1) What is your background ?
I am a gastrointestinal physiologist with an interest in understanding the contributions of the gastrointestinal tract in regulating energy balance and metabolism. I received my DVM (veterinary) degree and my PhD degree in physiology at the University of California, Davis. Under the mentorship of both Helen Raybould at UC Davis and Stephen Wank at the National Institutes of Health, I studied the mechanisms of luminal nutrient sensing by enteroendocrine cells of the gastrointestinal tract. Since 2010, I’ve served as a postdoctoral research fellow in Lee Kaplan’s laboratory at Massachusetts General Hospital (MGH) to examine potential mechanisms by which gastric bypass surgery causes rapid and sustained weight loss and remission of type 2 diabetic symptoms, using the mouse models of gastric bypass that were developed in his laboratory.
2) What is the context of this study ?
Gastric bypass surgery in obese human patients and in mice leads to profound weight loss, decreased adiposity, and improvements in type 2 diabetes. These effects are not due primarily to the inability to consume or absorb ingested nutrients. Rather, something about the anatomical rearrangement of the gastrointestinal tract (and the likely alteration in the luminal milieu) alters the way in which the gastrointestinal tract signals to other organ systems to regulate body weight, body fat, energy balance, and metabolic function. Given the increasing evidence supporting a role of the gut microbiota in influencing the pathophysiology of obesity and related metabolic disorders, we hypothesized that alterations in the gut microbiota following gastric bypass may be, in part, contributing to the beneficial effects of surgery. There has already been evidence in both human patients and in rat models of gastric bypass that the gut microbiota is altered after surgery, but the question remained whether this microbiota could directly mediate beneficial outcomes. For this study, we set out to achieve two aims: 1) to characterize how gastric bypass affects gut microbial communities in an obese mouse model (both across time and along the gastrointestinal axis) and 2) to determine whether there these microbial communities could have an effect on phenotype in non-operated mice. To be able to do these studies, we collaborated with Peter Turnbaugh and his laboratory at Harvard University. Working with the gnotobiotic facility at the Harvard Digestive Diseases Center (HDDC), we approached the second aim by transferring the microbial contents from surgically operated mouse donors to germ-free mice.
3) What was the most challenging part of this study ?
To design the experiment aimed towards answering our questions was relatively straightforward. The ability to logistically execute such a study and coordinate efforts between MGH, Harvard, and the HDDS was a bit of a challenge, but I’ve been fortunate to work closely with many talented, dedicated people who have helped move this study forward. It has also been challenging working within a germ-free mouse system, as the difficulty in performing routine physiological assessments is increased several fold once the mouse is placed in a sterile, space-restricted environment. Simple things I normally take for granted such as using a weigh scale, obtaining blood samples, and using a glucometer, suddenly becomes complicated when you are forced to consider what can and cannot be done in an absolutely sterile or gnotobiotic environment. It has involved a bit of creativity and a bit of compromise, but those are the things that keep working in the lab interesting.
4) What was the main findings ?
The main findings are as follows:
- the microbiota is substantially changed as a result of gastric bypass. These changes are unique to gastric bypass, are independent of diet, and are not due to weight loss alone.
- the altered microbiota after gastric bypass can confer several of the effects of surgery when transferred into a lean germ-free animal that has not had the surgery; those effects include decreased body weight and decreased body fat
- the altered microbiota may exert these beneficial effects in part by activating energy expenditure in the host
- the altered microbiota may influence body weight and fat in the host (mouse) by altering the balance of selected fats (short chain fatty acids) that are made by the gut bacteria and absorbed by the host
5) What are limitations ?
In these studies, the germ-free recipient mice were lean and maintained on normal chow. Therefore, we had unintentionally biased the experiment against ourselves in that the sensitivity of detecting an improvement in either body weight or glucose metabolism would be low. Despite these, we were pleasantly surprised that a change in adiposity and body weight, and what trends to be an improvement in some glucose parameters, were detected. Future studies, using germ-free animals maintained on high fat diet are ongoing to determine whether this gut microbial transfer can further improve the phenotype. A second limitation is that we do not know, for sure, how long the effects of a gut microbial transfer will last in a non-operated germ-free animal. Our experiment was limited to 2 weeks, of which we saw changes in body weight and adiposity. During this time, we also provide data on the fecal microbial community structure changes over this two week period. While some communities change, certain populations (particularly the Verrucomicrobiales) are still sustained, which leads us to believe that this micro-organism may have some role in mediating the effects. It would be interesting to know for how long the RYGB microbial community is maintained in a non-operated animals, and whether particular micro-organisms like the Verrucomicrobiales play a larger role in mediating the beneficial effects of surgery. Also, it will be important to know whether the effects of RYGB microbial transfers done in germ-free animals can be repeated in conventionally raised mice.
6) How your study could help clinicians in the future ?
This is the first study that has shown that the benefits of gastric bypass surgery can, in part, be mediated by the altered microbial communities. It remains to be seen whether a similar approach could be useful in humans, but it does support the now increasing evidence that manipulations of the gut microbiota can affect health and that a greater understanding of gut microbial-host interactions is necessary. It is the hope that the results of future studies, aimed towards understanding what micro-organisms may be contributing a greater role in promoting ‘leanness’ and how these gut microbial communities mediate host energy balance, may lead to the development of effective non-surgical therapies for obesity and diabetes.