Obesity and type 2 diabetes are arguably two of the most challenging health problems afflicting society today, with large amounts of research dedicated to their cause, prevention and amelioration. Many models of obesity in research are the product of genetic knock out (eg ob/ob mice), yet obesity in humans is widely accepted as resulting from dietary and lifestyle factors, often spanning generations.
The “Thrifty Jerry” is a model of multigenerational (50 generations) undernutrition, wherein undernourished rats become more obese and insulin resistant following unrestricted access to commercial chow (Transition/Obese rats). Obese rats show significant differences in gut microbial composition, with changes in proportions of Bacteroides and Firmicutes. In order to understand if differences in gut microbiome were causal to obesity and insulin resistance in these rats, we modulated gut microbial composition by exploiting the coprophagic nature of rodents. Repopulation of gut microbiota during 1 month of coprophagy was confirmed by sequencing. Surprisingly, during this time, an advantageous metabolic effects afforded for obese rats feeding from lean rat feacal matter was observed. Increased insulin sensitivity and circulating adiponectin was detected with reduced total adiposity (DXA) and circulating leptin. We observed that the beneficial effect may have been conferred by a group of bacteria that synthesize several short chain fatty acids. In order to understand the effect of short chain fatty acids (SCFA) on glucose-insulin metabolism, we used several in vitro and in vivo approaches. Exposure to SCFAs using in vitro gut epithelial explants as well as in vivo sustained delivery using Alzet pumps, confirmed the role of SCFA in conferring beneficial metabolic effects.
Our data indicates that changes in dietary habits can influence the propagation of specific gut microbiota that influence the expression of host transcriptome, epigenome and metabolome, thereby playing an important role in development of obesity and type 2 diabetes.