Discussion
obesity, weight gain, satiety
OBESITY
Microbial communities in the gut have a profound impact on mammalian host endocrinology, physiology, and energy balance, with most causal inferences historically restricted to preclinical animal modelsThe greater fecal energy loss translated to an additional 116 kcal/day lost in feces when participants were fed the MBD as compared to the WD. The clinical significance of this difference can be inferred from the reduction in food intake needed to maintain a weight-reduced state with obesity pharmacotherapy which has been modeled to be approximately 200 kcal/dayThe direction of change in energy absorbed from the diet by the host (lower on the MBD) was consistent in 16 out of 17 study participants. This means that the gut microbiome of most of our participants had the capacity to utilize available dietary substrates as evidenced by changes in relative abundance of species capable of utilizing those substrates. This observation is contrary to the “extinction” hypothesis proposed in miceThe reduction in host metabolizable energy on the MBD relative to the WD was not accompanied by a change in energy expenditure or an increase in hunger or ad libitum energy intake. However, the significant diet-induced modulation of the gut microbiome was accompanied by a modest change in weight/body composition and robust enteroendocrine signals from the adipose-pancreas-gut axis. Our results support the hypothesis that an intentional remodeling of the gut microbiome through provision of adequate dietary fiber, resistant starch, and a focus on whole, minimally processed foods resets the integrated sensing mechanisms known to affect food intake and body energy stores. One or more of these mechanisms or other unknown mechanisms might be responsible for the associations between a diverse human gut microbiome and lower body mass index in free-living humansThe quantitative contributions of gut microbes to host energy balance were addressed in two ways. First, the microbial biomass was modeled to contribute to >25% of the total fecal energy on both diets. Second, fermentation increased as evidenced by increased fecal and serum SCFAs on the MBD as compared to the WD. Thus, host energy absorption shifted towards microbially produced SCFAs and away from proximally digested and absorbed nutrients. While the quantitative contribution of microbially generated SCFAs as inputs to host energy balance was negated by the additional loss of microbial biomass in the feces, the uptake of more microbially produced SCFAs was associated with increased total GLP-1 and PP concentrations which may trigger important energy homeostasis signaling cascades to promote satiety and suppress hungerWe also found a taxonomic signature that was in alignment with the expected impacts of the substrates available to the gut microbes on the two diets. Many of the species detected at higher abundance on the MBD were fiber degraders and/or butyrate producers. We posit that the higher relative abundance of microbes that produce SCFAs could modulate several components of the energy balance equation. For example, Host metabolizable energy was highly variable on the MBD. Given our tight control of energy intake and energy expenditure, this suggests that the microbial contribution to this variability was greater in some hosts than others. Indeed, with a proportionally equivalent input of substrates for microbes, fecal energy losses varied over an ~5-fold range. Next steps should include investigating the mechanisms by which the microbial communities in the human colon modulate energy balance and their interaction with host factors such as CTT, which will provide valuable quantitative data to drive personalized strategies to optimize host-microbiota-diet interactions and prevent or treat obesity.Our in silico mathematical model, which accurately estimated host metabolizable energy measured in our study, allowed us to predict the quantitative contribution of biomass to fecal energy harvest and the 2-fold greater uptake of microbial derived SCFAs on the MBD than on the WD. In addition, we found that microbial biomass and fecal propionate (a surrogate of colonic fermentation) explained over half of the variance in host metabolizable energy. This further supports our hypothesis that the gut microbiome is an important component of diet modulation of host energy balance. We believe that by optimizing CTT, biomass, and SCFA production through diet, among other factors that may be revealed in future studies, the highly adaptable gut microbiome can serve as a target for personalized medicineOur results collectively indicate that when dietary substrates are less available to the gut microbes (as with the WD), the microbes are “starved” of host diet-derived substrates. This is in agreement with the findings from Sonnenberg et al.Our study had several limitations that should be considered when interpreting our results. Although our data revealed key gut microbiome contributions to human energy balance, we were unable to deconvolute the complex human host-diet-gut microbiome interactions and therefore, cannot establish whether the changes in energy balance we observed are causally attributable to the diet, the microbes, or some combination. Future directions to address these gaps include implementing bioinformatic pipelines that allow for absolute quantification of microbial speciesA key open question to advance this field is whether and how obesity or caloric restriction impact diet-gut microbiome effects on human energy balance. Given the size and scope of the global obesity epidemic and its continued increase, new solutions are needed. The scientific community has recently reoriented itself towards population interventions that promote small changes in energy intake and expenditure as a means of preventing weight gain