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Antioxidants & Redox Signaling logoLink to Antioxidants & Redox Signaling
. 2014 Feb 10;20(5):818–830. doi: 10.1089/ars.2013.5312

Hydrogen Sulfide Signaling in the Gastrointestinal Tract

David R Linden 1,
PMCID: PMC3910452  PMID: 23582008

Abstract

Significance: The current literature regarding the effects of the gaseous signal molecule hydrogen sulfide (H2S) in the gastrointestinal system is reviewed. Bacterial, host and pharmaceutical-derived H2S are all considered and presented according to the physiological or pathophysiological effects of the gaseous signal molecule. These subjects include the toxicology of intestinal H2S with emphasis on bacterial-derived H2S, especially from sulfate-reducing bacteria, the role of endogenous and exogenous H2S in intestinal inflammation, and the roles of H2S in gastrointestinal motility, secretion and nociception. Recent Advances: While its pro- and anti-inflammatory, smooth muscle relaxant, prosecretory, and pro- and antinociceptive actions continue to remain the major effects of H2S in this system; recent findings have expanded the potential molecular targets for H2S in the gastrointestinal tract. Critical Issues: Numerous discrepancies remain in the literature, and definitive molecular targets in this system have not been supported by the use of competitive antagonism. Future Directions: Future work will hopefully resolve discrepancies in the literature and identify molecular targets and mechanisms of action for H2S. It is clear from the current literature that the long-appreciated relationship between H2S and the gastrointestinal tract continues to be strong as we endeavor to unravel its mysteries. Antioxid. Redox Signal. 20, 818–830.

Introduction

Hydrogen sulfide (H2S) is intimately connected with the gastrointestinal system. Early biochemists, microbiologists, and physiologists recognized H2S as a product of digestive processes and studied its properties. While the perception of malodorous sulfur was certainly clear and present in antiquity as evidenced by the actual location of Gehenna, or hell, as the garbage dump of vial sulfur odors in Ben Hinnom just outside Ancient Jerusalem (61), or the description of rotten eggs, or “uria” by Aristotle (5), the first clear account of H2S that distinguishes it from other malodorous sulfur gases, such as methyl mercaptan (“rotten cabbage”) or sulfur dioxide (“burnt sulfur”), comes from the description of the Italian physician Ramazzini in 1713 of the eye irritation in sewer cleaners caused by chronic exposure to H2S in privy gas (88). It is likely not surprising to most people that early descriptions of H2S come from accounts of the contents or products of the mammalian intestines as H2S is a well-recognized constituent of flatus.

In 1777, the Swedish chemist, Carl Wilhelm Scheele, provided the first systematic study of H2S gas (94). Using the knowledge of Sheele, chemists of the late 18th and early 19th centuries, including Justis Leibig, recognized H2S as a common constituent of putrefaction and the intestines, which remain anaerobic, and yet, generate copious H2S gas after death, became a common observational and experimental preparation. In his classic text, Lehmann described the culmination of several studies in the first half of the 19th century that observed H2S as a constituent of intestinal gas before postmortem putrefaction (54). The small amount of H2S in normal flatus made early chemists consider that digestion in the large intestine is the same chemical process as putrefaction. The biological origin of H2S gas was solidified when Gayon described the ability of isolated bacteria to generate H2S from albuminous material (31). This experiment, during the advent of microbiology, started a considerable flurry of taxonomical and biochemical studies in the late 19th century and first half of the 20th century regarding the enzymatic production of H2S by intestinal bacteria.

This manuscript is designed to comprehensively review the current literature regarding the effects of H2S in the gastrointestinal system (Fig. 1). Current data are organized into five major themes and will be discussed with special emphasis regarding current areas of controversy.

FIG. 1.

FIG. 1.

Hydrogen sulfide (H2S) exerts numerous effects on the gastrointestinal system.

Bacterial H2S, Intestinal H2S Toxicology, and Cancer

Microbial origins of H2S are typically well understood but remain quite active areas of research in microbial biochemistry (Fig. 2). Oral malodor or halitosis is known to arise from the production of volatile sulfur compounds in the oral cavity, respiratory tract or the blood (106). Halitosis of oral origin is well understood and, in part, arises from the release of H2S via the desulfhydration of cysteine or serum proteins by subgingival bacteria, including Peptosteptococcus anaerobius, Micros prevotii, Eubacterium limosum, Centipedia periodontii, Selenomonas artermidis, Prevotella intermedia, Prevotella loescheii, Porphyromonas gingivalis, Treponema denticola, and several Bacteroides species, among them B. forsythus (62). There is controversy regarding halitosis that may arise from the production of H2S by Helicobacter pylori, the pathogen responsible for gastritis. While it is clear that H. pylori can produce H2S via cysteine and methionine desulfhydration (53), some cohorts following H. pylori eradication have improved halitosis (39, 43), while another did not (107). The effect of copious H2S from H. pylori during gastritis is not clear, but is likely a major contributor to the bacterium's defense against oxidative attack (101).

FIG. 2.

FIG. 2.

Bacterial H2S. Bacterial sources of H2S in the lumen of the gastrointestinal tract occurs via three biochemical pathways: desulfhydration, dissimilatory sulfate reduction, and assimilatory sulfite reduction.

Desulfococcus, Desulfonema, Desulfosarcina, Desulfobacter, Desulfobulbus, and Desulfovibrio are δ-Proteobacteria genera that utilize sulfate as a terminal electron acceptor in the production of ATP to produce H2S. Desulfovibrio account for 66% and Desulfobulbus account for 16% of all sulfate-reducing bacteria (SRB) in the human colon. These two genera are capable of using molecular hydrogen, an oxidation product of short-chain fatty acids produced by fermentation of undigested carbohydrates, as the electron donor for energy production (32). There are Firmicutes species belonging to the genera Desulfotomaculum, Desulfosporomusa, and Desulfosporosinus and Archaea species belonging to the genera Archaeoglobus, Thermocladium, and Caldivirga that are also capable of dissimilatory sulfate reduction with Desulfotomaculum species being the most robust (41).

H2S can also accumulate in the lumen of the colon from bacteria that degrade the sulfur-containing amino acids cysteine and methionine (via conversion to homocysteine), through the expression of desulfhydrases. These bacteria have a varied phylogeny and as a whole are relatively understudied but include members of the groups Enterococci, Enterobacteria, and Clostridia, including Escherichia coli (10). Interestingly, the products of desulfhydration, including pyruvate and α-ketobutyrate can be used as electron donors for the SRB described above to generate even more H2S. In addition, there is a small contribution of assimilatory sulfite-reducing γ-Proteobacteria, including Salmonella, Enterobacteria, and Klebsiella, Firmicutes, including Bacillus and Staphylococcus and numerous Bacteroidetes species to the production of luminal H2S via the expression of the iron flavoprotein sulfite reductase.

H2S is the major sulfur-containing constituent of cecal and rectal gas and can reach concentrations as high as 40 μM (∼1000 ppm) (103). Because of numerous lethal exposures to H2S from sewage and farm workers, the toxicity of H2S, primarily via the lung as the route of absorption, is well documented (9) and include toxic effects on lung, heart, vascular, and brain tissues. Among the most well known toxic effects of H2S is the noncompetitive inhibition of oxygen binding to cytochrome C oxidase (17), which inhibits cellular respiration in all tissue but seems particularly sensitive in respiratory centers of the brain (9), although a lung site of action has been put forth as a more probable site for acute toxicity (2). For the purpose of this manuscript, the toxic potential of H2S on intestinal cells, more specifically, cultured colonic epithelial cells are reviewed (Fig. 3). Sodium hydrosulfide (NaHS, 0.2–5 mM) increases the proliferation in nontransformed rat intestinal epithelial cells (IEC-18-cells) (20), but 1 mM NaHS decreases proliferation of an immortalized colon epithelial cell (YAMC cells) and a panel of colon cancer cell lines (HT-29, SW1116, and HCT116 cells) (118). H2S causes DNA damage in colonic cancer cells (HT-29-C1.16E cells) at concentrations of 250 μM, although only when DNA repair is inhibited (8). Evidence that intracellular signaling is not required for H2S to induce genotoxicity, is the observation that naked nuclei from Chinese hamster ovary cells treated with 1 mM sulfide demonstrated similar DNA damage. What is somewhat confusing is that the number of oxidized bases is increased after exposure to the highly reductive H2S and that butylhydroxyanisole, a radical scavenger, reduces DNA damage induced by H2S suggesting perhaps the involvement of mitochondrial radical production (7). In rat normal gastric epithelial cells (RGM1 cells), low concentrations of NaHS (0.5–1 mM) augments hydrogen peroxide-induced toxicity, while a higher concentration (1.5 mM) protects the cells from oxidative damage (119). In nontransformed human intestinal epithelial cells (FHs 74 Int cells), the expression of cell-cycle progression genes, inflammation genes, and DNA repair genes were modulated by H2S (6). In addition to causing DNA damage, H2S prevents the oxidation of butyrate and other short chain fatty acids in colonocytes, reducing nutritional support for colonocytes resulting in reduced absorption of sodium, reduced secretion of mucin, and a shorter life of the colonocytes (46, 74, 76, 89–91). As in other tissues, cytochrome C oxidase from colonic epithelial cells is inhibited by NaHS with an IC50 of 0.32 μM with concurrent reductions in oxygen consumption (55). Despite these findings that support the toxic effects of H2S, it does not alter the membrane integrity of isolated pig colonic crypts (56).

FIG. 3.

FIG. 3.

H2S and intestinal epithelial cells. H2S exerts numerous toxic effects on cultured gastrointestinal epithelial cells.

The toxic effects of exogenous H2S have led some to propose luminal H2S as a causative factor in both intestinal cancers and chronic intestinal inflammation. The former will be discussed here, while the latter will be discussed in the following section. Genotoxic effects of H2S (described above) suggest a potential causative role for the gas in cancer biology. Support for this concept comes from observations that H2S detoxifying genes are reduced in colorectal cancer (6), disulfide levels are increased in transplanted animal tumors (14), and fecal sulfide levels are increased in a sigmoid colon cancer group compared to disease-free controls (47). Mucosal biopsies of sigmoidal rectum exposed to 1 mM NaHS causes hyperproliferation with an expansion of the proliferative zone (16). In addition, H2S forces cell cycle entry of nontransformed rat epithelial cells (20) and increases the proliferation of the transformed epithelial cell line, Caco-2 (45). What is difficult to resolve is the conflicting evidence that diallyl sulfide and carbon disulfide, which may potentially have similar mechanisms of action as H2S, have potent antiproliferative effects and inhibit carcinogen-induced DNA damage in colonic, gastric, and esophageal epithelial cells (36, 77, 84, 116, 117). S-propargyl-cysteine, a H2S donor, is proapoptotic and causes cell cycle arrest in gastric cancer (SGC-7901) cells. In addition, S-propargyl-cysteine reduces the growth of tumor implants in nude mice (65).

H2S and Intestinal Inflammation

The role of H2S in intestinal inflammation is complex and at times contradictory (Fig. 4). Some experimental and clinical data suggest that H2S may be implicated in the etiology of ulcerative colitis, or at least serve to increase the risk of relapse. Ulcerative colitis is a mucosal inflammation of the colon with widespread epithelial cell damage and accumulation of neutrophils and eosinophils with crypt abscesses. As discussed above, H2S has many deleterious effects on intestinal epithelial cells, including reduced nutrition for colonocytes [for review see Refs. (86, 92)]. In some studies, fecal sulfide levels are increased in patients with ulcerative colitis (57, 85) and effective treatment of relapsed inflammation is associated with a reduction in sulfide levels (26). Increased sulfide levels are also observed in the trinitrobenzene sulfonic acid-induced murine colitis (115). Perhaps increased sulfide levels are due to reduced levels of rhodanese, or thiol methyltransferase, which is involved in H2S detoxification that has been demonstrated in human ulcerative colitis (75, 92) and dextran sodium sulfate induced colitis in mice (108). In addition, some investigators have suggested that widely used animal models of ulcerative colitis, with similar features of epithelial damage to ulcerative colitis, are due to increased availability of indigestible sulfate as a substrate for SRB (10).

FIG. 4.

FIG. 4.

H2S and inflammation. The literature describes both pro-inflammatory and anti-inflammatory effects of endogenously produced and exogenously delivered H2S.

Because of the toxic effects of H2S, the SRB have long been recognized as candidates in the etiology of ulcerative colitis but fecal and mucosal biopsy analysis of bacterial populations have failed to definitively implicate any change in SRB populations in the disease (93). It seems as though chronic pouchitis, a common condition that develops after total abdominal colectomy with ileal pouch anal anastomosis for the treatment for ulcerative colitis, is following the trail that its parent disease blazed. Ileal pouches accumulate more H2S when pouchitis is active versus remitted states (81), and SRBs colonize pouches of patients who undergo total abdominal colectomy with ileal pouch anal anastomosis for the treatment for ulcerative colitis but not in patients that have had the procedure for familial adenomatous polyposis in which cases the incidence of pouchitis is low (25). However, like ulcerative colitis, there is no correlation between populations of SRBs and mucosal inflammation (85, 99).

Evidence against H2S having a causative role in ulcerative colitis comes from a study that failed to demonstrate elevated fecal sulfide levels in the disease state (73) and animals models of colitis that fail to show improvement when bacterial sulfide is scavenged with bismuth (29), significantly improve when exogenous H2S is delivered (28, 68, 115), or significantly worsen when endogenous H2S production is inhibited (115). A potential mechanism of the anti-inflammatory effects of H2S is the ability of luminal H2S to modify secreted defensive proteins. Via reduction of disulfide bonds, H2S releases trefoil factor 3 (TFF3), which plays a key role in mucosal regeneration and repair processes, from its cosecreted disulfide-linked partner IgG Fc binding protein (1). In addition, recent evidence suggests that H2S reduces the sulfur groups of β-defensin which increases the potency of its antimicrobial activity (97).

Further support for an anti-inflammatory role of H2S comes from a number of studies conducted outside the colon. As has been demonstrated in the heart and central nervous system, exogenous H2S has a protective role in models of intestinal ischemia (37, 60, 66, 126, 127). H2S protects the gastric mucosa in models of ethanol-induced gastritis (15, 70). Exogenous H2S causes hypothermia which is thought to contribute to its effect of reducing stress-induced gastric ulcers (63). The most prolific work regarding the anti-inflammatory actions of H2S, mostly by the efforts of John Wallace and colleagues, is the protective role for both endogenous and exogenous H2S against nonsteroidal anti-inflammatory drug (NSAID)-induced gastritis (11, 27, 113, 114). These studies are culminating in the development of therapeutics designed to release H2S from NSAIDs to combat the gastric ulcer side effects of the most widely used class of pain medications (112).

While some investigators demonstrate that exogenous H2S (∼180 μmol/kg) increases lung injury after cecal ligation and puncture, a model for sepsis (4, 122–124) others demonstrate improvement with only a slightly smaller dose (100 μmol/kg) (18, 100). To confuse this issue further, both sides in this debate have demonstrated that inhibiting the endogenous production of H2S inhibits leukocyte trafficking in mesenteric arteries (124) and conversely, delivering exogenous H2S enhances leukocyte trafficking (18, 124). Completely opposite effects on leukocyte trafficking have been demonstrated in models of carageenan-induced hindpaw inflammation, aspirin-induced gastric ulceration, and air pouch-induced inflammation, where inhibition of endogenous H2S enhanced leukocyte migration, and exogenous H2S (100 μmol/kg) reduced leukocyte migration (27, 121). One study has also demonstrated that nanomolar concentrations of H2S can potentiate T lymphocyte activation (72). Because T cells are capable of both potentiating and resolving inflammation depending on polarization, it is possible that H2S can potentiate both pro- and anti-inflammatory effects through an action on T lymphocytes depending on which way any particular model is polarized.

As this section hopefully demonstrates, the role of H2S in intestinal inflammation is far from clear. But with increased works put forth by numerous established gas biologists, and those investigators new to the field, nuances between models, understanding of dose-dependent and release rate- and duration-dependent effects as well as definitive identification of multiple molecular targets for H2S are likely to resolve what is at present often conflicting and confusing data.

Endogenous H2S and Gastrointestinal Motility

The neuromuscular layers of the gastrointestinal tract contain the afferent, interneuronal, and efferent neurons and the effector smooth muscle cells that are capable of intrinsic neurogenic reflex control as well as myogenic control of motility (Fig. 5). When the neuromuscular layers of the mouse colon are isolated in a sterile manner without the luminal bacterial contents, the neurons, which express cystathionine-γ-lyase generate H2S from the amino acid cysteine (59). There is a robust mechanism that removes H2S in this system, partially through the degradation to thiosulfate through sulfide quinone reductase and partially through the degradation to sulfate (58). There is little evidence that sulfur from exogenously delivered H2S is incorporated into proteins in the mouse colon neuromuscular layers (58).

FIG. 5.

FIG. 5.

Endogenous H2S modulates gastrointestinal motility. The neural and muscular components of the peristaltic reflex, one pattern of gastrointestinal motility, are illustrated with observed actions of H2S on these components. There is little evidence that luminal (bacterial) H2S contributes directly to the neuromuscular components of motility as the epithelial cells efficiently oxidize H2S to thiosulfate and sulfate which is removed via the portal circulation. ICC, interstitial cells of Cajal; LM, longitudinal muscle; MP, myenteric plexus; CM, circular muscle; SMP, submucosal plexus; MUC, mucosa; IPANs, intrinsic afferent neurons.

The first work on the role of H2S on gastrointestinal smooth muscle was a relaxation of guinea pig ileum smooth muscle that is augmented by cyanide and nitroprusside, but reversed relaxations caused by nitric oxide (50). Further studies demonstrated that, like the cardiovascular system, gastrointestinal smooth muscle from different regions and species are relaxed by exogenous delivery of H2S (40, 109). Unlike the cardiovascular system, identifying the molecular mechanisms that contribute to H2S-induced smooth muscle relaxation has been more difficult. There are studies that have demonstrated a partial contribution of the ATP-sensitive potassium (KATP) channel to intestinal smooth muscle relaxation in the guinea pig antrum (125), rat jejunum (78), and the human, rat and mouse jejunum and colon (30). In addition, there are studies that demonstrate a lack of effect of KATP channels in H2S-mediated intestinal smooth muscle relaxations in the mouse gastric fundus (21), mouse distal colon (22), the rat jejunum (48), rat ileum (79), and guinea pig taenia caecum (19). These studies have suggested a role for voltage-gated potassium channels, myosin light chain phosphatase, mitochondria, or have failed to identify a molecular mechanism of action.

Importantly, H2S has an inhibitory role on spontaneous and agonist-mediated rhythmic contractile activity. A key finding was the demonstration that this occurs across species and in distinct gastrointestinal regions (30). Recent work from rainbow trout (Oncorhynchus mykiss) and coho salmon (Oncorhynchus kisutch) suggest that this pan-intestinal inhibitory effect also occurs in nonmammalian vertebrates as well (24). This latter work has demonstrated that hypoxia has similar effects to exogenous H2S and suggests that H2S may act as cellular oxygen sensor in the gastrointestinal tract. Spontaneous rhythmic contractions of the gastrointestinal tract are dependent on a cell type known as interstitial cells of Cajal (ICC), which generate intrinsic pacemaker potentials. In isolated ICC of the mouse small intestine, H2S inhibits pacemaker activity in ICC (83) and interacts with nitric oxide in regulating functional pacemaker activity (120). H2S stimulates the proliferation of ICC through the phosphorylation of AKT (42). H2S activates voltage-gated sodium channels (NaV1.5) in circular smooth muscle cells from the human jejunum (102) which play a role in propagating pacemaker activity. A recent study demonstrated that endogenous H2S contributes to resting membrane potential and spontaneous contractions in the rat colon as cystathionine-γ-lyase and cystathionine-β-synthase inhibitors are able to reduce H2S production, depolarize smooth muscle cells, and increase the frequency of contractions in muscle strips (33). Functional assessments in awake mice demonstrate that H2S enhances the gastric emptying of liquids via KATP and transient receptor potential V1 (TRPV1) channels (71).

H2S and Epithelial Cell Function, Including Neurogenic Secretion

Recent reviews have summarized current knowledge of all gaseous signal molecules involved in regulating small intestinal (105) and colonic ion secretion (87). In this review, I will discuss only H2S, but it should be noted that there is significant interaction in this system of H2S with nitric oxide and carbon monoxide. Exogenous H2S has a prosecretatory neuromodulator effect in isolated mucosal/submucosal preparations of the guinea pig and human colon (Fig. 6). Further pharmacological dissection of this effect demonstrate that H2S likely acts on TRPV1 receptors expressed by spinal afferent neurons that innervate the mucosa which release substance P to activate intrinsic submucosal secretomotor neurons that stimulate secretion via acetylcholine acting on mucosal epithelial cells (49, 96). It should be noted here that secretomotor neurons of the submucosal plexus are also involved in vasodilatation of submucosal arterioles to facilitate nutrient absorption. Like other cardiovascular regions, H2S relaxes gastric arterioles at high concentrations via KATP- dependent and independent mechanisms, but also contracts gastric arterioles at low concentrations by inhibiting NO release (51). Other neurogenic effects of H2S on intestinal vasodilator responses are likely to be found. While the studies in human, guinea pig, and mouse colonic secretion find no role for direct effects of H2S on epithelial cells, a subsequent study in the rat colon demonstrates that H2S increases anion secretion that is only partially blocked by tetrodotoxin, while the remaining response is via both apical and basolateral potassium channels (38). In the intact duodenum of the rat, H2S stimulates the release of bicarbonate from Brunner's glands via increased release of prostaglandins and nitric oxide. In addition, an inhibitor of cystathionine-γ-lyase reduces acid-induced bicarbonate secretion suggesting a role for endogenous H2S in the physiological response of the duodenum to stomach acid (44). An early work in this area described that H2S delivered to the isolated intestinal loop of the dog reduced the absorption of glucose without affecting xylose absorption (64).

FIG. 6.

FIG. 6.

H2S and intestinal secretion. H2S is prosecretory via direct epithelial and indirect neural mechanisms. CNS, central nervous system.

Many direct effects of H2S on epithelial cells were discussed above in the section regarding H2S toxicology. Mucosal epithelial cells have the functional role of not only transporting nutrients, but also in forming a barrier to potential luminal pathogens. Cysteine enhances barrier function in salmonella-infected rats independent of its role in glutathione production (111) suggesting that H2S may enhance barrier function. Bismuth which effectively removes luminal sulfide (82, 104) also reduces the invasion of epithelial cells by enteroinvasive bacteria (35) and thiol and disulfide compounds inhibit the secretory response of E. coli heat stable enterotoxin (34). Further protective roles of H2S in this system are suggested by the finding that cysteine enhances ileal mucosal growth following ileal resection in rats (98). The breakdown products of H2S, thiosulfate, and sulfate inhibit the transport of selenium across monolayers of the transformed epithelial cell, Caco-2 (52), suggesting that not only H2S, but also its catabolic products may have roles in the function of intestinal epithelial cells. Work in this area is growing at a fast pace as more investigators study the effects of H2S on different and new epithelial cell lines.

H2S and Gastrointestinal Nociception

H2S modulates nociceptive sensitivity of the gastrointestinal tract (Fig. 7). Studies in the human and guinea pig colon suggest a role for TRPV1 receptors on spinal afferent neurons in the response to exogenous H2S (49, 96) which has also been reviewed (95). Interestingly, H2S has an antinociceptive effect for the spinal and supraspinal visceromotor response and decreases spinal Fos immunoreactivity in response to colonic distension (23). On the other hand, studies have also demonstrated a pronociceptive effect of H2S on visceromotor responses to colonic distension via the activation of T-type calcium channels (69). The chelation of zinc usually bound to T-type calcium channels by H2S, appears to be a key step in their activation in colonic afferents (67, 68). Support for a pronociceptive role of H2S comes from the demonstration that H2S directly activates jejunal mesenteric afferents (49). In addition to TRPV1 receptors, H2S activates TRPA1 receptors (3, 80). TRPA1 receptors are partially responsible for mechanosensitive responses of afferent neurons in mouse colon (12, 13). Recent evidence suggests that H2S acts on TRPA1 directly in colonic afferent neurons to enhance nociceptive function (110).

FIG. 7.

FIG. 7.

H2S and gastrointestinal nociception. H2S modulates nociceptive reflexes of the gastrointestinal tract through several identified molecular targets, including the TRPV1 receptor, TRPA1 receptor and T-type voltage-gated calcium channels (VGCC). There are both pro-nociceptive and anti-nociceptive actions of H2S. TRP, transient receptor potential.

Conclusion

While the role of H2S in gastrointestinal physiology is becoming clearer, it is by no means clear. There are a plethora of targets for H2S in this system and numerous complimentary and conflicting studies. While studies in the last century focused on the toxicology of H2S in the gut, and found roles for H2S from bacterial sources in gastrointestinal diseases, studies in the last decade have focused on endogenous host H2S and are finding numerous physiological effects of this gaseous signal molecule. The major effects of H2S in this system continue to remain both pro- and anti-inflammatory, smooth muscle relaxation, prosecretory, and pro- and antinociceptive. Future work will hopefully resolve discrepancies in the literature and identify molecular targets and mechanisms of action for H2S. One thing is clear; the intimate relationship between H2S and the gastrointestinal tract continues to be strong as we persist to unravel its mysteries.

Abbreviations Used

CM

circular muscle

H2S

hydrogen sulfide

ICC

interstitial cells of Cajal

IPANs

intrinsic afferent neurons

KATP channel

ATP-sensitive potassium channel

LM

longitudinal muscle

MP

myenteric plexus

MUC

mucosa

NSAID

non-steroidal anti-inflammatory drug

SMP

submucosal plexus

SRB

sulfate-reducing bacteria

TFF3

trefoil factor 3

TRP

transient receptor potential

Acknowledgments

I gratefully acknowledge the secretarial support of Ms. Janice Applequist. This work was supported by NIH grant DK76665.

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