Editors' ChoiceMicrobiome

From mouse to man? Not necessarily!

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Science Translational Medicine  10 Aug 2016:
Vol. 8, Issue 351, pp. 351ec129
DOI: 10.1126/scitranslmed.aah5488

The human intestine is home to trillions of bacteria, which in some estimates outnumber host cells in the body. Emerging evidence suggests that resident intestinal microbial communities not only enable us to efficiently harvest energy from our food but also function as an underappreciated endocrine organ capable of secreting metabolites that act as hormone-like factors to impact host metabolism and metabolic disease. There is now unequivocal evidence that microbes resident in the intestine can directly contribute to the pathogenesis of obesity, insulin resistance, cardiovascular disease, and several other related metabolic disturbances. However, the vast majority of studies supporting such links have been conducted exclusively in rodent models. Now, Reijnders et al. provide provocative evidence that the well-established links between gut microbiome communities and host metabolism in mice are not so easily translated in humans.

In their new study, Reijnders and colleagues performed one of the first randomized, double-blind, placebo-controlled trials in obese men with the primary focus of identifying metabolic effects of antibiotic treatment. The cohort under study was randomized into one of two antibiotic treatment groups (amoxicillin or vancomycin) or a placebo control group, and carefully monitored for either short-term (7 days) or long-term (8 week follow-up) effects on energy metabolism, glucose homeostasis, and metabolic endotoxemia (translocation of microbial- associated molecular patterns and lipopolysaccharide into the circulation). As expected, the vancomycin-treatment group showed drug-selective reorganization of gut microbial diversity and composition, which was associated with significant alterations in gut microbial metabolites such as short chain fatty acids and secondary bile acids. Surprisingly, even with large effects on bacterial metabolite levels, there were no significant alterations in energy or glucose homeostasis in either cohort treated with antibiotics. Although this study does highlight key differences between humans and mice after selective antibiotic treatment, it is limited by several factors including the short duration of antibiotic treatment, small sample size, and focus only on obese men. Even with these limitations, this study provides important new information for drug discovery in the microbiome space and strongly suggests that additional human studies are needed with additional antibiotic regimens and more targeted therapeutics.

Although drug discovery has historically targeted pathways in the human host, a fertile period in biomedical research lies ahead as we instead target the microorganisms that live within us to treat or prevent human disease. Within the last decade, technological advances have rapidly facilitated the identification of disease-relevant microbial participants, microbe-derived metabolites, and dedicated host receptor systems that sense microbial products. With this new information in hand, there is little doubt that “drugging” the gut microbiome will be an attractive approach to treat metabolic disease in the near future. However, it is unlikely that antibiotics will be viable drugs for this purpose given their pleiotropic effects and potential to promote antibiotic resistance. Given these caveats, antibiotics really only are tools to inform whether certain microbial communities are associated with disease risk factors. The results from Reijnders and colleagues remind us that the clinically-relevant understanding of microbe-host interactions is still in its infancy and highlight the critical need for additional clinical investigation into gut microbial pathways regulating host metabolism.

D. Reijnders et al., Effects of gut microbiota manipulation by antibiotics on host metabolism in obese humans: A randomized double-blind placebo-controlled trial. Cell Metab. 24, 63–74 (2016). [Full Text]

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