Progression of diabetes is associated with changes in the ileal transcriptome and ileal-colon morphology in the UC Davis Type 2 diabetes mellitus rat

Authors: PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC); GRAHAM, JAMES - University Of California, Davis; KANG, PING - Arkansas Children'S Nutrition Research Center (ACNC); RANDOLPH, CHRISTOPHER - Arkansas Children'S Hospital; SHANKAR, KARTIK - University Of Colorado; Yeruva, Laxmi; FOX, RENEE - Arkansas Children'S Nutrition Research Center (ACNC); ROBESON, MIKE - University Arkansas For Medical Sciences (UAMS); MOODY, BECKY - Arkansas Children'S Nutrition Research Center (ACNC); LEROITH, TANYA - Virginia Polytechnic Institution & State University; STANHOPE, KIMBER - University Of California, Davis; Adams, Sean; HAVEL, PETER - University Of California, Davis

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/18/2021
Publication Date: 11/21/2021
Citation: Piccolo, B.D., Graham, J.L., Kang, P., Randolph, C.E., Shankar, K., Yeruva, V., Fox, R., Robeson, M.S., Moody, B., LeRoith, T., Stanhope, K.L., Adams, S.H., Havel, P.J. 2021. Progression of diabetes is associated with changes in the ileal transcriptome and ileal-colon morphology in the UC Davis Type 2 diabetes mellitus rat. Physiological Reports. 9(22):e15102. https://doi.org/10.14814/phy2.15102.
DOI: https://doi.org/10.14814/phy2.15102

Interpretive Summary: Diabetes can lead to gut dysfunction, which can is manifested in clinical outcomes such as diarrhea or constipation. More recently, obesity and diabetes has been shown to alter the composition of the bacteria residing in the gut, with some suggesting that these conditions increase bacteria that are more harmful to the gut environment and host. Therefore, we used a rat model of diabetes to investigate how the advancement of diabetes changes the structure and regulation of the cells that make up the small and large intestines. The rat model we studied uniquely develops diabetes spontaneously, therefore, no diet or chemical stimulation is required to establish diabetes. This means that any changes to the gut are likely due to changes associated with diabetes only. We found that after 3 months of diabetes, the surface of the gut increased in both the small- and large-intestine. The gut bacteria of large intestine was analyzed and we found that rats with 3-months post onset of diabetes had a distinct bacteria profile compared to those were non-diabetic or had less than one month of diabetes. We also measured the global RNA transcripts in both small and large intestines. The RNA transcripts help translate DNA into proteins, which provide insight into the function of a particular cell or tissue. We found very few RNA transcripts in the large intestine that were altered by diabetes, but we found > 2000 that were altered in the small intestine. This suggests that small intestine could be more susceptible to diabetes compared to the large intestine. Two of the RNA transcripts that differed were coded for Sptlc3 and Enpp7 enzymes, which have both been shown to be crucial for allowing gut cells to expand, which may partially link this analysis to the increase in gut surface area. In summary, the advancement of diabetes increased the surface area of both the small and large intestine in a rat model of diabetes. Diabetes also may have a larger effect on the transcriptional regulation within the small intestine, relative to the large intestine.

Technical Abstract: Deterioration in glucose homeostasis has been associated with intestinal dysbiosis, but it is not known how metabolic dysregulation alters the gastrointestinal environment. We investigated how the progression of diabetes alters ileal and colonic epithelial mucosal structure, microbial abundance, and transcript expression in the University of California Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rat model. Male UCD-T2DM rats (age ~170 days) were included if <1-month (n=6, RD) or 3-month (n=6, D3M) post-onset of diabetes. Younger non-diabetic UCD-T2DM rats were included as a non-diabetic comparison (n=6, ND, age ~70 days). Ileum villi height/crypt depths and colon crypt depths were assessed by histology. Microbial abundance of colon content was measured with 16S rRNA sequencing. Ileum and colon transcriptional abundances were analyzed using RNA sequencing. Ileum villi height and crypt depth were greater in D3M rats compared to ND. Colon crypt depth was greatest in D3M rats compared to both ND and RD rats. Colon abundances of Akkermansia and Muribaculaceae were lower in D3M rats relative to RD, while Oscillospirales, Phascolarctobacterium, and an unidentified genus of Lachnospiraceae were higher. Only two transcripts were altered by diabetes advancement within the colon; however, 2039 ileal transcripts were altered. Only colonic abundances of Sptlc3, Enpp7, Slc7a15, and Kctd14 had log fold changes > 1 between RD and D3M rats. The advancement of diabetes in the UCD-T2DM rat results in a trophic effect on the mucosal epithelia and was associated with regulation of gastrointestinal tract RNA expression, which appears more pronounced in the ileum relative to the colon.