title: Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis.
abstract: Vitamin B deficiencies, which can lead to hyperhomocysteinemia (Hhcy), are commonly reported in patients with inflammatory bowel disease (IBD) and may be a causative underlying factor. However, the mechanism for this effect is not known. Hydrogen sulfide (H2S) is a gaseous mediator that promotes tissue repair and resolution of inflammation. In experimental colitis, a marked increase in colonic H2S synthesis drives ulcer healing and resolution of inflammation. Because H2S synthesis is in part dependent upon enzymes that require vitamin B6 as a cofactor, we tested the hypothesis that Hhcy in rodent models would increase the susceptibility to colitis. In all three models tested, diet-induced Hhcy significantly exacerbated colitis. The usual elevation of colonic H2S synthesis after induction of colitis was absent in all three models of colitis. Administration of an H2S donor to Hhcy rats significantly decreased the severity of colitis. Compared with wild-type mice, interleukin (IL) 10-deficient mice on a normal diet had decreased levels of colonic H2S synthesis, a 40% increase in serum homocysteine, and a phenotype similar to wild-type mice with Hhcy. IL-10-deficient mice fed the vitamin B-deficient diet exhibited more severe colonic inflammation, but the normal elevation of colonic H2S synthesis was absent. Administration of IL-10 to the IL-10-deficient mice restored colonic H2S synthesis and significantly decreased serum homocysteine levels. These results suggest that the exacerbation of colitis in Hhcy is due in part to impaired colonic H2S synthesis. Moreover, IL-10 plays a novel role in promoting H2S production and homocysteine metabolism, which may have therapeutic value in conditions characterized by Hhcy.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Flannigan
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Terence A
authors.initials: TA
authors.lastname: Agbor
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Rory W
authors.initials: RW
authors.lastname: Blackler
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8;
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.affiliation: Departments of Medicine and.
authors.forename: Jose G P
authors.initials: JG
authors.lastname: Ferraz
authors.affiliation: Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1; and Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8 altapharm@hotmail.com.
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004032:Diet; D018450:Disease Progression; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D011994:Recombinant Proteins; D016753:Interleukin-10; D016264:Dextran Sulfate; D009195:Peroxidase; D006862:Hydrogen Sulfide