function. In a recent experiment, Cani et al. assessed the effect of the prebiotic fermentable

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oligofructose on gut microbiota composition,

intestinal permeability, and hepatic and systemic inflammation in obese ob/ob mice (88).
The prebiotic-supplemented diet increased the
intestinal proportion of Lactobacilli and Bifidobacteria, increased the expression of epithelial
tight-junction proteins occludin and zonulin-1
(restoring normal intestinal permeability), and
reduced systemic endotoxinemia as well as hepatic inflammation and oxidative stress. These
effects were associated with an increased intestinal GLP-2 level, were prevented by pretreatment with a GLP-2 antagonist, and were mimicked by the administration of a GLP-2 agonist.
These findings suggest GLP-2 may link gut microbiota, intestinal permeability, and systemic
endotoxinemia and inflammation.
An alternative pathway for LPS absorption
from the gut involves chylomicron secretion
from enterocytes, rather than loss of intercellular tight-junction integrity. Cell cultures
and animal models suggested that endotoxin
is actively secreted into the blood along with
chylomicrons, and that inhibiting chylomicron
synthesis blocks endotoxin secretion (89).
Collectively, these data strongly connect
gut-derived endotoxin to the pathogenesis of
obesity-associated disorders and suggest therapeutic strategies targeting various steps of
LPS-triggered inflammation. In particular, reduction of inflammation through dietary manipulation, pre/probiotic supplementation, or
directly affecting intestinal-barrier permeability, chylomicron secretion, or TLR4 axis activation may have therapeutic implications.
ROLE OF GUT MICROBIOTA

IN THE PATHOGENESIS
OF TYPE 1 DIABETES
Type 1 diabetes (T1D) is believed to be a multistage T cellmediated autoimmune disease that
involves slow and progressive islet cell destruction and complete loss of insulin secretion
(90). The role of the adaptive immune system
in the autoimmune islet destruction has been
established over the past few decades; the importance of the innate immune system has been

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only recently recognized with the discovery of

TLR-regulated pathways.
Increasing evidence indicates that aberrant
gut microbiota, impaired intestinal mucosal
barrier, and altered mucosal immunity contribute to the pathogenesis of T1D. The first
suggestion of a modulatory role of microbiota exposure in the risk of T1D came from
nonobese diabetic (NOD) mice, which are
more prone to develop T1D under specific
pathogen-free conditions, and Bio-Breeding
diabetes-prone (BBDP) rats, which developed
accelerated disease when subjected to Cesarean
derivation (91, 92). In these models, protection against the onset of T1D after antibiotic
or probiotic administration was associated with
marked changes in gut microbiota composition and with decreased intestinal mucosal expression of several oxidative response proteins
(Gpx1, GR, Cat), reduced levels of the proinflammatory cytokine IFN- and inducible NO
synthase (iNOS), increased levels of the antiinflammatory interleukin IL-10, and higher
levels of the tight-junction protein claudin
(9396). These data suggest gut microbiota manipulation may protect against T1D by modulating mucosal oxidative stress and pro/antiinflammatory balance, and eventually restoring
the intestinal mucosal barrier function.
Recently, a more complex view integrating microbeinnate immunity interactions was
provided by Wen et al. (97). They generated
a model of NOD mice in which the myeloid
differentiation factor 88 (MyD88), a key intracellular adaptor molecule that mediates multiple TLR signaling pathways, was knocked out.
Compared to wild-type animals, MyD88 KO
mice were protected from T1D, and their pancreatic lymph node (PLN)-derived T lymphocytes showed a decreased reactivity (assessed
by IFN- production) to diabetes-associated
peptides. In contrast to MyD88 KO mice, genetic ablation of a single TLR, including TLR2,
TLR3, or TLR4, did not attenuate T1D incidence and progression.
Furthermore, CD4+ T cells harboring
diabetogenic T cell receptor BDC2.5 failed
to proliferate in the PLN of MyD88 KO
mice, when compared with MyD88-competent

animals. In contrast, no significant differences
were observed in T cells derived from spleen
and mesenteric lymph nodes, suggesting
that the antidiabetogenic effect of MyD88
deficiency was localized to PLN and not due to
a systemic suppression of MyD88-mediated T
cell autoimmune activation. As the PLNs drain
both the pancreas and the gut, the authors
hypothesized that abnormal sensing of certain
commensal microbes at the intestinal-barrier
level may trigger T1D through the hosts failure to prevent development of autoimmune T
cells. Therefore, they tested the hypothesis that
T1D resistance in MyD88 KO mice could be
induced by certain microbiota-derived signals.
Consistently, in MyD88 KO mice, lifelong gut
microflora depletion by oral broad-spectrum
antibiotics was associated with a significant
increase in T1D incidence, as shown by
comparing germ-free mice to those kept under
specific pathogen-free (SPF) conditions. In
contrast, T1D occurrence was similar in NOD
animals raised in either germ-free or SPF
conditions.
Collectively, these data suggested that an
as-yet-unidentified component of the microbiota might protect from activation of an autoimmune T cell response independently of
MyD88. The authors therefore investigated
which microorganisms might be antidiabetogenic in MyD88 KO mice. They found that
MyD88 deletion was associated with a lower
Firmutes/Bacteroidetes ratio, and with an increased proportion of Lactobacilli, Rikenellae,
and Porphyromonadaeae. Consistent with previous findings, antibiotic therapy of MyD88
KO mice normalized the Firmutes/Bacteroidetes
ratio. Conversely, cross-fostering experiments
revealed that the micriobiota of MyD88 KO
mice was sufficient to protect germ-free NOD
mice from T1D, as was a cocktail of bacteria
contained in the altered Schaedler flora transfected to adult germ-free MyD88 KO NOD
mice.
These experiments support the notion that
host recognition of the digestive flora is essential in preventing T1D onset and progression
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through involvement of a MyD88-independent

signaling pathway that remains to be
elucidated.
SUMMARY AND FUTURE

DIRECTIONS

Modern molecular techniques have disclosed

a tight relationship between mammalian gut
microbial composition and functions and host
metabolism (Table 1). This relationship can
eventually contribute to the development of
metabolic disease, including obesity, NAFLD,
and diabetes.
These findings have profound implications
for human health. If intestinal microflora represent an important source of metabolic variability in the host, modulating for instance the
amount of energy absorbed from the diet or
the distribution of fat deposition in the host,

then future research on human susceptibility
to metabolic disease will have to consider not
only the host genome or lifestyle, but also
the gut microbiome. Modern metagenomic and
metabolomic approaches will add insight into
aberrant microbial mechanisms that could be
targeted by disease-prevention strategies. Future research on probiotics and prebiotics will
have to better elucidate molecular mechanisms
underlying microbe-microbe and microbe-host
reciprocal metabolic and immunological interactions, to enable the design of more targeted
approaches tailored to the individual needs of
patients. This concept is illustrated by the discovery that lacticin 3147, a peptide bacteriocin
synthesized by Lactococcus, has antimicrobial activity against C. difficile comparable to that of
conventional antibiotics (98).
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was supported in part by grants from the Piedmont Regional Funds Comitato Interministeriale per la Programmazione Economica 2008.
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Annual Review of
Medicine

Contents
Volume 62, 2011
Role of Postmarketing Surveillance in Contemporary Medicine

Janet Woodcock, Rachel E. Behrman, and Gerald J. Dal Pan 1
Genome-Wide Association Studies: Results from the First Few Years

and Potential Implications for Clinical Medicine
Joel N. Hirschhorn and Zofia K.Z. Gajdos 11
Imaging of Atherosclerosis
D.R.J. Owen, A.C. Lindsay, R.P. Choudhury, and Z.A. Fayad 25
Novel Oral Factor Xa and Thrombin Inhibitors in the Management
of Thromboembolism
Bengt I. Eriksson, Daniel J. Quinlan, and John W. Eikelboom 41
The Fabry Cardiomyopathy: Models for the Cardiologist

Frank Weidemann, Markus Niemann, David G. Warnock, Georg Ertl,
and Christoph Wanner 59
Kawasaki Disease: Novel Insights into Etiology
and Genetic Susceptibility
Anne H. Rowley 69
State of the Art in Therapeutic Hypothermia

Joshua W. Lampe and Lance B. Becker 79
Therapeutic Potential of Lung Epithelial Progenitor Cells Derived
from Embryonic and Induced Pluripotent Stem Cells
Rick A. Wetsel, Dachun Wang, and Daniel G. Calame 95
Therapeutics Development for Cystic Fibrosis: A Successful Model

for a Multisystem Genetic Disease
Melissa A. Ashlock and Eric R. Olson 107
Early Events in Sexual Transmission of HIV and SIV

and Opportunities for Interventions
Ashley T. Haase 127
HIV Infection, Inflammation, Immunosenescence, and Aging

Steven G. Deeks 141
v
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15:56
The Increasing Burden of HIV-Associated Malignancies

in Resource-Limited Regions
Corey Casper 157
Biliary Atresia: Will Blocking Inflammation Tame the Disease?

Kazuhiko Bessho and Jorge A. Bezerra 171
Advances in Palliative Medicine and End-of-Life Care
Janet L. Abrahm 187

Clostridium difficile and Methicillin-Resistant Staphylococcus aureus:

Emerging Concepts in Vaccine Development
David C. Kaslow and John W. Shiver 201
Antiestrogens and Their Therapeutic Applications in Breast Cancer

and Other Diseases
Simak Ali, Laki Buluwela, and R. Charles Coombes 217
Mechanisms of Endocrine Resistance in Breast Cancer

C. Kent Osborne and Rachel Schiff 233
Multiple Myeloma
Jacob Laubach, Paul Richardson, and Kenneth Anderson 249
Muscle Wasting in Cancer Cachexia: Clinical Implications, Diagnosis,
and Emerging Treatment Strategies
Shontelle Dodson, Vickie E. Baracos, Aminah Jatoi, William J. Evans,
David Cella, James T. Dalton, and Mitchell S. Steiner 265
Pharmacogenetics of Endocrine Therapy for Breast Cancer

Michaela J. Higgins and Vered Stearns 281
Therapeutic Approaches for Women Predisposed to Breast Cancer

Katherine L. Nathanson and Susan M. Domchek 295
New Approaches to the Treatment of Osteoporosis
Barbara C. Silva and John P. Bilezikian 307
Regulation of Bone Mass by Serotonin: Molecular Biology
and Therapeutic Implications
Gerard Karsenty and Vijay K. Yadav 323
Alpha-1-Antitrypsin Deficiency: Importance of Proteasomal

and Autophagic Degradative Pathways in Disposal of Liver
DiseaseAssociated Protein Aggregates
David H. Perlmutter 333
Hepcidin and Disorders of Iron Metabolism

Tomas Ganz and Elizabeta Nemeth 347
vi
Contents
ME62-Frontmatter
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15 December 2010
15:56
Interactions Between Gut Microbiota and Host Metabolism

Predisposing to Obesity and Diabetes
Giovanni Musso, Roberto Gambino, and Maurizio Cassader 361
The Brain-Gut Axis in Abdominal Pain Syndromes

Emeran A. Mayer and Kirsten Tillisch 381

Cognitive Therapy: Current Status and Future Directions

Aaron T. Beck and David J.A. Dozois 397
Toward Fulfilling the Promise of Molecular Medicine
in Fragile X Syndrome
Dilja D. Krueger and Mark F. Bear 411
Stress- and Allostasis-Induced Brain Plasticity

Bruce S. McEwen and Peter J. Gianaros 431
Update on Sleep and Its Disorders

Allan I. Pack and Grace W. Pien 447
A Brain-Based Endophenotype for Major Depressive Disorder
Bradley S. Peterson and Myrna M. Weissman 461
Indexes
Cumulative Index of Contributing Authors, Volumes 5862 475
Cumulative Index of Chapter Titles, Volumes 5862 479

Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml
Contents
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Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.

Interactions Between Gut

Gradenigo Hospital, Turin, Italy; email: giovanni_musso@yahoo.it

Department of Internal Medicine, University of Turin, Italy

Annu. Rev. Med. 2011. 62:36180

The Annual Review of Medicine is online at

microbiome, gut flora, endotoxin, energy homeostasis, TLR4

This articles doi:

c 2011 by Annual Reviews.

Novel, culture-independent, molecular and metagenomic techniques

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

ALTERED GUT MICROBIOTA

in the gut owing to intrinsic limitations: the

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

Microbial Degradation of Starch

Besides their capacity to hydrolyze starch, gut

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

(a) Model of Bacteroides thetaiotaomicron starch

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

numerous plant- and host-derived glycoconjugates (glycans) including cellulose, chondroitin

Host Utilization of Gut

isolated colonocytes (30). Absorbed acetate and

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

frequency, fecal excretion and concentrations

GUT MICROBIOTA MODULATES

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

microbial species inhabiting human gut might

GUT MICROBIOTA MODULATES

emulsification. Bile acids are amphipathic

on emulsification and absorption of bile acids

flora (Figure 2). In a subsequent experiment,

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

methylamines, resulting in decreased plasma

GUT MICROBIOTA MODULATES

choline deficiency can cause nonalcoholic fatty

intestine enterocytes and a twofold increased

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

microflora to host metabolism and fat storage

Suppression of Intestinal Secretion of

Annu. Rev. Med. 2011.62:361-380. Downloaded from www.annualreviews.org

Complex polysaccharide (starch,

Microbial transport proteins, glycoside

Increased CHO uptake from the diet

Increased glucose absorption

Increased Glut1 expression in small intestine

Increased CHO enterocyte absorption

Increased monosaccharide transfer to

Increased microbiota-driven density of

Increased CHO portal flow to the liver

Enhanced de novo lipogenesis

ChREBP- and SREBP-1-mediated expression

Increased liver and adipose tissue Tg

Increased hydrolisis of circulating

Reduced intestinal Fiaf secretion, leading to

Increased storage of circulating Tg in

Reduced FFA oxidation

Reduced Fiaf-induced (PGC)-1 expression

Reduced FFA oxidation in liver and

Reduced FFA oxidation

Reduced AMPK-induced expression of

Reduced FFA oxidation in liver and