Hydrogen sulfide protects from colitis and restores intestinal microbiota biofilm and mucus production.
BACKGROUND
Microbiota dysbiosis and impaired barrier function are among the most prominent features of inflammatory bowel disease. In the gastrointestinal tract, hydrogen sulfide (H(2)S) is an important regulator of mucosal homeostasis. We hypothesized that H(2)S promotes resolution of colonic inflammation through actions on microbiota biofilm and the mucus barrier.


METHODS
We used mice genetically deficient for a key enzyme for H(2)S production (cystathionine γ-lyase) and pharmacologically inhibited that enzyme during colitis in wild-type mice. We tested the effects of administering an H(2)S donor (diallyl disulfide) to rodents during hapten-induced colitis. Colonic microbiota biofilm was visualized by fluorescent in situ hybridization, and mucus granules were quantified with periodic acid-alcian blue staining. We exposed human microbiota biofilms and planktonic bacteria to H(2)S donors ex vivo to determine changes in their growth, viability, and biomass.


RESULTS
Intestinal microbiota formed linear biofilms in the colon of healthy rodents. During colitis, microbiota biofilms were fragmented and mucus granule production decreased. Endogenous production of H(2)S had beneficial effects on establishment of microbiota biofilms and colonic mucus production. Therapeutic delivery of H(2)S into the colon reduced inflammation, restored the microbiota biofilm, and increased the production of mucus granules. In ex vivo human microbiota, H(2)S not only promoted biofilm formation but also reduced growth of planktonic bacteria.


CONCLUSIONS
Our results suggest that H(2)S donors could be used therapeutically during colitis, facilitating correction of microbiota biofilm dysbiosis and mucus layer reconstitution.
Departments of *Biological Sciences, and †Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; ‡Department of Medicine, McMaster University, Hamilton, ON, Canada; §Centre of Neurosciences and Cell Biology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; and ‖Department of Biology, Lakehead University, Thunder Bay, ON, Canada.
Jean-Paul
JP
Motta
Kyle L
KL
Flannigan
Terence A
TA
Agbor
Jennifer K
JK
Beatty
Rory W
RW
Blackler
Matthew L
ML
Workentine
Gabriela J
GJ
Da Silva
Rui
R
Wang
Andre G
AG
Buret
John L
JL
Wallace
D000818:Animals; D018441:Biofilms / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity; D064426:Gasotransmitters / Q000627:therapeutic use; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D006801:Humans; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D064426:Gasotransmitters; D016264:Dextran Sulfate; D006862:Hydrogen Sulfide