Microenvironment Mediated Metabolic-Reprogramming Regulate Self-renewal and Chemo-resistance in CD133+ Tumor Initiating Cells

Abstract

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas with loss of exocrine/endocrine functions as well as development of fibrosis. Dysbiosis of gut microbiome has been shown to be involved in the pathogenesis of many disease processes. Therefore, we aim to investigate the alteration in gut microbiome associated with CP in caerulein-induced mouse model.CP was induced in C57Bl/6 by using caerulein injections (50 μg/kg/h, i.p., x7, twice weekly for 10 weeks). Stool samples were collected either one week after end of injection (10-week CP) or 6 weeks (16-week CP). DNA was extracted from stool samples and V4 region of 16S rDNA was sequenced for microbiome analysis.CP was strongly associated with the alteration in the composition of the gut microbiome, evidenced by differences in α and β diversity. When β diversity was measured using both weighted and unweighted UniFrac distances, stool from control mice is significantly different from mice on 10-week or 16-week CP (q < 0.01). The α-diversity measured by Faith's phylogenetic diversity was lowest in stool from healthy control and highest in stool from mice with 16-week CP (p < 0.001). Bacteria taxa differentially enriched in CP samples were detected using linear discriminant analysis. Bacteria from genera Bifidobacterium, Akkermansia, and Desulfovibrio were enriched in samples from 10-week CP mice. Bacteria from genera Allobaculum, Prevotella, and Bacteroides were enriched in samples from 16-week CP mice.Together, these analyses reveal pronounced alteration in the gut microbiome composition, diversity, and function when mice develop CP.