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Growing evidence indicates an important link between gut microbiota, obesity, and metabolic syndrome. Alterations in exocrine pancreatic function are also widely present in patients with diabetes and obesity. To examine this interaction, C57BL/6J mice were fed either a chow diet, high-fat diet (HFD) or HFD plus oral vancomycin or metronidazole to modify the gut microbiome. HFD alone leads to a 40% increase in pancreas weight, decreased glucagon-like peptide-1 and peptide YY levels, and increased glucose-dependent insulinotropic peptide in the plasma. Quantitative proteomics identified 138 host proteins in fecal samples of these mice, of which 32 were significantly changed by HFD. The most significant of these were the pancreatic enzymes. These changes in amylase and elastase were reversed by antibiotic treatment. These alterations could be reproduced by transferring gut microbiota from donor C57BL/6J mice to germ-free. By contrast, antibiotics had no effect on pancreatic size or exocrine function in C57BL/6J mice fed a chow diet. Further, one week vancomycin administration significantly increased amylase and elastase levels in obese prediabetic men. Thus, the alterations in gut microbiota in obesity can alter pancreatic growth, exocrine function and gut endocrine function, and may contribute to the alterations observed in patients with obesity and diabetes.

Recently, we identified four insulin/IGF-1 like peptides (VILPs) in the sequence of viruses belonging to the Iridoviridae family. These VILPs show up to 50% homology with the sequence of the human insulin/IGF-1. Moreover, the predicted tertiary structures and major receptor binding residues are conserved between the VILPs and insulin/IGF-1. Although these viruses are known to infect primarily fish, sequences of VILPs have been found in human blood and feces. VILPs can interact with the human and murine insulin and IGF-1 receptors and induce the activation of their downstream signaling. Functionally, VILPs are able to induce glucose uptake and cell proliferation. VILPs can be synthesized as a single-chain (SC) or double-chain (DC) peptides, i.e., more IGF-1 like or more insulin like structures. In the present study, we show that SC and DC forms of lymphocystis disease virus (LCDV-1) VILP interact differently with the human insulin and IGF-1 receptor. Competition binding assay reveals that SC is more potent than DC in binding to the IGF-1 receptor. In vivo, following i.p. injection in mice both LCDV-1 SC and DC produced similar mild decreases in blood glucose compared to insulin, even at a 166-fold excess. In vitro, however, DC LCDV1-VILP acts as a weak agonist to stimulation of IGF1R, whereas SC LCDV-VILP serves as a strong antagonism effect on the IGF-1 receptor. Thus, the activation of the IGF1R by IGF-1 is strongly repressed by the SC LCDV-1 VILP, even at equal concentrations. This antagonistic action of SC VILP is restricted to the IGF1R and does not affect insulin receptor. As a functional consequence of IGF1R blockade, SC LCDV-1 VILP inhibits IGF-1 stimulated migration of a cervical cancer cell line. In summary, we have shown that SC VILP may provide a novel inhibitor of IGF1R signaling and IGF-1 action on tumor cell migration, with minimal effects on glucose metabolism, thus providing a potentially unique reagent for treatment of IGF-1 sensitive tumors. Disclosure F. Moreau: None. B. Brandao: None. C. Cederquist: None. T.M. Batista: None. R. DiMarchi: Employee; Self; Novo Nordisk Inc. E. Altindis: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.

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. Disclosure 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. Funding National Institutes of Health