P0585 - Colonic Circadian Rhythm Disruption Alters Expression of Short Chain Fatty Acids and Intestinal Receptors in Mice

Zoe Post, MD¹, Philip A. Engen, MS¹, Maliha Shaikh, MS¹, Sarah B. Jochum, MD¹, Sherry Wilber, ¹, Mark J. Brown, MD², Khashavarsha Khazaie, PhD³, Dana M. Hayden, MD¹, Robin M. Voigt, PhD¹, Christopher B. Forsyth, PhD¹, Ali Keshavarzian, MD¹, Garth R. Swanson, MD^1
1Rush University Medical Center, Chicago, IL; ²University of Pennsylvania, Philadephia, PA; ³Mayo Clinic, Rochester, MN

Introduction: Circadian rhythms (CR) are essential for intestinal homeostasis. Disruption of CR is a possible environmental factor associated with more severe disease course in inflammatory bowel disease (IBD). Central CR disruption models night shift work, whereas peripheral CR disruption models wrong time eating. A possible mechanism for how CR disruption affects intestinal homeostasis is through gut-derived short-chain fatty acids (SCFA). SCFA are key metabolites that act on intestinal receptors and are known critical regulators of colonic barrier homeostasis. Prior animal models have shown that lack of SCFA receptors GPR109A and GPR43 increases susceptibility to chemically-induced colitis. Our aim is to explore the effects of colon-specific peripheral CR disruption on SCFA receptor expression and stool concentrations.

Methods: Study was approved by Institutional Animal Care and Use Committee. Peripheral CR was disrupted by deleting BMAL1 in the colon of TS4Cre-BMAL1lox (cBMAL1KO) male/female mice. TS4Cre mice were controls. Acetic acid, propionic acid and butyric acid in stool collected from proximal colon were quantified by gas chromatography-mass spectrometry. SCFA receptors GPR109A and GPR43 in proximal colon were measured through Western Blot and quantified using densitometric analysis with GAPDH normalization.

Results: GPR109A expression was significantly higher (q˂0.01) in male and female cBMAL1KO mice compared to TS4Cre mice (Fig 1a). GPR43 expression was not different in cBMAL1KO vs TS4Cre mice (Fig 1b). Female cBMAL1KO mice’s total SCFA (p=0.018) and acetic acid (p=0.024) stool concentrations were higher and butyric acid trended upward, as compared to female TS4Cre mice (Fig 1c-f). Contrarily, male cBMAL1KO mice stool butyric acid concentrations were lower (p=0.038) and total SCFA and acetic acid trended downward, as compared to male TS4Cre mice (Fig 1c-f).

Discussion: Our genetic peripheral CR disruption model shows that SCFA receptor GPR109A upregulation could be a possible mechanism for intestinal barrier homeostasis disruption. In addition, this study showed that peripheral CR disruption affects stool SCFA with opposite gender effects. This may explain why female cBMAL1KO mice were more resistant to chemically-induced colitis in our prior study. These gender-dependent findings warrant further investigation. Given the importance of SCFA production in the gut, future microbiome research should consider intestinal dysbiosis due to peripheral CR disruption.



Disclosures:


Zoe Post, MD¹, Philip A. Engen, MS¹, Maliha Shaikh, MS¹, Sarah B. Jochum, MD¹, Sherry Wilber, ¹, Mark J. Brown, MD², Khashavarsha Khazaie, PhD³, Dana M. Hayden, MD¹, Robin M. Voigt, PhD¹, Christopher B. Forsyth, PhD¹, Ali Keshavarzian, MD¹, Garth R. Swanson, MD¹. P0585 - Colonic Circadian Rhythm Disruption Alters Expression of Short Chain Fatty Acids and Intestinal Receptors in Mice, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.