A Role for the Host-Microbe Interface in Obesity

by Tim

Our bodies are home to 10 times more bacterial cells than human cells. With such sheer numbers, we have developed an intricate balance with the mutualists living on our skin and in our guts. Their mere presence is vital for protection from pathogenic species; but at the same time, our immune system must keep their numbers in check to prevent overgrowth.

Those bacteria within our guts perform important roles in fermenting carbohydrates and producing essential nutrients like vitamin K and biotin. As such, it is not too difficult for us to realize the importance of our gut flora in our health. I do not even need to mention the countless mainstream (and not so mainstream) probiotic supplements available in grocery stores.

Over the last few years, there have been a number of studies demonstrating the importance of gut flora in proper metabolic function, where dysfunction yields obesity. One article published in Nature in 2006, described a microbiome sequence comparison of obese vs. lean mice, finding the ratios of different phyla between the two mice strains. A few complementary studies have been performed since with the same result: the metabolism of the microbes in the gut is directly linked to the host's metabolic health.

This raises the question, how is gut flora composition determined? While studying up on some innate immunology literature for my qualifying exam, I came across this fantastic article set for publication in Science describing the role of the innate immune system in regulating those microbes necessary for proper metabolic function.

The authors describe the metabolic dysfunction of Toll-like Receptor 5 knockout mice. TLR5 is a receptor present on innate immune cells and intestinal epithelium and is responsible for sensing bacterial flagellin, subsequently priming cells for an immune response. Interestingly, mice deficient in TLR5 show drastic metabolic dysfunction; the authors go to a great extent characterizing this phenotype. Everything from fat pad size, to blood glucose, insulin, cholesterol and triglyceride levels are significantly increased in the mutants.

Furthermore, when the gut flora of the TLR5 knockout mice are depleted by antibiotics, the metabolic dysfunction clears and the mice's metabolism returns to wild-type levels. To top it off, the gut flora of TLR5 knockout mice were removed and introduced to wild-type germ-free mice. The introduced gut flora induced metabolic dysfunction in these wild-type mice identical to that of the TLR5 knockouts.

Unlike previous studies which saw different ratios of bacterial populations between obese and lean mice (ie. %Firmicutes vs %Bacteroidetes), this study found that instead specific species were present or absent in the TLR5 knockouts, indicating a role for TLR5 in maintaining specific characteristics in population of gut microbes.

This is the first study, to my knowledge, which equates mucosal immune surveillance with a metabolic phenotype. Furthermore, it strengthens the argument that the complex interactions we have with our bacterial symbiotes are vital to our physiology. The microbes around us do more than just cause disease or ferment our cheese, but are also key in allowing us as an organism to function.

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Source:
Vijay-Kumar, M., Aitken, J., Carvalho, F., Cullender, T., Mwangi, S., Srinivasan, S., Sitaraman, S., Knight, R., Ley, R., & Gewirtz, A. (2010). Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 Science DOI: 10.1126/science.1179721

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Other Articles of Interest:
How Helicobacter Gets Around
A Home for the Bugs in Our Appendix
A MAP to Crohn's Disease: Revisiting Koch's Postulates
Altruism in Bacteria: Allowing Yourself to Die for the Good of the Species