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Synthesis of H2S in the Gastrointestinal Tract

Xu Huang, Wen-Xie Xu

Xu Huang, Wen-Xie Xu, Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China

Correspondence to: Wen-Xie Xu, Professor, Department of Physiology, Shanghai Jiaotong University School of Medicine, 800 Dongchuan Road, 328 Wenxuan Medical Building, Shanghai 200240, China.
Email: wenxiexu@sjtu.edu.cn
Telephone:+86-21-34205639
Received: September 2, 2014
Revised: October 21, 2014
Accepted: Ocotber 26, 2014
Published online: February 21, 2015

ABSTRACT

Hydrogen sulfide (H2S) is the third gaseous signal molecule with interest which is endogenously generated in gastrointestinal tract. H2S play important physiological and pathophysiological roles in regulation of gastrointestinal functions, for example, gastrointestinal motility, secretion and nociception. In the present review we have mainly reviewed the recent findings about the study of H2S in regulation of gastrointestinal motility and its mechanism. The effect of H2S on gastrointestinal smooth muscle shows difference in different concentration of H2S and different regions. In gastric smooth muscle, H2S exhibits dual effects, that is, excitatory (low concentration) and inhibitory (high concentration) effects via suppressing voltage- dependent potassium channels and activating ATP-sensitive potassium channels (KATP), respectively, in guinea-pig and mouse. In intestinal smooth muscle, NaHS induced a biphasic effect, that is, a transient excitatory effect followed a long-lasting inhibitory effect in rat. The excitatory effect is mediated by TRPV1 and NK1 receptors and the inhibitory effect is mediated by KATP. In colonic smooth muscle, H2S induces inhibitory effect mediated by both KATP and SKCa channels in human, rat and mouse. This review gives a synopsis of the H2S function in regulation of gastrointestinal motility and its mechanism.

Key words: Gastrointestinal motility; Hydrogen sulfide (H2S); Voltage-dependent potassium channel; ATP sensitive potassium channel

© 2015 The Authors. Published by ACT Publishing Group Ltd.

Huang X, Xu WX. Synthesis of H2S in the Gastrointestinal Tract. Journal of Gastroenterology and Hepatology Research 2015; 4(1): 1459-1464 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/1071

Introduction

Hydrogen sulfide (H2S) has been regarded as “toxic gas” with an odor of “rotten eggs” for hundreds of years. In 1996, Abe and Kimura[1] found that endogenous H2S maybe functioned as a neuromodulator during induction of long-term potentiation in the hippocampus, which brought about a new perception of H2S. Since then more and more studies have emerged to explore the possible physiological and pathophysiological roles of endogenous H2S. And so far H2S has been proved to be involved in many physiological and pathophysiological processes such as vasodilation[2], angiogenesis[3,4], pro-[5,6] or anti-inflammation[7,8] and cytoprotection[9,10], which makes it to be regarded as the third gasotransmitter along with nitric oxide (NO) and carbon monoxide (CO)[11], although others consider “gaseous signaling molecule” to be more accurate[12]. The roles of H2S and the mechanisms have been well summarized in some excellent reviews[11,13-16], in which a little is mentioned in the gastrointestinal tract. Since H2S has been proved to be endogenously generated in the gastrointestinal tract (see below), the physiological function of H2S in the gastrointestinal tract is intriguing and also several reviews have covered the roles of H2S in the gastrointestinal tract such as modulating the gastrointestinal motility and secrection, pro- or anti-inflammation, pro- or anti-nociception[12,17-22]. As the basis of the gastrointestinal function, gastrointestinal motility can triturate the food into pieces and mix the food with digestive juice sufficiently, which facilitate food digestion and absorption. Consequently, to make sure the effect of endogenous H2S on the gastrointestinal motility is quite significant, as has been focused on in the present review.

ynthesis of H2S in the gastrointestinal tract

H2S can be produced by enzymatic or non-enzymatic pathways in mammalian tissues, of which the enzymatic pathway was mostly focused on (see reference 14, 16 for review). Three enzymes responsible for H2S synthesis have been found in the mammals which are cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). CBS and CSE are pyridoxal phosphate-dependent and expressed exclusively in the cytosol. While 3-MST, which catalyzes the generation of H2S in combination with another enzyme, cysteine aminotransferase, is zinc denpendent and is both mitochondrial and cytosolic. All the enzymes use L-cysteine as the common substrate. In the gastrointestinal tract, CBS and CSE are the main enzymes catalyzing the generation of endogenous H2S.

In the stomach, CBS and CSE have been proved to be expressed in the cultured antral smooth muscle cells of mouse in our previous studies[23,24]. Western blotting results also demonstrated that both CBS and CSE were expressed in the rat and mouse stomach, and H2S synthesis in the rat stomach was about 75 nmol/g/h[25]. CBS and CSE were also identified in the small intestine[25-30]. In the rat duodenum and jejunum, both enzymes were expressed in the neurons of myenteric plexus, but not the smooth muscle cells or the interstitial cells of Cajal (ICCs)[27,29]. The expressions of CBS and CSE were also found in the ileum of rat and guinea pig where H2S production were about 6.6±1.3 nM/min/g tissue and 20.3±3.2 nM/min/g protein, respectively. And the inhibitor of CBS or CSE could inhibit the H2S generation[26,28]. CSE was found to be mainly expressed in the submucosal and myenteric neurons of the colon[31-34], but also found in the circular and longitudinal smooth muscle layers in the rat colon[34]. Myenteric interstitial cells of Cajal were CSE-immunoreactive in the guinea-pig and human colon[33]. However, CBS was mainly expressed in the neurons of enteric neuron system and in the mucosa of the colon[31,33,34]. In the presence of L-cysteine, homogenate of rat colonic tissue could generate about 2 nM/min/g protein H2S[35].

It is noteworthy that aside from endogenous production, H2S also can be produced exogenously in colonic tract by colonic microbiota, in which sulfate-reducing bacteria (SRB) is a main source[21]. Under physiological conditions, H2S level in the colon is still not so high because of the marked capacity of colonic epithelial cells to metabolize H2S[36]. Nevertheless, if the epithelium barrier is impaired, high concentration of H2S maybe results in some colonic disease because of its toxic effect.

H2S and the gastrointestinal motility

Since H2S can be generated endogenously, it is implied that H2S play an important role in regulation of gastrointestinal functions under physiological and pathophysiological conditions. Many results about the effect of H2S on gastrointestinal motility from different researchers exhibit diversity in different regions and different dose of H2S. In vascular smooth muscle H2S also reveals the complexity in regulation of smooth muscle tension, for example, H2S relaxed the vascular smooth muscles in most cases[2,37,38], however, in the aorta, the inhibitory effect was induced by high concentrations of H2S, while at low concentrations, H2S increased the contraction of pre-contracted smooth muscles[37,38]. Consequently, it is important to clarify the effect of H2S on the smooth muscle motility for better understanding the physiological significance of this gaseous signal molecule.

In the stomach

Our previous studies demonstrated that exogenous H2S showed dual effects on the spontaneous contraction of antral smooth muscles, i.e., low concentrations of H2S increased the basal tension, however, at high concentrations, H2S inhibited the spontaneous contraction[23,24,39]. In guinea-pig, sodium hydrogen sulfide (NaHS), an H2S donor, had a dual effect on the spontaneous contraction of gastric antrum muscle strips. At high concentrations (300 μM~1000 μM), NaHS suppressed the amplitude of spontaneous contraction. At low concentrations (100 μM~300 μM), NaHS enhanced the resting tension of muscle strips while slightly reduced the contractile amplitude[39]. Similar effect of NaHS was also observed in murine stomach, for example, NaHS inhibited the amplitude and frequency of spontaneous contraction at high concentrations (>200 μM), however, at low concentrations (<200 μM) enhanced the basal tension and increased the contractile amplitude of muscle strips. In addition, NaHS at low concentrations (<200 μM) produced a depolarization of the membrane potential, whereas AOA, an inhibitor of CBS, hyperpolarized the membrane potential and decreased the amplitude of slow waves[23].

It has been demonstrated that the contractile effect of H2S on the vascular smooth muscle is associated with NO. As we all know, NO is an endothelium-derived relaxing factor which relaxes vascular smooth muscles. Consequently, H2S is thought to induce contractile effect by inhibiting endothelial nitric oxide synthase (eNOS) which is a kind of enzyme catalyzing the generation of NO or combining with NO to form a novel nitrosothiol to reduce NO release[37,38,40]. But in our studies, the excitatory effect was not via these pathways. We found that the excitatory effect was inhibited by 4-AP, an inhibitor of voltage-dependent potassium channel, and exogenous H2S directly inhibited voltage-dependent potassium current. AOAA, an inhibitor of CBS, was shown to increase voltage-dependent potassium current. In another aspect, the inhibitory effect of H2S was reversed by glibenclamide, an inhibitor of KATP channel, and exogenous H2S directly increased KATP current, as reported in some studies of vascular smooth muscle[2,38]. All these results indicate that the excitatory effect of H2S at low concentrations was mediated via inhibition of voltage-dependent potassium channel, while the inhibitory effect was mediated via activation of KATP channel[23,24,39] (Figure 1). It has been reported that physiological levels of endogenous H2S may be from nanomolar to micromolar range in the mammalian tissues with the development of measurement methods[14]. In our studies, we used NaHS as H2S donor (60 μM~200 μM ), one third of which was reported to exist as the undissociated H2S[26]. That is, physiological level of endogenous H2S may be as an excitatory modulator in regulation of gastric motility, and our result that AOAA inhibited the spontaneous contraction of antral smooth muscle partly confirmed the speculation[23,24].

H2S donor was also displayed to accelerate gastric emptying of liquid in awake mice in a dose-dependent manner, which maybe mainly resulted from the relaxation effect of H2S on the pyloric sphincter muscles[41]. Glibenclamide and a transient receptor potential vanilloid type 1 (TRPV1) receptors antagonist capsazepine abolished the inhibitory effect of H2S, which indicate the involvement of KATP channel and TRPV1 receptors located on afferent nerves in this effect[41].

In the mouse gastric fundus, NaHS inhibited PGF2α-contracted muscle strips in a dose-dependent manner. The exact mechanism of the relaxant effect was unclear because it was not associated with the activation of potassium channels including KATP channels, Ca2+-activated K+ channel, voltage dependent K+ channel and inward rectifier K+ channel, the release of NO, and not influenced by TTX, a nerve blockers. However, the inhibitory effect of NaHS on PGF2α-induced contraction was suppressed by calyculin-A, an inhibitor of myosin light chain phosphatase (MLCP), the result suggests H2S may be directly participated in MLCP phosphorilation[42].

Generally speaking, the effect of H2S on the gastric motility seems to be adapted to the function of the stomach. As the main movement of gastric fundus, receptive relaxation is important for fundus function which makes stomach accommodate more food with less increase of lumen pressure. Since H2S relax the fundus smooth muscle, it maybe facilitates the receptive relaxation. Meanwhile, the excitatory effect of H2S on the antrum together with the inhibitory effect on the pyloric sphincter may facilitate the gastric emptying. Therefore, H2S may be an important modulator in the stomach.

In the small intestine

Effects of H2S on the intestinal motility were different because of different species and different regions of the intestine. In the duodenum of Wistar rats, NaHS induced a biphasic effect on the spontaneous contraction of the smooth muscle, that is, a transient excitatory effect followed a long-lasting inhibitory effect[27]. The excitatory effect was attenuated by both TRPV1 antagonist and NK1 receptor antagonist, which is consistent with the H2S-induced effect on the rat urinary bladder[43], indicating that NaHS might activate TRPV1 channels in the afferent nerve fibers resulting in the release of substance P and subsequent activation of NK1 receptor on the smooth muscle cells to increase the smooth muscle contraction. That is, the excitatory effect of NaHS resulted from the direct influence on the enteric neurons but not the smooth muscle cells. But the inhibitory effect of NaHS resulted from the open of KATP channels on the smooth muscle cells. Interestingly, both L-cysteine and SAM, an activator of CBS, increased the duodenal motility, indicating an excitatory effect of endogenous H2S[27]. Although not describing in details, the authors of the study also found that NaHS had similar biphasic effects on the spontaneous contraction of the longitudinal muscle in the jejunum, ileum and colon of the Wistar rats[27], which is different with others studies (see below).

Different from the Wistar rats, in the Lewis rats and mouse jejunum, NaHS induced an inhibitory effect on the smooth muscle motility[29,44,45]. Gallego et al[45] demonstrated that NaHS inhibited the spontaneous contraction of the jejunal smooth muscle in mouse, which may be a direct effect on the smooth muscle cells because TTX had no significant effect on the NaHS-induced inhibition and in the TRPV1-/- animals the inhibitory effect still existed. Similarly, Sarr team[29,44] also found that NaHS inhibited both spontaneous and bethanechol stimulated contraction of the jejunal smooth muscle in Lewis rats. Although the exact mechanism of NaHS-induced inhibition is unclear, there is a little difference between the circular muscle and the longitudinal muscle. Neither the effect on the circular muscle nor on the longitudinal muscle was via neural pathway, which means a direct effect on the smooth muscle. Interestingly, KATP channel may be in part involved in the NaHS-induced inhibition of the spontaneous contraction in the circular muscle of the jejunum, but not involved in the effect on the longitudinal muscle, indicating a complex function of H2S in modulating jejunum motility.

In the ileum, most studies manifested that H2S inhibited the smooth muscle motility[26,46-48]. The first study about H2S modulating the gastrointestinal motility was in the guinea-pig ileum which found that NaHS relaxed acetylcholine pre-contracted smooth muscle[26]. The following study reported by Teague et al[46] confirmed the result, which also found that NaHS relaxed both the spontaneous contraction of rabbit ileum and electrical field stimulation (EFS)-induced contraction of guinea-pig ileum. Moreover, the inhibitory effect of NaHS on the guinea-pig ileum to electrical stimulation was not via the open of KATP channel[46]. Similarly, the study in the rat ileum also found NaHS inhibited the spontaneous contraction which was not mediated by KATP channel[48]. Differently, Teague suspected that endogenous H2S may be generated by intramural nerves to modulate the smooth muscle motility because PAG, an inhibitor of CSE, increased EFS-induced contraction[46], whereas, H2S was supposed not to be produced enough by enteric neurons to play such a role in the rat ileum[48]. Recent study in mouse ileum also found that AOAA increased the contraction of smooth muscle to repeated electrical stimulations (ES) which was suspected to activate CBS, and substrate for generation of H2S L-cysteine decreased the EFS-induced contraction, indicating an inhibitory effect of H2S endogenously produced by enteric neurons[47]. The results that glibenclamide increased EFS-induced contraction but reduced NaHS-induced inhibition of EFS-induced contraction suggest KATP channel in the smooth muscle and enteric neurons involved in the inhibitory effect of H2S. Meanwhile, NaHS induced-decrease of basal tone in the mouse ileum was insensitive to TTX, but blocked by apamin, a blocker of small conductance Ca2+-activated K+ (SKCa) channel, which suggest that SKCa channels in the smooth muscle are responsible for the effect[47].

Aside from enteric neurons and smooth muscle cells, as the pacemaker cells, the interstitial cell of Cajal (ICC) may be also a target of H2S to regulate the gastrointestinal motility. Albeit no expression of CBS or CSE in ICC, exogenous H2S was shown to inhibit the pacemaker activity of ICC[30] which may be partially responsible for the H2S-induced inhibition of small intestine motility.

In the colon

In the mouse colon, it has demonstrated that NaHS inhibited the spontaneous and pre-contracted smooth muscle contraction in a dose-dependent manner, which was not via neuronal pathway because both TTX and TRPV1 blocker capsazepine had no significant effects on the inhibition[45,49]. Since glibenclamide and L-NAME, a nitric oxide synthase, did not affect the NaHS-induced inhibition, so that KATP channel and NO were not involved in the effect[49]. In the rat and human colon, NaHS also inhibited the colonic motility[45,50,51]. Interestingly, H2S exhibited different effects on different colonic motility patterns, for example, NaHS inhibited rhythmic propulsive motor complexes (RPMCs) which is associated with outflow, but enhanced the amplitude of ripples which may be associated with promoting mixing. The inhibitory effect of NaHS on the colonic motility was reduced by KATP channel blocker and small conductance calcium-activated potassium channel (SKCa) blocker, which suggest that both KATP and SKCa channels are involved in the effect[45,50,51]. Furthermore, the inhibitor of CBS or CSE increased the colonic motility and hyperpolarized the smooth muscle cell, suggesting that the endogenous H2S induced an inhibitory effect on colon[34]. However, different from the small intestine, NaHS did not alter the frequency of slow waves, which indicates that ICC may be not the main target of H2S in the colon[50].

Mechanisms of H2S in regulating the gastrointestinal motility

From all the studies above, the effect of H2S on gastrointestinal motility is very complicated (Table 1). For example, the effect is different in different regions of gastrointestinal tract and different species, and the targets of the effect are also dissimilarity. We can summarize the mechanism of H2S in regulation of gastrointestinal motility as below: (1) H2S can affect enteric neurons. H2S can activate TRPV1 channel in the primary afferent neurons to release a neurotransmitter[27,41], or H2S can affect the cholinergic neuromuscular transmission[46,50] to regulate the smooth muscle motility; (2) H2S can directly influence the channels in the smooth muscle cells, such as KATP channel[27,39,41,45,47,50,51], voltage-dependent K+ channel[23,39] and SKCa channel[45,47,50]. However, it is not clear how H2S affect these channels. Recently, it has been well-established that H2S directly regulates the physiological functions by sulfhydrating a large number of cellular proteins[16], for example, NaHS sulfhydrating sulfonylurea receptor 2B (SUR2B) subunit of KATP channel might partially interpret the effect of H2S on these channels; (3) H2S also can affect the pacemaker activity of ICC to modulate the smooth muscle motility[30]; (4) As two of the important gaseous signal molecules, H2S and NO have interaction in regulating the gastrointestinal smooth muscle motility. They can cooperate with each other to relax the smooth muscle[46], alternatively, they counteract each other to regulate the motility[24]. Although the exact mechanism is still needed to investigate, a finding that endogenous H2S inhibited the production of NO provides a clue[32]. Albeit these possible pathways, the mechanism of H2S in regulating the gastrointestinal motility is still ongoing.

Problems in studies

Since the studies on the physiological function of H2S are ongoing, there are still some problems to be resolved. The most important problem is that the present used inhibitors of CBS and CSE are considered nonspecific, especially AOAA which was proved to inhibit other pyridoxal phoophate-dependent enzymes[52,53]. Although it has been the exclusive inhibitor of CBS so far and also proved to reduce the generation of H2S[25,34], the possible side effects of AOAA make it suspect to speculate the function of endogenous H2S. Using the animals targeted deleted CBS and CSE may be an effective method to study the function of endogenous H2S in the gastrointestinal tract. Secondly, the exact concentration of H2S in vivo is ambiguous. The H2S levels are from nanomolar to low micromolar ranges by using different measurement methods under different conditions (see reference 14 for review). Consequently, whether the H2S donor used in the studies is close to the physiological level of H2S is questionable. Does the effect of H2S result from its toxicity? H2S has been reported to inhibit cytochrome C oxidase resulting in decrease of cellular adenosine triphosphate (ATP) which directly activate KATP channel responsible for many biological functions of H2S[54]. If H2S regulating the gastrointestinal motility via activation of KATP channel is a toxic effect? Thirdly, as the two important gaseous signal molecules in the gastrointestinal tract, the cross talk between H2S and NO in regulating the gastrointestinal motility is intriguing. Although there are a few studies on this topic, the exact mechanism is still unclear. In the future studies it is needed to clarify how H2S changes channel function and why the effect of H2S on gastrointestinal smooth muscle motility is different in different regions and what the physiological meanings is. In addition, it is also significant to definite whether there is cross talk between H2S and NO in regulating the gastrointestinal motility and its mechanism.

Conclusion

H2S can be endogenously generated by gastrointestinal tract and significantly affect the gastrointestinal motility. The effect of H2S on gastrointestinal smooth muscle shows difference in different concentration of H2S and different regions. In gastric smooth muscle, H2S exhibits excitatory (low concentration) and inhibitory (high concentration) effects via suppressing voltage-dependent potassium channels and activating ATP-sensitive potassium channels (KATP), respectively. In intestinal smooth muscle, NaHS induced a transient excitatory effect followed a long-lasting inhibitory effect in rat. The excitatory effect is mediated by TRPV1 and NK1 receptors and the inhibitory effect is mediated by KATP. In colonic smooth muscle, H2S induces inhibitory effect mediated by both KATP and SKCa channels in human, rat and mouse. Although the exact mechanism of H2S on the gastrointestinal motility is still unclear and there are still some unresolved problems in the studies, we believe studying the effect of H2S will contribute to clinical medicine to resolve the disorders of gastrointestinal motility in the future.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

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Peer reviewers: Weibiao Cao, MD, Assistant Professor of Medicine, Department of Medicine & Pathology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick St, Room 337, Providence, RI 02903, USA; Sebastiano Bonventre, Department of Surgical and Oncological Sciences, University of Palermo, Via Resuttana Colli, 367, 90146 Palermo, Italy; Mech-Sense, Aalborg Hospital, Aarhus University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark.

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