University of Michigan Medical Center Ann Arbor, MI
Award: Presidential Poster Award
Prashant Singh, MD1, Shi-Yi Zhou, PhD1, Gintas Grabauskas, PhD1, Weiyang Zheng, MD2, Yawen Zhang, MD2, Chung Owyang, MD1; 1University of Michigan Medical Center, Ann Arbor, MI; 2University of Michigan, Ann Arbor, MI
Introduction: A diet high in FODMAPs (HFM) induces symptoms in patients with irritable bowel syndrome (IBS) and a diet low in FODMAPs (LFM) improves symptoms in up to 60% of IBS patients. Studies report increased colonic mast cell abundance and activation in a subset of IBS patients. However, the role of mast cells in pathophysiology of FODMAPs related symptom-generation has not been well studied. Methods: C57Bl/6 mice and mast cell deficient W-sash c-kit mutant (KitW/W-v) mice were randomized to HFM or regular chow (RC) daily for 2 weeks. Ex vivo and in vivo epithelial barrier function was assessed using trans-epithelial electrical resistance (TEER), and plasma measurement of 4-kDa fluorescein isothiocynate (4-kDa-FITC–dextran) 1-hour after oral gavage. In addition, gene expression of tight junction proteins and inflammatory cytokines were measured. We also measured serum markers of mast cell activation in diarrhea-predominant IBS (IBS-D) patients after LFM. Statistical analysis was performed using t-test and P< 0.05 was considered significant. Results: Wild-type mice (n=8/ group) fed on HFM had 18% reduction in TEER compared to those fed on RC (25.7 Ω.cm2 vs. 31.4 Ω.cm2, P=0.04) as well as 5-fold increase plasma 4-kDa-FITC–dextran (30.8µg/ml vs. 6.2µg/ml, P=0.04). In addition, HFM-fed rats had 24% reduction in colonic gene expression of occludin and 37% reduction in ZO-1 (P< 0.05 for both) compared to RC group. KitW/W-v mast-cell deficient mice (n=4/group) fed on HFM did not have any significant changes in TEER measurement, plasma 4-kDa-FITC–dextran concentration and colonic expression of tight junction proteins compared to KitW/W-v mice fed on RC. Furthermore, there was 2-fold increase in gene expression of IFN-γ in wild-type mice fed on HFM compared to those fed on RC (P=0.04). This increase in IFN-γ gene expression was also not seen in KitW/W-v mast-cell deficient mice fed on HFM compared to mast-cell deficient mice fed on RC. There was no difference in gene expression of TNF-α and IL-1β in wild type mice or mast-cell deficient mice groups. Consistent with this, we also found significant decrease in levels of markers of mast cell activation- serum histamine (P=0.026) and tryptase (P=0.034) in eight IBS-D patients after 4 weeks of LFM. Discussion: HFM causes colonic epithelial barrier impairment and mucosal inflammation in wild-type mice but these changes are absent in mast-cell deficient mice. Mast cells play a critical role in HFM-induced colonic epithelial barrier dysfunction and inflammation.
Disclosures: Prashant Singh indicated no relevant financial relationships. Shi-Yi Zhou indicated no relevant financial relationships. Gintas Grabauskas indicated no relevant financial relationships. Weiyang Zheng indicated no relevant financial relationships. Yawen Zhang indicated no relevant financial relationships. Chung Owyang indicated no relevant financial relationships.