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Special thanks to Theodore Li (The English Teacher) for editing help.
Can you imagine getting the benefits of stomach stapling in pill form? Is it science fiction that bacteria in your gut can influence your mind? What are we talking about?
What are we talking about?
Biological pathways amaze me. What appears to be obvious and logical rarely is. Take the case of the surgical procedure called the VSG (Vertical Sleeve Gastrectomy). A VSG reduces the size of the stomach so that it resembles a tube, rather than a balloon, from the esophagus to the intestine. For a person struggling with obesity, the benefit of a VSG seems obvious. Reduced stomach size logically means less food in the stomach, which means that fewer calories can be consumed, which means weight loss and obvious benefits.
Reality, however, doesn’t always adhere to our logic. What if you could achieve some of the effects of VSG surgery without the surgery?
The really strange finding.
Restriction of stomach size doesn’t explain the fact that a substantial proportion of diabetic patients are able to stop taking their medications before weight loss has occurred. Something else must be happening.
Figuring out where to look.
The research group first used RNA Seq to look at changes in gene expression in the distal small intestine following VSG. They found that the expression of several genes had changed, and that the genes with changed expression levels were involved in lipid and bile metabolism. Some changes in gene expession implied changes in the populations of intestinal bacteria. The group found a common theme amongst the RNA seq data, which led them to focus on the Farsenoid-X Receptor, FXR.
Their hypothesis was that FXR helped to generate some of the benefits associated with VSG, so they predicted that a mouse without FXR would not get all the benefits of VSG.
Generating obese mice that don’t respond to VSG.
The group then created FXR, farsenoid-x receptor, knockout mice. After feeding the mice a high fat diet, basically cookie dough, the mice became obese. The group then performed VSG on both regular mice (wild type) and FXR knockouts.
The results
The wild type mice maintained weight loss while the weight of those lacking FXR rebounded. This data lead the group to believe that FXR was somehow necessary to maintain the weight loss. It wasn’t just the fact that the mice’s stomachs had been made smaller.
During the week following surgery both the knock-outs (missing FXR) and the wild-types (with FXR) decreased the amount they ate, but in the following weeks the wild type groups continued to eat less. The group missing FXR began to eat more. This indicates that FXR is necessary to stop the mice from returning to their original eating habits (eating a great deal).
The group also investigated the original claim that VSG patients gained back the ability to deal with glucose by clearing glucose from the blood stream. In the week after surgery, the regular VSG mice showed low resting glucose levels, a good sign. Animals with FXR (wt) were also able to clear glucose from the bloodstream more effectively than those without it. The mice showed the same results that people getting the surgery did, but only if they had FXR.
The really interesting results.
As there is a great deal of bacteria living in the intestine, the type of bacteria living there matters. I don’t want to oversimplify this and say that there are good and bad types, but some species ARE associated with lower rates of disease. Transplantation of bacteria from an obese animal to a healthy one has shown to induce weight gain. (Tremaroli, 2012)
Using a technique called UniFrac the group found changes in the intestinal bacteria of the VSG mice when compared to the VSG mice without FXR.
The end.
This brings us to the heart, or perhaps gut, of this paper. The group showed that FXR is necessary for some of the benefits of the VSG surgery in mice. Some of this effect is likely because FXR is effecting the amount of bile in the blood, which is in turn affecting the bacterial community in the gut and vice versa.
The new and exciting thing isn’t necessarily that the gut microbiota is influencing our eating habits. It IS a strange idea that bacteria in our stomach can influence our thoughts. It is that FXR may be mediating that relationship.
A couple notes. The research group was extremely careful when designing their experiments to be sure that they weren’t attributing the effects they saw to the fact that some of the mice they were dealing with were knockouts. They also noted that when a synthetic FXR was administered to mice, by other labs, there were different results.
KO
KO mice display some phenotypes that may have clouded some of the data collected. The group was careful in elucidating the difference between the KO phenotypes and the effect of the VSG.
RNA Seq
RNA Seq is an unbiased approach to looking at changes in gene expression. Rather than identifying a certain gene and looking at its expression it allows scientists to look at the total RNA produced in a group of cells and examine changes in expression. The scientists therefore aren’t looking at the effect of a procedure on a certain gene while disregarding all other genes.
Author’s conclusion
The thing that I love most about biology, is that it is humbling. No matter how creative, twisted, or strange our imaginations are, it always seems that the reality of biology is just a little better. What made this paper so interesting to me is the idea that we aren’t all human. I know it’s a little sensational, but the individual writing this article is made possible because of the interplay between many different life forms, specifically the human cells that compose the body proper and the bacterial cells that co-inhabit the same space. Neglecting them is a bad idea.
Obesity background
This paper is about the vertical sleeve gastrectomy (VSG), a treatment for obesity. Obesity is a complex problem involving myriad hormones, genetics, epigenetics and their interplay in the brain, the stomach, the intestine, and the pancreas. . . few things seem to work against obesity partly because nobody truly understands it. (That whole “just telling people to work out and eat better” doesn’t seem to be doing the trick)
References
Belstrøm, D., Damgaard, C., Nielsen, C. H., & Holmstrup, P. (2012). Does a causal relation between cardiovascular disease and periodontitis exist? Microbes and Infection. doi:10.1016/j.micinf.2011.12.004
Conterno, L., Fava, F., Viola, R., & Tuohy, K. M. (2011). Obesity and the gut microbiota: does up-regulating colonic fermentation protect against obesity and metabolic disease? Genes & Nutrition, 6(3), 241–60. doi:10.1007/s12263-011-0230-1
Ionut, V., & Bergman, R. N. (2011). Mechanisms responsible for excess weight loss after bariatric surgery. Journal of Diabetes Science and Technology, 5, 1263–82.
Ryan, K. K., Tremaroli, V., Clemmensen, C., Kovatcheva-Datchary, P., Myronovych, A., Karns, R., … Seeley, R. J. (2014). FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. doi:10.1038/nature13135
Tremaroli, V., & Bäckhed, F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature, 489(7415), 242–9. doi:10.1038/nature11552
Wang, Z., Gerstein, M., & Snyder, M. (2009). RNA-Seq: a revolutionary tool for transcriptomics. Nature Reviews. Genetics, 10, 57–63. doi:10.1038/nrg2484
VSG Information
http://www.nlm.nih.gov/medlineplus/ency/article/007435.htm
