Somatostatin regulates NHE8 protein expression via the ERK1/2 MAPK pathway in DSS-induced colitis mice

Li, Xiao; Cai, Lin; Xu, Hua; Geng, Chong; Lu, Jing; Tao, Liping; Sun, Dan; Wang, Chunhui

doi:10.1152/ajpgi.00239.2016

Cited by 30 publications

(37 citation statements)

References 38 publications

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“…This membrane transport is mediated by three antiporters, NHE2, NHE3, and NHE8, with subtle differences in colonic expression pattern. The latter two are inhibited in animal models of IBD, 9 – 11 as well as in human patients, 11 , 34 , 35 and deletion of NHE3 in mice was sufficient to lead to microbiome changes similar to that observed in human IBD, 22 microbiota-dependent spontaneous colitis, 20 and increased susceptibility to mucosal injury or T-cell mediated colitis. 21 , 26 These observations prompted us to hypothesize that impaired Na + /H + exchange, be it the result of initial subclinical inflammation or infection, lead to microbial dysbiosis, which in turn lowers the inflammatory threshold or otherwise modulates mucosal immune responses.…”

Section: Discussionmentioning

confidence: 88%

Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice

et al. 2018

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Intestinal epithelial Na+/H+ exchange facilitated by the apical NHE3 (Slc9a3) is a highly-regulated process inhibited by intestinal pathogens and in inflammatory bowel diseases. NHE3−/− mice develop spontaneous, bacterially-mediated colitis, and IBD-like dysbiosis. Disruption of epithelial Na+/H+ exchange in IBD may thus represent a host response contributing to the altered gut microbial ecology, and may play a pivotal role in modulating the severity of inflammation in a microbiome-dependent manner. To test whether microbiome fostered in an NHE3-deficient environment is able to drive mucosal immune responses affecting the onset or severity of colitis, we performed a series of cohousing experiments and fecal microbiome transplants into germ-free Rag-deficient or IL-10−/− mice. We determined that in the settings where the microbiome of NHE3-deficient mice was stably engrafted in the recipient host, it was able accelerate the onset and amplify severity of experimental colitis. NHE3-deficiency was characterized by the reduction in pH-sensitive butyrate-producing Firmicutes families Lachnospiraceae and Ruminococcaceae (Clostridia clusters IV and XIVa), with an expansion of inflammation-associated Bacteroidaceae. We conclude that the microbiome fostered by impaired epithelial Na+/H+ exchange enhances the onset and severity of colitis through disruption of the gut microbial ecology.

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Section: Discussionmentioning

confidence: 88%

Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice

et al. 2018

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“…158,159 Indeed, somatostatin agonists are able to increase intestinal tight junctions in models of dextran sulfate sodium (DSS) and Citrobacter rodentium induced colitis 160 and modulate the water and sodium uptake protein NHE8, associated with UC pathology, via MAPK signaling. 161 Neurotensin þ cells are seen to increase in the mouse DSS model and blocking signaling via antagonists increases pathology via a cyclooxygenase (COX)-2 mediated pathway, 162 indicating a protective effect. Indeed, therapeutic use of peptides or agonists has been beneficial in mouse models, GLP-2 can rescue DSS colitis 163 and small intestinal enteritis 164,165 possibly by reducing bacterial translocation, 166 while nanodelivery of GLP-1 is also protective.…”

Section: Inflammatory Bowel Disease-animal Modelsmentioning

confidence: 99%

“…Enteroendocrine cell detection of inflammation/infection via toll-like receptors 74,76,239 and microbiome dysbiosis via microbial metabolites 75,[77][78][79] Alter epithelial absorption/efflux 161,[242][243][244] Increased sIgA 253,282 Increase tight junction function 160,97,249,250 Direct enteroendocrine cytokine release 74,239,240 Influence cytokine and anti-microbial production from enterocytes 241,248 and Paneth cells 102 Increase crypt cell proliferation via increased growth factor release from myofibroblast 140,141,251,252 Eosinophil 302…”

Section: Direct Immune Modulationmentioning

confidence: 99%

Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

2018

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The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies' largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity.

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“…A follow-up study also showed that octreotide treatment stimulates colonic NHE8 expression in colitic mice. Both somatostatin receptor 2 (SSTR2) and somatostatin receptor 5 (SSTR5) were involved in restoring NHE8 expression via their roles in suppressing ERK1/2 phosphorylation (174). …”

Section: Regulation Of the Na+/h+ Exchangers Expressed In The Digestimentioning

confidence: 99%

“…Recently, the expression of NHE8 in human UC patients has also been studied. In active UC patients, the expression of NHE8 protein was significantly reduced by ~55% (174). Similar findings were also observed in TNFα-treated Caco-2 cells, where TNFα treatment at 10 ng/mL reduced NHE8 mRNA expression by 40% (311).…”

Section: Na+/h+ Exchange In Pathological Statesmentioning

confidence: 99%

SLC9 Gene Family: Function, Expression, and Regulation

Kiela

2018

Comprehensive Physiology

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The Slc9 family of Na /H exchangers (NHEs) plays a critical role in electroneutral exchange of Na and H in the mammalian intestine as well as other absorptive and secretory epithelia of digestive organs. These transport proteins contribute to the transepithelial Na and water absorption, intracellular pH and cellular volume regulation as well as the electrolyte, acid-base, and fluid volume homeostasis at the systemic level. They also influence the function of other membrane transport mechanisms, affect cellular proliferation and apoptosis as well as cell migration, adherence to the extracellular matrix, and tissue repair. Additionally, they modulate the extracellular milieu to facilitate other nutrient absorption and to regulate the intestinal microbial microenvironment. Na /H exchange is inhibited in selected gastrointestinal diseases, either by intrinsic factors (e.g., bile acids, inflammatory mediators) or infectious agents and associated bacterial toxins. Disrupted NHE activity may contribute not only to local and systemic electrolyte imbalance but also to the disease severity via multiple mechanisms. In this review, we describe the cation proton antiporter superfamily of Na /H exchangers with a particular emphasis on the eight SLC9A isoforms found in the digestive tract, followed by a more integrative description in their roles in each of the digestive organs. We discuss regulatory mechanisms that determine the function of Na /H exchangers as pertinent to the digestive tract, their regulation in pathological states of the digestive organs, and reciprocally, the contribution of dysregulated Na /H exchange to the disease pathogenesis and progression. © 2018 American Physiological Society. Compr Physiol 8:555-583, 2018.

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Somatostatin regulates NHE8 protein expression via the ERK1/2 MAPK pathway in DSS-induced colitis mice

Cited by 30 publications

References 38 publications

Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice

Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice

Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

SLC9 Gene Family: Function, Expression, and Regulation

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