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Keywords
Abstract
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INTRODUCTION
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.
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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.
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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
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
364
Disaccharides
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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).
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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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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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MICROBIAL MODULATION OF
HOST ENERGY HOMEOSTASIS
AND METABOLISM
Following these key experiments, four other
molecular mechanisms potentially linking gut
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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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Mechanisms whereby gut microbiota may modulate host energy homeostasis, fat storage, and insulin sensitivity
Mechanism
Molecular mediators
Ultimate effects
LPS-TLR4-mediated induction of
proinflammatory cytokines SOCS-1,
SOCS-3, IL-6, TNF-, MCP-1 in adipose
tissue, liver and macrophages
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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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
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
ME62-Frontmatter
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15:56
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
vi
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Contents
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