Does the cure for obesity lie in the gut?

The human intestinal tract is host to tens of trillions of microorganisms. This vast population of microbes, collectively called the gut microbiota, is essential for normal gastrointestinal function and immunity. It also plays a vital role in metabolism — synthesizing micronutrients and regulating the process whereby calories are extracted from food and stored in fat tissue for future use.

Gastroenterologist John K. DiBaise, M.D., of Mayo Clinic in Arizona, notes that the gut microbiota has received increased scientific scrutiny over the past decade. In 2008, Dr. DiBaise's own interest in the influence of microbes on intestinal health and a search for viable alternatives to gastric bypass surgery led him to collaborate on a unique study with researchers at Arizona State University's Biodesign Institute.

Study goals were twofold: to explore how gut microbes facilitate the breakdown of nutrients and to examine the effects of successful weight-loss surgery on the intestinal microbiota. Nine test subjects were enrolled, three in each of three groups — people of normal weight, those who were morbidly obese and patients who had undergone successful Roux-en-Y gastric bypass surgery.

Corroborating the findings of previous research, the study confirmed marked differences in the gut microbiota of obese and normal weight individuals. The microbial populations in the obese group were high in Prevotellaceae, a hydrogen-producing subgroup of Bacteroidetes. These bacteria have a uniquely cooperative relationship with hydrogen-consuming methanogens, which were found in large numbers only in obese participants.

Methanogens aid the fermentation of dietary fiber by hydrogen producers such as Prevotellaceae. This increases the production of short-chain fatty acids, which are taken up by the intestinal epithelium and converted to fat. "Over time, more efficient breakdown of normally indigestible plant polysaccharides may lead to weight gain and ultimately to obesity," Dr. DiBaise says.

The study, the first of its kind, also demonstrated that surgical weight loss caused a significant shift in gut microbe populations, including a large increase in Gammaproteobacteria, a decrease in Firmicutes and a loss of methanogens. "Although the reasons for this dramatic change aren't entirely clear," Dr. DiBaise says, "we think it results from alterations to the intestine caused by the surgical procedure itself as well as subsequent changes in food consumption and digestion."

Expanding the research

Encouraged by the initial findings, Dr. DiBaise is continuing the investigation with a four-year study, funded by the National Institutes of Health, that aims to further explain the effect of surgical weight loss on gut populations.

The new study will have both a retrospective and a prospective phase. Researchers will retrospectively evaluate 30 patients who have undergone Roux-en-Y gastric bypass and, for comparison, 30 others who have undergone laparoscopic gastric banding. Half the surgeries in each group will have led to successful weight loss.

The prospective phase will focus on baseline assessments of the gut microbes in 10 gastric bypass and 10 laparoscopic banding patients using both stool samples and sigmoid mucosal biopsies. This is important because the microbes in stool and biopsy specimens play different roles in metabolism and immunity. The tests will be repeated at nine and 18 months postoperatively.

As in the original study, Arizona State University scientists will perform the gene sequencing using pyrosequencing, which allows the identification of larger and more diverse gut populations, and assist with other testing and interpretation of the findings.

"Right now, surgical interventions, especially Roux-en-Y gastric bypass, are the most effective way to treat morbid obesity long term," Dr. DiBaise says. "With this line of investigation, we hope to better understand the role that gut microbial changes play in a person's ability or inability to lose weight after bariatric surgery. Ultimately, a better understanding of the link between microbes and obesity may lead to nonsurgical methods for modifying the intestinal makeup — with prebiotics and probiotics, for example. These might prove an effective adjunctive treatment for obesity — one that has few adverse effects."