The upper small intestinal microbiota regulates nutrient sensing pathways to influence glucose homeostasis
Sedentary lifestyles, excessive food intake and genetic predisposition all contribute to the development of Type 2 Diabetes, which is characterized by a dysregulation in glucose homeostasis. The microbiota within the gastrointestinal tract has been suggested to play a role in glucose regulation. However, the majority of work to date has focused on the distal intestinal microbiota despite the fact that the upper small intestine has immense glucoregulatory function and harbors a significant microbial community. Indeed, nutrients that enter the upper small intestine activate negative feedback pathways to maintain glucose homeostasis. Interestingly, some nutrient sensing mechanisms are impaired in response to a high fat diet (HFD). However, whether HFD-induced changes in the gut microbiota alter these selective pathways to impair glucose regulation, remains unknown. Furthermore, the anti-diabetic therapy metformin alters the distal gut microbiota and modifies small intestinal nutrient sensing. However, whether changes in the upper small intestinal microbiota and/or nutrient sensing mediate the antidiabetic action of metformin is currently unknown. Through Study 1 and 2 we demonstrate that upper small intestinal lipids and glucose activate nutrient sensing pathways to regulate glucose homeostasis in healthy rodents, while HFD-feeding impairs these pathways in parrallel to reductions in key nutrient sensing proteins. In addition, in conditions of HFD-feeding we see a reduction in the abundance of the bacterial genus Lactobacillus in the upper small intestine, while metformin treatment restores Lactobacillus abundance to healthy conditions. Interestingly, restoration of Lactobacillus abundance via administration of Lactobacillus probiotics, or transplantation of upper small intestinal microbiota from healthy or metformin-treated donor rats, improves nutrient sensing and glucose homeostasis via upregulation of nutrient sensor expression in the upper small intestinal mucosa. This work highlights a novel role for the upper small intestinal microbiota in glucose regulation and will lay the groundwork for the development of gut microbiota-targeted antidiabetic therapy.
Diabetes, Gastrointestinal tract, Microbiota, Nutrient sensing, Obesity
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