Obesity and the Human Microbiome

Ruth E. Ley

Disclosures

Curr Opin Gastroenterol. 2010;26(1):5-11. 

In This Article

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 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 reported 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 how they relate. In addition, researchers are calling for standardized approaches for sample processing.[15,16]

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 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 patients 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.

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