title: Detrimental effects for colonocytes of an increased exposure to luminal hydrogen sulfide: The adaptive response.
abstract: Protein fermentation by the gut microbiota releases in the large intestine lumen various amino-acid derived metabolites. Among them, hydrogen sulfide (H2S) in excess has been suspected to be detrimental for colonic epithelium energy metabolism and DNA integrity. The first objective of this study was to evaluate in rats the epithelial response to an increased exposure to H2S. Experiments from colonocyte incubation and intra-colonic instillation indicate that low millimolar concentrations of the sulfide donor NaHS reversibly inhibited colonocyte mitochondrial oxygen consumption and increased gene expression of hypoxia inducible factor 1α (Hif-1α) together with inflammation-related genes namely inducible nitric oxide synthase (iNos) and interleukin-6 (Il-6). Additionally, rat colonocyte H2S detoxification capacity was severely impaired in the presence of nitric oxide. Based on the γH2AX ICW technique, NaHS did not induce DNA damage in colonocytes. Since H2S is notably produced by the gut microbiota from sulfur containing amino acids, the second objective of the study was to investigate the effects of a high protein diet (HPD) on large intestine luminal sulfide content and on the expression of genes involved in H2S detoxification in colonocytes. We found that HPD markedly increased H2S content in the large intestine but the concomitant increase of the content mass maintained the luminal sulfide concentration. HPD also provoked an increase of sulfide quinone reductase (Sqr) gene expression in colonocytes, indicating an adaptive response to increased H2S bacterial production. In conclusion, low millimolar NaHS concentration severely affects colonocyte respiration in association with increased expression of genes associated with intestinal inflammation. Although HPD increases the sulfide content of the large intestine, the colonic adaptive responses to this modification limit the epithelial exposure to this deleterious bacterial metabolite.
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Martin
authors: M
authors: Beaumont
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Mireille
authors: M
authors: Andriamihaja
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Annaïg
authors: A
authors: Lan
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Nadezda
authors: N
authors: Khodorova
authors: INRA, UMR 1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France.
authors: Marc
authors: M
authors: Audebert
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Jean-Marc
authors: JM
authors: Blouin
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Marta
authors: M
authors: Grauso
authors: Laboratory of Applied Nutrition and Metabolism, University of Sao Paulo, Brazil.
authors: Luciana
authors: L
authors: Lancha
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Pierre-Henri
authors: PH
authors: Benetti
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France; Department of Gastroenterology, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France.
authors: Robert
authors: R
authors: Benamouzig
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Daniel
authors: D
authors: Tomé
authors: INSERM U1016, Institut Cochin, Paris, France; CNRS UMR8104, Institut Cochin, Paris, France; Université Paris Descartes UMRS1016, Institut Cochin, Paris, France.
authors: Frédéric
authors: F
authors: Bouillaud
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France.
authors: Anne-Marie
authors: AM
authors: Davila
authors: UMR PNCA, AgroParisTech, INRA, Université Paris-Saclay, Paris, France. Electronic address: francois.blachier@agroparistech.fr.
authors: François
authors: F
authors: Blachier
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D004249:DNA Damage / Q000187:drug effects; D004734:Energy Metabolism; D005285:Fermentation / Q000187:drug effects; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007420:Intestine, Large / Q000378:metabolism / Q000382:microbiology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D013440:Sulfides / Q000494:pharmacology
chemical_list: D000596:Amino Acids; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D013440:Sulfides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C025451:sodium bisulfide; D006862:Hydrogen Sulfide
keywords: Colonocyte; Genotoxicity; High-protein diet; Hydrogen sulfide; Inflammation; Microbiota; Mitochondria; Nitric oxide