Transplanting fecal microbiota from twins discordant for obesity differentially affects metabolic activities in mice

The team of Jeffrey Gordon (Ridaura et al. Science 2013) published that the phenotype of obesity (increased adiposity) of an obese twin in a discordant twin pair is transmissible. In other words, they found that mice receiving an obese twin’s fecal microbiota display a greater fat mass than the mice receiving lean twin’s gut microbes.

Cohousing is widely used in mice studies to investigate the impact of sharing microbial communities (mice are coprophagic) on the host phenotype. In this paper, they found that cohousing obese and lean animals prevents increased adiposity. Thus obese cohoused mice exhibited a lower increased adiposity compared with obese animals that had never been exposed to mice harboring a lean “gut microbiota”. They identified several members of the Bacteroidetes phylum as successful “invaders” from the lean microbiota into the obese microbiota, however, whether these species were responsible for the lean-like state remain to be proven.

 

Meta-transcriptomic analyses revealed that mice harboring the microbiome from obese twins had 305 KEGG enzyme commission numbers (EC numbers) that were differentially expressed. More specifically, mice with the obese twin’s microbiomes exhibited a higher expression of microbial genes involved in detoxification and stress responses, metabolism of amino acids, biosynthesis of cobalamin and in the pentose phosphate pathway. Interestingly, they link these microbial functional changes with specific modifications of the amino acids profile in the sera of mice. They found that BCAA’s (branched amino acids) among others were increased in recipients of microbiota from obese compared with lean twins.

 

In contrast, the microbiome from lean co-twins was enriched in genes involved in digestion of plant-derived polysaccharides, fermentation of short chain fatty acids (SCFA’s) such as butyrate and propionate. Here again, the authors found that these transcriptomic signatures were associated with SCFA’s content, since they demonstrated that butyrate and propionate concentrations were increased in the cecal content of mice colonized with the transplanted microbiota from lean co-twins. Although these findings are not in accordance with their previous hypothesis which was directly linking energy harvest with SCFAs abundance, (Turnbaugh et al Nature 2006), these results are in accordance with previous studies showing that increased microbial fermentation of non-digestible carbohydrates in favor of propionate and butyrate production is associated with decreased body weight, adiposity and improved glucose/lipid metabolism (Cani et al. Brit J Nutr 2004, Delzenne and Cani Curr Opin Clin Nutr Metab Care 2005, Zhou et al J Agric Food Chem 2009). Interestingly, cohousing was also able to rescue these differences in SCFA’s profile.

 

The team also suggests a potential links between bile acids metabolism and metabolic effects. Several bile acids were more abundant in lean than in obese mice, and were similarly modified during cohousing. Accordingly, they found that intestinal mRNA’s of FXR, Fgf15 were up-regulated and hepatic Cyp7a1 down-regulated by the obese gut microbiota, thus the authors suggests that this may contribute to obesity since overexpression of Cyp7a1 in the liver of transgenic mice protects against obesity and insulin resistance (Li et al Hepatology 2012), however, the direct implication of bile acids in the phenotype observed in the present studies merits further investigation.

 

Thus this paper provides substantial evidence that specific microbial communities as well as their related metabolic capacities contribute to the modulation of energy homeostasis. This study also emphasize that a phenotype observed in human may be mimicked in mice and therefore used as a powerful preclinical model to screen the impact of specific nutrients or drugs on the gut microbiota and its impact on host phenotype.

Patrice D. Cani
Patrice D. Cani
Professor Patrice D. Cani is researcher from the Belgian Fund for Scientific Research (FRS-FNRS), group leader in the Metabolism and Nutrition research group at the Louvain Drug Research Institute (LDRI) from the Université catholique de Louvain (UCL), Brussels, Belgium, and WELBIO (Walloon Excellence in Lifesciences and BIOtechnology) investigator. He is currently member of several international associations, he is member of the Alumni College from the Royal Belgian Academy of Sciences, and he has been elected in the board of directors of the LDRI (UCL). Patrice D. Cani has a M.Sc. in Nutrition and another M.Sc. in health Sciences, he is registered dietitian and PhD in Biomedical Sciences. His main research interests are the investigation of the role of the gut microbiota in the development of metabolic disorders, such as obesity, type 2 diabetes and low grade inflammation. More specifically, he is investigating the interactions between the gut microbiota, the host and specific biological systems such as the endocannabinoid system and the innate immune system in the context of obesity, type 2 diabetes and metabolic inflammation. Prof Cani is author and co-author of more than 110 scientific research papers published in peer-reviewed international journals, conferences and book chapters.