Immune and microRNA responses toHelicobacter muridaruminfection and indole-3-carbinol during colitis

Abstract

BACKGROUND Indole-3-carbinol (I3C) and other aryl hydrocarbon receptor agonists are known to modulate the immune system and ameliorate various inflammatory and autoimmune diseases in animal models, including colitis induced by dextran sulfate sodium (DSS). MicroRNAs (miRNAs) are also gaining traction as potential therapeutic agents or diagnostic elements. Enterohepatic Helicobacter (EHH) species are associated with an increased risk of inflammatory bowel disease, but little is known about how these species affect the immune system or response to treatment. AIM To determine whether infection with an EHH species alters the response to I3C and how the immune and miRNA responses of an EHH species compare with responses to DSS and inflammatory bowel disease. METHODS We infected C57BL/6 mice with Helicobacter muridarum ( H. muridarum ), with and without DSS and I3C treatment. Pathological responses were evaluated by histological examination, symptom scores, and cytokine responses. MiRNAs analysis was performed on mesenteric lymph nodes to further evaluate the regional immune response. RESULTS H. muridarum infection alone caused colonic inflammation and upregulated proinflammatory, macrophage-associated cytokines in the colon similar to changes seen in DSS-treated mice. Further upregulation occurred upon treatment with DSS. H. muridarum infection caused broad changes in mesenteric lymph node miRNA expression, but colitis-associated miRNAs were regulated similarly in H. muridarum- infected and uninfected, DSS-treated mice. In spite of causing colitis exacerbation, H. muridarum infection did not prevent disease amelioration by I3C. I3C normalized both macrophage- and T cell-associated cytokines. CONCLUSION Thus, I3C may be useful for inflammatory bowel disease patients regardless of EHH infection. The miRNA changes associated with I3C treatment are likely the result of, rather than the cause of immune response changes.

Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor

“…Tryptophan supplementation did not modify the severity of symptoms in AhR-deficient mice, confirming the dependency on AhR activation (34). Consistent with these observations, symptoms of DSSinduced colitis were mildly ameliorated when mice fed on normal chow were given tryptophan supplementation in the drinking water (37) or I3C by oral gavage (38). In mice fed on AhR ligand-free synthetic diet, increased epithelial damage may be due to the lack of IL22 production in response to DSSinduced inflammation (26,34).…”

Aryl Hydrocarbon Receptor Regulates Muc2 Production Independently of IL-22 during Colitis

“…We previously published I3C, a naturally derived AhR ligand and molecule found in cruciferous vegetables, was effective at reducing disease severity in animal models of colitis [13], which was similarly reported by others [29][30][31][32][33]. In one of the earliest reports of this by Li et al, the researchers established that I3C-mediated protective effects were dependent on AhR since global knockout of AhR in mice prevented I3C from reducing disease severity in the DSS model [34].…”

Aryl Hydrocarbon Receptor Activation Ameliorates Acute Respiratory Distress Syndrome through Regulation of Th17 and Th22 Cells in the Lungs

“…Our lab has also previously shown that I3C attenuates staphylococcal enterotoxin B-mediated liver injury by downregulating miR-31 expression ( 64 ). I3C-mediated miRNA dysregulation was also shown in other inflammatory and cancer models ( 65 , 66 ). In the current study, we performed scRNAseq and miRNAseq to look at the dysregulated mRNAs and miRNAs in whole lungs when comparing the LPS+Veh versus LPS+I3C groups of mice.…”