Is Bacteria to Blame for Obesity?

Recent news of a possible correlation between bacteria and obesity could have some patients asking clinicians for a quick fix to rid their bodies of the offending microorganism. A better approach may be to give patients a quick lecture in microbiology.

Burning more calories than one takes in is generally considered to be an effective weight management strategy. Yet some individuals do not lose weight despite strict adherence to this energy-balance equation. Why this is true is yet to be determined, but the search for an answer is under way at Washington University's Center for Genome Sciences and Genome Sequencing Center in St. Louis, where researchers are looking at the human body from the inside out.

“Our genetic landscape is a combination of human genes and microbial genes,” says Jeffrey I. Gordon, MD, “[and] they have formed strategic partnerships that are mutually beneficial.” Gordon guides an interdisciplinary team through their research of the gut microbiome portion of the genome to decipher the role these microbes play in human health.

Gordon's team initially identified a link between gut microbiota and the amount of energy mice harvested and stored from food. The team observed that conventionally raised mice—those harboring microbiota since birth—had 42% more total body fat than comparable mice raised in the absence of microorganisms. This held although the conventional mice consumed about 29% less chow than the germ-free mice. When the researchers colonized distal intestine microbiota from the conventional mice to the germ-free mice, the previously lean germ-free mice increased body fat by roughly 60% in just 14 days.¹

Clay F. Semenkovich, MD, chief of Washington University's Division of Endocrinology, Metabolism, and Lipid Research and a collaborator in the study, notes this “amazing observation” led to continued examinations in other mouse models and human subjects.

MICROBIAL PROPORTIONS MATTER

During their analysis of the gut microbial community structure of two mice sets from a common mother, researchers led by microbial ecologist Ruth Ley found differing proportions of two principal groups of gut bacteria most commonly associated with mammals, including humans, in the obese and lean mice. One set was genetically obese because of a leptin gene mutation, while the other was lean, carrying either a single copy or no copy of this mutation. Despite having the same diet, obese mice had a 50% higher representation of the gut bacterium Fermicutes and a proportionally lesser representation of the bacterium Bacteroidetes than the lean mice.²

Gordon notes that, among the obese mice, not just one member of the Fermicutes and Bacteroidetes respectively bloomed or diminished: “It was the entire group; a huge collection of microbes had shifted up or down.”

The gut microbial community of these same obese and lean mice then underwent sequencing by Peter J. Turnbaugh, a graduate student at the university's Center for Genome Sciences, with a new generation parallel DNA sequencer.³

“He discovered that the number of genes dedicated to breaking down complex carbohydrates (polysaccharides) was much better represented in the obese community than in the lean community,” Gordon says.

After confirming this finding through DNA-level biochemical testing, the researchers transplanted the gut microbial community from obese mice to germ-free mice and, likewise, from lean mice to germ-free mice. Though the germ-free mice weighed the same prior to transplantation and consumed the same amount of chow, the recipients of the obese microbes gained a greater amount of fat than recipients of the lean microbes.³

These findings “provided evidence that this increased capacity to harvest energy and to promote fat deposition was transmissible,” Gordon says, and again suggested gut microbes as participants.

BACTEROIDETES AND FERMICUTES: THE HUMAN SIDE

Because Bacteroidetes and Fermicutes are also the principal microbial groups in the human gut, a study involving human subjects was then initiated. Gordon, Ley, and Turnbaugh collaborated with Samuel Klein, director of the Center for Human Nutrition at Washington University, in a year-long analysis of the gut microbial communities in 12 obese volunteers randomly assigned to either a fat-restricted or a carbohydrate-restricted low-calorie diet.⁴

They compared each person's gut microbiota at baseline, 12 weeks, 26 weeks, and 52 weeks and report:

1. As in mice, baseline assessments showed obese subjects with a higher proportion of Fermicutes and a lower proportion of Bacteroidetes than lean controls;

2. As subjects lost weight, the proportional representation of the Fermicutes decreased and the proportional representation of the Bacteroidetes increased; and

3. These changes were irrespective of diet as well as proportional to the amount of weight lost.⁴

“And again, just like in mice, it wasn't one member of the Bacteroidetes that bloomed or one member of the Fermicutes that became more diminutive; it was the whole group,” Gordon notes.

“Whether this turns into anything that is therapeutically useful is completely unknown,” Klein reports, adding, “It was surprising that obese people had a different composition of gut flora than lean people and, when obese people lost weight, it was surprising their gut flora more resembled that of a lean person.”

Researchers found “remarkably constant” microbial lineages within individuals over time, noting “communities from the same person were generally more similar to one another than to those from other people.”⁴

Semenkovich says these combined findings “suggest the efficiency of our metabolism of food might be altered by the way our bodies interact with the millions of inhabitants of our intestines—the bacteria we live with from the time of birth.”

But, Gordon cautions, “We have not fully explored all aspects of digestion” and “are not in the position right now to be able to make any specific recommendations about how to adjust microbial communities [in] an individual or a group of individuals.” Gordon cautions against prescribing antibiotics for patients seeking to tamper with their digestive flora and fears many patients will seek probiotic pills found in health food or nutrition stores.

RESEARCH CONTINUES

The Genome Sequencing Center, with support from the National Human Genome Research Institute, is sequencing 100 human distal gut bacteria. Sequencing of the fairly abundant Fermicutes and Bacteroidetes, as well as other gut organisms, should help scientists to better identify the organisms' exact niches in the human digestive process. Additional sequencing of the gut microbiome of obese and lean individuals should distinguish any similarities or differences there.

University researchers also are assessing individual representatives of the human gut community, how they act in isolation, and how they interact in response to one or more other representatives. The researchers continue their work with mice, recently reporting that gut microbes alter lipid metabolism and fat cell deposits in mice. And the researchers have extended their reach to underfed people to see how altered energy intake affects gut microbes in this population.⁵

This research will not uncover “a magic bullet” or “a single contributor to obesity in an individual person,” says Semenkovich. But that does not detract from its importance: Klein asserts that these findings will “open up an entirely new area to evaluate regarding the potential therapeutic approaches for treating obesity in the future.” ▪