title: Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes.
abstract: The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1-secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25-33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)-secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo.
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY.
authors: Franklin F
authors: FF
authors: Duan
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY.
authors: Joy H
authors: JH
authors: Liu
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY jcm224@cornell.edu.
authors: John C
authors: JC
authors: March
mesh_terms: D000818:Animals; D002460:Cell Line; D065150:Cellular Reprogramming; D003920:Diabetes Mellitus / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007413:Intestinal Mucosa / Q000166:cytology; D007778:Lactobacillus / Q000235:genetics / Q000502:physiology*; D051381:Rats
chemical_list: D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose
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