Growing evidence suggests a link between alterations in gut microbiota, diabetes, and metabolic syndrome. We recently showed that treatment with antibiotics to alter gut microbiota could improve insulin signaling and glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on high-fat diet (HFD). This occurred in part through changing metabolite composition in plasma and decreasing adipose tissue inflammation. We also showed that these changes could be induced in germ-free mice by transferring the gut microbiota. It is known that diabetes is associated with exocrine pancreatic dysfunction, and diseases of the exocrine pancreas can be associated with diabetes. To explore the role of gut microbiota on host pancreatic exocrine function and its crosstalk with the endocrine system, mice were given either normal chow or HFD, or HFD and treatment with vancomycin or metronidazole. As expected, HFD alone produced signs of metabolic syndrome but also increased total pancreas weight by ~20%, an amount that could not be explained by islet hyperplasia. Analysis of the fecal proteome of these mice identified 138 host proteins of which 32 changed with either HFD or antibiotic treatment. Notably, the most significantly changed proteins by diet and altered microbiome were pancreatic enzymes: amylase, lipase and elastase. Furthermore, the plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) levels were decreased, while glucose-dependent insulinotropic peptide (GIP) was increased by the HFD. These alterations of pancreas growth, acinar cell hyperplasia, exocrine pancreas function, and hormone secretion were reversed by antibiotic treatment of the host. These changes could also be reproduced in germ free mice by transfer of gut microbiota. Together, these data indicate that gut microbiota can regulate pancreatic growth and both exocrine and endocrine function. Better understanding pancreas-gut microbiome crosstalk can help us develop probiotics to cure pancreas dysfunction in diabetes.
E. Altindis: None. M. Soto: Employee; Self; LNC Therapeutics. Other Relationship; Self; biomeostasis. L. Orliaguet: None. Q. Huang: None. C. Cederquist: None. E. Dirice: None. S. Fujisaka: None. J. Hu: None. R. Kulkarni: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.
National Institutes of Health