The impact of multigenerational high-fat diet feeding on the gut microbiome and host metabolism

Although human genetics partially explain the heritability of obesity and type 2 diabetes (T2D), the human gut microbiome also plays a significant role. While changes in human genetics at the population level occur only after many generations, the gut microbiome evolves over a shorter time span. The gut microbiome is also vertically transmitted across generations, therefore, changes in one generation can be passed on to subsequent generations. However, it is unknown whether the gut microbiome influences natural selection of its host under obesogenic pressure. Here, we show that C57BL/6 mice fed a high-fat diet (60% fat, HFD) over four generations develop resistance to obesity and the metabolic syndrome (MetS). Unexpectedly, the mice were increasingly leaner as well as more glucose tolerant and insulin sensitive across generations. This phenomenon was attributed to the most obese mice not yielding progenies, whereas the leanest mice successfully reproduced, and their offspring were also resistant to obesity. In other words, a population bottleneck was observed. Because all the mice were nearly genetically identical inbred C57BL/6J mice, the large variation in body weight gain in response to HFD feeding was likely independent of genetics. We explored whether microbial factors enriched in obesity-resistant mice promote healthier host metabolic phenotypes under HFD feeding, thereby contributing to the heterogeneity in body weight gain and providing an adaptive advantage to the host. Pearson correlation analysis revealed that body weight gain was positively correlated with Lactococcus lactis, as well as negatively correlated with Lactobacillus johnsonii and pathways for coenzyme A biosynthesis, amino acid biosynthesis (lysine, isoleucine, valine), and nucleotide biosynthesis (adenosine, guanosine). Overall, we observed multigenerational adaptation in the gut microbiome correlated with improved metabolism, yet further studies are needed to validate that these adaptations drive metabolic health.