Dr. Alip Borthakur
Role of gut microbiota in health and disease
My research interests broadly encompass the role of gut microbiota cross-talk with host intestinal epithelium and its relevance to the pathophysiology of inflammatory bowel disease (IBD) and obesity.
Project 1: Probiotic bacteria stimulate intestinal nutrient/ion absorption and counteract dysregulated ion transport in IBD and infectious diarrhea
Project 2: Gut microbes regulate energy homeostasis in obesity
Project 1: Probiotic bacteria stimulate intestinal nutrient/ion absorption and counteract dysregulated ion transport in IBD and infectious diarrhea: Inhibition of electrolyte (NaCl) absorption is a hallmark of IBD and infectious diarrhea. Our studies delineated novel mechanisms underlying the beneficial effects of the probiotic Lactobacillus acidophilus in enhancing intestinal nutrient/ion absorption and counteract pathogen infection. We have partially characterized the L. acidophilus-secreted factors that stimulate intestinal Cl- absorption and counteract Citrobacter rodentium infection-induced diarrhea. My NIH-funded current research utilizes crypt-derived human intestinal organoids to delineate the molecular pathophysiology of cryptosporidiosis, a widespread diarrheal disease caused by Cryptosporidium infection and an emerging global health problem. Utilizing this novel ex vivo model as well as in vivo mouse models, our studies, for the first time, have demonstrated that Cryptosporidium infection disrupts intestinal epithelial barrier function via downregulation of key tight junction proteins and inhibits Cl- absorption by downregulating the expression of DRA (DownRegulated in Adenoma, SLC26A3), the apical membrane Cl-/HCO3- exchanger protein responsible for Cl- absorption. Our results implicate that dysregulated ion transport and impaired barrier function could be major contributing factors to cause cryptosporidiosis. Our subsequent studies will investigate the mechanisms of Cryptosporidium infection in immunocompromised hosts, such as HIV patients, in which the parasite is known to cause fatal diarrhea.
Project 2: Gut microbes regulate energy homeostasis in obesity: Obesity commonly results from imbalance in the body’s regulation of energy intake, expenditure, and storage. Gut hormones, more particularly glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) secreted by enteroendocrine cells (EECs) of the intestinal epithelium in response to food intake regulate energy balance and glucose homeostasis by stimulating insulin secretion, regulating appetite, gut motility and gastric emptying. Generation of EECs from intestinal stem cells is controlled by the sequential expression of HATH1 and two other basic helix-loop-helix transcription factors, Neurogenin 3 (Ngn3) and NeuroD1, a process significantly decreased in obesity. This results in decreased secretion of GLP1/GIP that critically regulate appetite via gut-brain axis and blood glucose via stimulating insulin secretion. Our studies showed that the probiotic gut bacterium Lactobacillus acidophilus significantly increased EECs in the intestinal mucosa by increasing the transcription factors Math1 (mouse counterpart of Hath1) and Ngn3 in mouse intestine and mouse intestinal organoid model. Our studies unravel a novel facet of gut microbiota involvement in the pathogenesis of obesity via its effects on EEC differentiation and production of gut hormones that regulate glucose homeostasis and energy balance which will be investigated in detail.