Intestinal Reg3g as a mediator of dietary, pharmacological and surgical therapies for obesity and diabetes

The gastrointestinal (GI) tract has become an important source for our most effective therapies to manage obesity and type 2 diabetes. This includes both surgical interventions, such as vertical sleeve gastrectomy (VSG), as well as pharmacological agents that mimic the effects of one or more GI hormones. Despite this, there remains a great deal unknown about the impact of the GI tract on systemic metabolism and the regulation of energy balance.

The GI tract is uniquely situated because it must compromise between keeping out toxins and bacteria while simultaneously absorbing necessary calories and nutrients. The gut-barrier keeps host and bacteria appropriately segregated using both physical components such as tight junctions and mucus production, as well as secreted factors such as anti-microbial peptides.

One such anti-microbial peptide is Reg3g (regenerating islet-derived protein 3 gamma) is abundantly secreted by paneth cells in the small intestine. We have spent the last 4-years carefully documenting how Reg3g regulates gut function, energy balance and glucose levels in response to VSG.

Bariatric surgeries such as VSG greatly increase gastric emptying rates, placing an enormous burden on the intestine. This results in many intestinal adaptations, which includes increasing the prevalence and abundance of Lactobacillus as well as increasing both expression and circulating levels of Reg3g. We found that Reg3g knockout (KO) mice fail to mount many of these important adaptations, including an increase in the integrity of the gut-barrier.

Importantly, these mice also fail to lose significant body fat, improve their glucose tolerance and increase their insulin secretion after VSG. Moreover, pharmacological administration of Reg3g in the periphery improved glucose tolerance, and direct administration of Reg3g in the central nervous system (CNS) reduced food intake. These results support our overarching hypothesis that Reg3g acts both within the lumen and as a circulating gut hormone to regulate energy balance and glucose levels in effective dietary, surgical and pharmacological therapies. We will test this overarching hypothesis in 3 aims:

Specific Aim 1: To test the hypothesis that dietary and pharmacological treatments that improve glucose regulation and increase Lactobacillus exert key beneficial effects by increasing the expression and/or circulating levels of intestinal Reg3g. Our data show that VSG increases Lactobacillus and both intestinal expression and circulating levels of Reg3g.

In addition, we found that Reg3g is required for many of the positive metabolic outcomes of VSG. Both oral administration of metformin and diets high in the soluble fiber inulin also increase the abundance of Lactobacilli in the small intestine and improve glucose regulation, such as occurs with VSG. We hypothesize that these interventions will also increase Reg3g in the intestine and in circulation and that Reg3g will be essential for metformin and inulin to improve gut function, body weight and glucose regulation. We will use these interventions in WT and Reg3g KO mice to test this hypothesis.

Specific Aim 2: To test whether intestinal microbiota and its products can produce beneficial effects on GI and metabolic function by increasing intestinal Reg3g. First, we will administer a variety of probiotics to mice and test their ability to increase Reg3g intestinal expression and circulating levels. These probiotics will include various species of Lactobacillus or a pre and probiotic combination that can also produce lactate.

Then, we will determine whether their effects on gut function, energy balance and glucose regulation are dependent on Reg3g using WT and Reg3g KO mice.

Despite the centrality of the gut for treatments of obesity and diabetes, the relationship between the intestinal microbiome, gut health and metabolic regulation is fraught with unanswered questions. This proposal hypothesizes a novel role for Reg3g as a signal that communicates the status of intestinal bacteria and the gut barrier to regulate multiple aspects of systemic metabolism.

As such, the proposed work provides a new framework for understanding how the gut affects metabolic disease and opens new therapeutic approaches that might range from dietary supplements and pharmacology to surgical procedures that can harness Reg3g biology to prevent and/or treat GI and metabolic disease.