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Cited by 151Gut microbiota and healthSulfur Compounds in BiologyHelicobacter pylori-related gastroenterology studies

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Effects of Hydrogen Sulfide on the Microbiome: From Toxicity to Therapy

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Buret, Andre G., Allain, Thibault, Motta, Jean-Paul, Wallace, John L.·2022·Antioxidants & Redox Signaling
DOI 10.1089/ars.2021.0004PMC PMC8861923
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Abstract

Significance: Hydrogen sulfide (H 2 S), an important regulator of physiology and health, helps resolve inflammation and promotes tissue repair in the gastrointestinal tract. Recent Advances: Gut microbiota live as a multispecies biofilm in close interaction with the upper mucus layer lining the epithelium. The relative abundance, spatial organization, and function of these microorganisms affect a broad range of health outcomes. This article provides a state-of-the-art review of our understanding of the cross talk between H 2 S, the gut microbiota, and health. H 2 S can have toxic or therapeutic effects, depending on its concentration and source. When produced at excessive concentrations by local microbiota, H 2 S may cause mucus disruption and inflammation and contribute to development of cancer. In contrast, low levels of endogenous or exogenous H 2 S directly stabilize mucus layers, prevent fragmentation and adherence of the microbiota biofilm to the epithelium, inhibit the release of invasive pathobionts, and help resolve inflammation and tissue injury. Although scarce, research findings suggest that dietary H 2 S obtained from plants or ingestion of the H 2 S precursor, L-cysteine, may also modulate the abundance and function of microbiota. Critical Issues: A critical issue is the lack of understanding of the metagenomic, transcriptomic, and proteomic alterations that characterize the interactions between H 2 S and gut microbiota to shape health outcomes. Future Directions: The ambivalent roles of H 2 S in the gut offer a fertile ground for research on such critical issues. The findings will improve our understanding of how H 2 S modulates the microbiota to affect body function and will help identify novel therapeutic strategies. Antioxid. Redox Signal . 36, 211–219.

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FIG. 1. Summary graphic illustration of the findings discussed in this review. Representative micrograph of the rat colonic mucosa (left panel), identifying the microbiota biofilm (Eubacterial stain; Molecular Probes) separated from the host epithelial cells (IECs, DAPI stain) by mucus layers. Endogenous and exogenous H2S, as well as H2S produced by microbiota, promotes (→) or inhibits (-I) a variety of characteristics in mucosal microbiota biofilms. It can alter the relative abundance, spatial organization, and function of bacteria in these biofilms. H2S also prevents the fragmentation and epithelial adherence of these microbiota, while maintaining the integrity of mucus layers separating the microbiota from host tissues. H2S inhibits the formation and invasiveness of pathobionts, which further contribute to the anti-inflammatory actions of this gaseous mediator. H2S, hydrogen sulfide; IECs, intestinal epithelial cells.
FIG. 1. Summary graphic illustration of the findings discussed in this review. Representative micrograph of the rat colonic mucosa (left panel), identifying the microbiota biofilm (Eubacterial stain; Molecular Probes) separated from the host epithelial cells (IECs, DAPI stain) by mucus layers. Endogenous and exogenous H2S, as well as H2S produced by microbiota, promotes (→) or inhibits (-I) a variety of characteristics in mucosal microbiota biofilms. It can alter the relative abundance, spatial organization, and function of bacteria in these biofilms. H2S also prevents the fragmentation and epithelial adherence of these microbiota, while maintaining the integrity of mucus layers separating the microbiota from host tissues. H2S inhibits the formation and invasiveness of pathobionts, which further contribute to the anti-inflammatory actions of this gaseous mediator. H2S, hydrogen sulfide; IECs, intestinal epithelial cells.CC BY-NC · PubMed Central
FIG. 2. H2S donors maintain mucus barrier and microbiota biofilm integrity. Dysbiotic microbiota (red) in rats with DNBS colitis exhibit abnormal biofilm fragmentation and adhesion to the host intestinal tissues (nuclei stained in blue), coinciding with the formation and invasion of pathobionts through the epithelial lining (A). Daily oral administration of an H2S donor (ATB-429; Antibe Therapeutics, Inc.) completely abolishes these defects by maintaining microbiota integrity and the mucus barrier, illustrated as the unstained shadow between microbiota (red) and host tissues (blue), and preventing the formation of invasive pathobionts (B). Bar = 50 μm [modified from the study by Buret et al. (7)]. DNBS, dinitrobenzene sulfonic acid.
FIG. 2. H2S donors maintain mucus barrier and microbiota biofilm integrity. Dysbiotic microbiota (red) in rats with DNBS colitis exhibit abnormal biofilm fragmentation and adhesion to the host intestinal tissues (nuclei stained in blue), coinciding with the formation and invasion of pathobionts through the epithelial lining (A). Daily oral administration of an H2S donor (ATB-429; Antibe Therapeutics, Inc.) completely abolishes these defects by maintaining microbiota integrity and the mucus barrier, illustrated as the unstained shadow between microbiota (red) and host tissues (blue), and preventing the formation of invasive pathobionts (B). Bar = 50 μm [modified from the study by Buret et al. (7)]. DNBS, dinitrobenzene sulfonic acid.CC BY-NC · PubMed Central
FIG. 3. Oral administration of the H2S donor ATB-429 (50 mg/kg, twice daily, per os) reduces the severity of colitis and inhibits the translocation of commensal bacteria to the liver in C57Bl/6 mice with DNBS colitis, compared with mice given vehicle (veh) [modified from the study by Motta et al. (44)]. (A) Colitis (DNBS/veh) caused a significant granulocyte infiltration (indicated by an increase in MPO) compared with healthy mice (Healthy); treatment with ATB-429 (DNBS/ATB-429) significantly reduced MPO activity. (B) Colitis (DNBS/veh) caused significant microbial translocation to the liver (CFU counts per mL); treatment with ATB-429 (DNBS/ATB-429) reduced colitis-induced bacterial translocation; n = 8 mice per group. Kruskal–Wallis test, followed by Dunn's tests. *p < 0.05; ***p < 0.001. For detailed methodology, see Motta et al. (44). MPO, myeloperoxidase activity.
FIG. 3. Oral administration of the H2S donor ATB-429 (50 mg/kg, twice daily, per os) reduces the severity of colitis and inhibits the translocation of commensal bacteria to the liver in C57Bl/6 mice with DNBS colitis, compared with mice given vehicle (veh) [modified from the study by Motta et al. (44)]. (A) Colitis (DNBS/veh) caused a significant granulocyte infiltration (indicated by an increase in MPO) compared with healthy mice (Healthy); treatment with ATB-429 (DNBS/ATB-429) significantly reduced MPO activity. (B) Colitis (DNBS/veh) caused significant microbial translocation to the liver (CFU counts per mL); treatment with ATB-429 (DNBS/ATB-429) reduced colitis-induced bacterial translocation; n = 8 mice per group. Kruskal–Wallis test, followed by Dunn's tests. *p < 0.05; ***p < 0.001. For detailed methodology, see Motta et al. (44). MPO, myeloperoxidase activity.CC BY-NC · PubMed Central
FIG. 4. Production of pathobionts in colitis coincides with elevated iron intake by commensal microbiota bacteria. Administration of an H2S donor (ATB-429) reduces the intracellular iron content in fecal bacteria from mice with DNBS colitis. ATB-429 has iron-chelating properties [modified from Motta et al. (44)]. (A) Intracellular concentrations of iron in fecal microbiota (normalized to 1 g of feces) are significantly higher in microbiota from mice with colitis (DNBS) compared with those of control animals (vehicle, veh) and groups treated with ATB-429 (50 mg/kg, twice daily, per os); n = 8 mice per group. Kruskal–Wallis test, followed by Dunn's tests. ***p < 0.001. (B) H2S-relasing compounds have iron-chelating properties, at least in part, in a drug-selective manner. H2S-releasing ATB-429 (mesalamine linked to the donor ADT-OH), ATB-428 (to a lesser extent; mesalamine linked to the H2S donor TBZ), and the positive control iron chelator 2,2-bipyridil, but not mesalamine (5-ASA) or the TBZ H2S donor alone, have dramatic iron-chelating properties. Drugs were dissolved in bacterial media containing 100 μm of FeCl2. After 24 h, the remaining concentration of free iron measured by ferrozine spectrophotometry was markedly reduced in a positive control iron chelator (2,2-bipyridil) and in ATB-429, ATB-428, and ADT-OH, but not in TBZ and mesalamine (5-ASA); n = 3 to 9 duplicates per concentration of drugs. For detailed methodology, see Motta et al. (44).
FIG. 4. Production of pathobionts in colitis coincides with elevated iron intake by commensal microbiota bacteria. Administration of an H2S donor (ATB-429) reduces the intracellular iron content in fecal bacteria from mice with DNBS colitis. ATB-429 has iron-chelating properties [modified from Motta et al. (44)]. (A) Intracellular concentrations of iron in fecal microbiota (normalized to 1 g of feces) are significantly higher in microbiota from mice with colitis (DNBS) compared with those of control animals (vehicle, veh) and groups treated with ATB-429 (50 mg/kg, twice daily, per os); n = 8 mice per group. Kruskal–Wallis test, followed by Dunn's tests. ***p < 0.001. (B) H2S-relasing compounds have iron-chelating properties, at least in part, in a drug-selective manner. H2S-releasing ATB-429 (mesalamine linked to the donor ADT-OH), ATB-428 (to a lesser extent; mesalamine linked to the H2S donor TBZ), and the positive control iron chelator 2,2-bipyridil, but not mesalamine (5-ASA) or the TBZ H2S donor alone, have dramatic iron-chelating properties. Drugs were dissolved in bacterial media containing 100 μm of FeCl2. After 24 h, the remaining concentration of free iron measured by ferrozine spectrophotometry was markedly reduced in a positive control iron chelator (2,2-bipyridil) and in ATB-429, ATB-428, and ADT-OH, but not in TBZ and mesalamine (5-ASA); n = 3 to 9 duplicates per concentration of drugs. For detailed methodology, see Motta et al. (44).CC BY-NC · PubMed Central

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  1. Du Toit A. The health benefits of hydrogen sulphide. Nat Rev Mol Cell Biol, 16: 68, 2015. · DOI

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Metadata

Authors
Buret, A. G., Allain, T., Motta, J.-P., & Wallace, J. L.
Affiliations
  • Host–Parasite Interactions Program, Inflammation Research Network, Biological Sciences, University of Calgary, Calgary, Canada.
  • University of Calgary (CA)
  • Inserm (FR)
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2022-02
Volume
36
Issue
4-6
Pages
211-219
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2021.0004
PMC
PMC8861923
OpenAlex
W3133888684
Cited by
151
References
81
Citations by year
2026: 33 · 2025: 29 · 2024: 30 · 2023: 32 · 2022: 23
FWCI
6.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants and Redox Signaling (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Health Sciences › Medicine › Gastroenterology › Helicobacter pylori-related gastroenterology studies
Keywords
hydrogen sulfide, gut microbiota, mucus layer, inflammation resolution, tissue repair, gastrointestinal cancer, pathobionts, cysteine, microbiota-metabolite interactions
MeSH terms
Gastrointestinal Microbiome, Hydrogen Sulfide, Proteomics, Gastrointestinal Tract, Microbiota

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