From Current Opinion in Gastroenterology
Obesity and the Human Microbiome
Ruth E. Ley
Posted: 01/18/2010; Curr Opin Gastroenterol. 2010;26(1):5-11. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review Obesity was once rare, but the last few decades have seen a rapid expansion of the proportion of obese individuals worldwide. Recent work has shown obesity to be associated with a shift in the representation of the dominant phyla of bacteria in the gut, both in humans and animal models. This review summarizes the latest research into the association between microbial ecology and host adiposity, and the mechanisms by which microbes in the gut may mediate host metabolism in the context of obesity.
Recent findings Studies of the effect of excess body fat on the abundances of different bacteria taxa in the gut generally show alterations in the gastrointestinal microbiota, and changes during weight loss. The gastrointestinal microbiota have been shown to impact insulin resistance, inflammation, and adiposity via interactions with epithelial and endocrine cells.
Summary Large-scale alterations of the gut microbiota and its microbiome (gene content) are associated with obesity and are responsive to weight loss. Gut microbes can impact host metabolism via signaling pathways in the gut, with effects on inflammation, insulin resistance, and deposition of energy in fat stores. Restoration of the gut microbiota to a healthy state may ameliorate the conditions associated with obesity and help maintain a healthy weight.
Introduction
Up until the last few decades, obesity has been a rare physiological state. Now however, the number of obese or overweight humans has come to outnumber those suffering from malnutrition.[1] This is an unprecedented state for our species, resulting from a mismatch between our evolutionary biology and our modern environment. The human body is a complex system, made all the more complex through its interactions with the trillions of microorganisms that coat the body surface and densely po
pulate the gut. Recent work has shown that the microbes of the gut may play a role in human metabolism and adiposity. Because they are environmentally acquired, microbes constitute one part of our environment that may contribute to the obese state. This review discusses the most recent findings and insights into the relationship between the human microbiota, obesity, and obesity-associated diseases.
Patterns of Microbial Diversity in Relation to Obesity
The initial link between gut microbial ecology and obesity was made in leptin-deficient mice (mice homozygous for an aberrant leptin gene, ob/ob) by Ley et al.[2] Results from a 16S rRNA gene sequence survey revealed that the bacterial communities in the ceca of ob/ob mice had a different proportion of bacteria belonging to the two dominant phyla when compared with those of lean wild-type (+/+) or heterozygous (ob/+) mice, with a greater representation of Firmicutes and fewer Bacteroidetes characterizing the obese host microbiota. A subsequent metagenomic analysis of these same microbial communities, which was based on shotgun sequencing of the microbial community DNA, showed an enrichment in genes involved in energy extraction from food in the obese host's microbiome relative to that of the lean host's microbiome. A microbiota with greater energy extraction efficiency resulted in less energy left over in feces and greater levels of short-chain
fatty acids (SCFAs) in the cecum. Furthermore, when the luminal contents from the ceca of obese or lean mice were provided to lean germ-free recipients, the mice receiving the microbes from the obese donors gained more weight over a 2-week period than recipients of the lean microbes, despite equivalent food
donors gained more weight over a 2-week period than recipients of the lean microbes, despite equivalent food intake.[3] In a study extending these observations to humans, 12 obese participants were randomly assigned to either carbohydrate-restricted or fat-restricted diets, and on average, the proportion of Bacteroidetes bacteria enumerated via 16S rRNA gene sequencing increased over time, mirroring reductions in host weight but not changes in diet.[4] Together these studies showed that the gut microbiota was generally altered in the obese host and could contribute to host adiposity in humans and mice.
Metagenomics and Obesity
A subsequent and much larger study of the microbiome associated with obesity conducted with humans also showed that obesity was associated with a depletion of Bacteroidetes, together with an enrichment in carbohydrate and lipid-utilizing genes in the microbiome as a whole. Turnbaugh et al.[
5••] focused on twins to assess the gut microbiota's relationship to host weight. The fecal microbial communities of young adult female monozygotic (n = 31) and dizygotic (n = 23) twin pairs concordant for either leanness or obesity were compared, along with those of their mothers (n = 46), using a combination of traditional 16S rRNA gene clone libraries and high-throughput metagenomic analyses of the microbiome. Fecal samples were obtained from the majority of participants at an initial time point and then again 2 months later. Comparisons between all 154 participants showed obesity to be associated with reduced bacterial diversity and reduced representation of the Bacteroidetes. Furthermore, the microbiome differed between obese and lean hosts in much the same way it had in the obese mouse model, with obese host microbiomes enriched in gene categories involved in carbohydrate and lipid metabolism.
Varied Patterns of Microbial Ecology in Relation to Weight
This and other patterns of fecal microbial ecology in relation to body weight in humans have been reported
recently,[4,5••,6–9,10••,11•,12,13,14•] and these are summarized in Table 1 . In studies that examine the effect of weight loss on the abundance of Bacteroides-related taxa, the relationship has been rep
orted as positive,[12] neutral,[9] and negative.[11•] It is noteworthy that rather than using broad 16S rRNA gene surveys or metagenomics to assess the composition of microbial communities, these studies enumerated specific taxa using probes, which can differ between studies (e.g., [11•], vs. [9]). Thus, the varying patterns of association between microbial taxa and host weight raise the question of how much impact the differences in methodology can have on the patterns observed. Biases are inherent to all of the methods employed in studies of microbial ecology, and the degree of bias can vary between samples within a study. For instance, several of the studies listed in Table 1 use fluorescent in-situ hybridization (FISH) with group-specific oligonucleotide probes targeting the ribosomal RNA as a starting point to enumerate (by microscopic counts or cell sorting) cells belonging to specific microbial taxa. FISH reveals a limited fraction of cells (roughly 20–30% of bacterial cells in a given sample cannot be stained with FISH[6,9]) either due to cell permeability or probe mismatch issues. In addition, any method that relies on specific oligonucleotide probes (e.g., qPCR and FISH) is inherently limited by the fact that without a 16S rRNA gene-based survey of the overall diversity within a sample, the specificity of the selected probes will be uncertain. Indeed, each time a new participant's microbiota is surveyed, novel diversity is described: the overall diversity of humanity's microbial diversity is far from circumscribed. It would be highly informative for all of these common methods to be applied together within a single study so that we can begin to understand ho
w they relate. In addition, researchers are calling for standardized approaches for sample processing.[15,16]
Table 1. Human studies of gut microbial ecology in relation to body weight
Author Participants Method
(sample type)
Finding
Ley et 12 obese
participants on one
of two diets,
16S rRNA
surveys by
Sanger
Proportion of Bacteroidetes sequences increased over time, on
average, and correlated with weight loss. No difference between
Ley et al.[2]of two diets,
carbohydrate or fat-
reduced, for 1 year;
two lean controls
Sanger
sequencing
(feces)
average, and correlated with weight loss. No difference between
diets
Turnbaugh et al.[5••]154 participants, MZ波多野结衣作品
and DZ twins and
mothers, obese or
lean
16S by Sanger
and 454
pyrosequencing,
metagenomics
(feces)
Reduced levels of diversity, and reduced levels of Bacteroidetes
in obese participants; metagenomes of obese participants
enriched in energy-harvesting genes
Schwiertz et al.[6]30 lean, 35
overweight, 33
obese participants期中考试反思总结
qPCR for
Bacteroidetes,
Actinobacteria,
Archaea (feces)
More Bacteroidetes in overweight and obese vs. lean
participants, and more Methanobrevibacter in lean participants
Collado et al.[7]Women before and
during pregnancy, 18
overweight
participants and 36
controls
FISH/flow
cytometry and
qPCR (feces)
Higher levels of Bacteroidetes and S. aureus in overweight,
positive correlation between Bacteroides levels and weight gain
over pregnancy
Sotos et al.[8]8 obese and
overweight
adolescents during
weight loss
FISH (feces)
Enterobacteriaceae and sulfate-reducing bacteria reduced in
group with greatest weight loss. Reduced levels of
Roseburia–Eubacterium in those with less weight loss
Duncan et al.[9]Participants on
weight loss diets
over 8 weeks vs.
weight maintenance
FISH counts
(feces)
No difference in Bacteroidetes levels between groups; reduced
levels of Roseburia and Eubacterium, and increased levels of
Clostridium spp., correlate with reduced carbohydrate intake
Kalliomaki et al.[10••]Obese and
overweight children
(n=25) and normal
weight children
(n=24); prospective
study
文梦洋个人资料qRT-PCR and
FISH/flow
cytometry
(feces)
Children remaining lean at age 7 had higher levels of
Bifidobacteria and lower levels of S. aureus, as infants
Santacruz et al.[11•]36 adolescents on
diet and physical
activity, 10 weeks
qPCR (feces)
Bacteroides fragilis abundance correlated with carbohydrate
intake. Levels of Bacteroides and Lactobacillus increased with
weight loss
Nadal et al.[12]39 adolescents on
diet and physical
activity, 10 weeks
qPCR (feces)
Clostridium histolyticum and E. rectale–C. coccoides reduced
with weight gain; increase in Bacteroides–Prevotella in high
weight loss group
Sabate et al.[13]137 obese patients,
40 healthy controls
Glucose-
hydrogen breath
test (for H2)
and liver biopsy
(breath, liver)
Bacterial overgrowth in small intestine more common in obese
vs. lean participants
Zhang et al.[14•]3 lean, three obese,
and three postgastric
bypass participants
Sanger and 454
sequencing of
16S rDNAs,
qPCR (feces)
Firmicutes more abundant in lean participants, lowest after
gastric bypass. Gamma-Proteobacteria and Verrucomicrobia
enriched after gastric bypass; higher Archaea in obese
participants; overall communities of gastric bypass and obese
participants more similar to each other than to lean participants
DZ, dizygotic; FISH, fluorescent in-situ hybridization; MZ, monozygotic.
Table 1. Human studies of gut microbial ecology in relation to body weight
Author Participants Method
(sample type)
Finding
Ley et al.[2]12 obese
participants on one
of two diets,
carbohydrate or fat-
reduced, for 1 year;
two lean controls
16S rRNA
surveys by
Sanger
sequencing
(feces)
Proportion of Bacteroidetes sequences increased over time, on
average, and correlated with weight loss. No difference between
唐于鸿个人资料diets
Turnbaugh et al.[5••]154 participants, MZ
and DZ twins and
mothers, obese or
长途跋涉的肉羹lean
16S by Sanger
and 454
pyrosequencing,
metagenomics
(feces)
Reduced levels of diversity, and reduced levels of Bacteroidetes
in obese participants; metagenomes of obese participants
enriched in energy-harvesting genes
Schwiertz et al.[6]30 lean, 35
overweight, 33
obese participants
qPCR for
Bacteroidetes,
Actinobacteria,
Archaea (feces)
More Bacteroidetes in overweight and obese vs. lean
梦见佛祖participants, and more Methanobrevibacter in lean participants
Collado et al.[7]Women before and
during pregnancy, 18
overweight
participants and 36
controls
FISH/flow
cytometry and
qPCR (feces)
Higher levels of Bacteroidetes and S. aureus in overweight,
positive correlation between Bacteroides levels and weight gain
over pregnancy
Sotos et al.[8]8 obese and
overweight
adolescents during
weight loss
FISH (feces)
Enterobacteriaceae and sulfate-reducing bacteria reduced in
group with greatest weight loss. Reduced levels of
Roseburia–Eubacterium in those with less weight loss
Duncan et al.[9]Participants on
weight loss diets
over 8 weeks vs.
weight maintenance
FISH counts
(feces)
No difference in Bacteroidetes levels between groups; reduced
levels of Roseburia and Eubacterium, and increased levels of
Clostridium spp., correlate with reduced carbohydrate intake
Kalliomaki et al.[10••]Obese and
overweight children
(n=25) and normal
weight children
qRT-PCR and
FISH/flow
cytometry
Children remaining lean at age 7 had higher levels of
Bifidobacteria and lower levels of S. aureus, as infants
Animal vs. Human Studies
In contrast to studies performed in humans, studies of gut microbial ecology and obesity conducted in animals tend to have less variable outcomes. Studies in rats and pigs have reported greater abundances of Bacteroidetes associated with the lean state,[16–18,19••] as observed in ob/ob mice.
In a systems-biology approach, Waldram et al .[20••] studied a rat model of obesity, characterizing gut microbiotas in parallel with metabolites. Results broadly support patterns of
greater Firmicutes/Bacteroidetes ratios observed in other animal studies. In addition, specific bacteria were associated with the obese phenotype (Halomonas and Sphingomonas ), as were lower total bacterial counts and lower
Bifodobacterial counts; furthermore, differences in microbial community composition correlated with differences in
metabotypes.[20••]
Is the variation in outcomes of human studies related to the complexity of the human lifestyle? In animal studies, diet can be controlled precisely – this precludes any potentially modulating effects of variations in diet between participants (e.g., see [21] where specific microbial taxa respond to changes in a diet's content of specific carbohydrates). Yet,
average human diets that are not designed for weight loss may add noise to data rather than skew results one way or another. Indeed, in a comparison of human vegetarians and omnivores allowed to
eat their normal diet, Tap et al .[22•]did not note any major differences between gut microbiotas for the two diet groups. Rather than the composition of the diet, another factor that may be important to consider is how the food is ingested throughout the day, for instance, how long the fasting periods last. Fasted mice have been shown to harbor a greater proportion of Bacteroidetes in their ceca compared with unfasted mice with equivalent body fat.[23] Thus, the frequency with which food enters the bowel and its transit time may be important factors to control for, or at least note, when comparing studies in humans.
Prospective Studies
The question of whether or not a microbial community can predispose a host to weight gain or loss has been
addressed in animal models and human studies. One approach to this question has been to control the composition of (n =24); prospective
study
(feces)Santacruz
et al .[11•]
36 adolescents on diet and physical activity, 10 weeks qPCR (feces)Bacteroides fragilis abundance correlated with carbohydrate intake. Levels of Bacteroides and Lactobacillus increased with weight loss Nadal et
al .[12]39 adolescents on diet and physical
activity, 10 weeks qPCR (feces)
Clostridium histolyticum and E. rectale –C. coccoides reduced with weight gain; increase in Bacteroides –Prevotella in high weight loss group Sabate et
al .[13]137 obese patients,40 healthy controls Glucose-hydrogen breath test (for H 2)and liver biopsy
(breath, liver)
Bacterial overgrowth in small intestine more common in obese vs. lean participants Zhang et
al .[14•] 3 lean, three obese,and three postgastric bypass participants Sanger and 454sequencing of
16S rDNAs,qPCR (feces)Firmicutes more abundant in lean participants, lowest after gastric bypass. Gamma-Proteobacteria and Verrucomicrobia enriched after gastric bypass; higher Archaea in obese participants; overall communities of gastric bypass and obese participants more similar to each other than to lean participants DZ, dizygotic; FISH, fluorescent in-situ hybridization; MZ, monozygotic.
addressed in animal models and human studies. One approach to this question has been to control the composition of the initial microbial community directly. This is accomplished by administering whole microbiotas of known composition by oral gavage straight into the stomach of germ-free (usually mouse) recipients housed in asceptic isolators. As mentioned above, the result of such 'transplantation' of the gut microbes from obese (genetic or diet-induced models) to lean germ-free recipient mice is greater weight gain for mice that received obese-microbiotas.[3,19••] Although these transplantation experiments are highly artificial, they show that a microbiota can predispose the host to greater weight gain, and recent studies have shown these findings to be relevant to human health. Kalliomaki et al.[10••] compared groups of children over time and observed that those who became overweight by age 7 had had lower levels of Bifidobacteria and higher levels of Staphylococcus aureus as infants compared with those that kept a healthy weight. These researchers had banked samples over time and were able to go back to interrogate the microbiota of
the same individuals prospectively. In shorter-term study, Santacruz et al.[11•] found that the response of overweight adolescents to a diet and exercise weight-loss program was dependent on the initial microbiota prior to the treatment. Both of these studies demonstrate that the microbiota are differentiated between people prior to the change in weight, which suggests that therapeutic interventions aimed at reshaping the gut microbiota may be beneficial for weight loss as well as preventive against weight gain.
Other Body Habitats
Clearly, obesity can be associated with a dysbiosis of the microbiota from the lower intestinal tract; recently, researchers have extended this observation to other parts of the body. In a study of the oral microbiota, Goodson et al.[24] show differences in the diversity and abundances of salivary bacteria between overweight and healthy weight people. Specifically, they found that Prevotellas (a group within the Bacteroidetes phylum) were in greater abundance
in the overweight and Selenomonas was present only in the overweight individuals, suggesting that these taxa could be biomarkers for excess adiposity. Traveling further down the gastrointestinal tract, bacterial overgrowth in the small intestine has been shown to be more common in morbidly obese p
atients than in healthy weight individuals.[13] Although preliminary, these studies indicate that obesity may be associated with a dysbiosis of the normal microbiota throughout the body.
Mechanisms Linking the Microbiota to Obesity
Obesity is associated with a number of chronic conditions, including inflammation, insulin resistance, type II diabetes, hepatic steatosis, and cardiovascular disease. A number of recent studies have focused on the mechanistic links between gut microbes and specific conditions associated with obesity (for more in-depth reviews see [25•,26]). Combining studies of host-microbial interactions relevant to obesity with studies of microbial diversity should lead to a more comprehensive understanding of which microbes, or microbial products, are the best targets for interventions (such as pharmaceutical mimicry) aimed at improving health, aiding weight loss, or preventing weight gain.
Gut Microbes and Host Metabolism
The microbiota can influence host adiposity through energy extraction from the diet, with variable efficiency depending on community composition; furthermore, the microbiota can also affect host adiposity by influencing metabolism throughout the body. Germ-free mice raised in asceptic isolators are significantly leaner than conventionally raised mice despite their considerably greater food intake,
and, in addition, they are resistant to diet-induced obesity and insulin resistance.[27,28] Presence of a microbiota increases serum levels of glucose and SCFAs, which can induce triglyceride production in the liver, and is associated with greater adiposity and reduced glucose tolerance.[28]
Bäckhed et al.[27] showed that the gut microbiota regulates an important gut-derived regulator of host lipid metabolism, angiopoietin-like protein 4 (Angptl4), also known as Fiaf, or fasting-induced adipose factor. Angptl4 regulates fatty acid oxidation in both muscle and adipose tissue.[29] When a normal mouse microbiota is administered to germ-free mice, Angptl4 production is suppressed in the intestine and a greater proportion of triglycerides are deposited in adipose
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