Na-H Exchanger Isoform-2 (NHE2) Mediates Butyrate-dependent Na+ Absorption in Dextran Sulfate Sodium (DSS)-induced Colitis

Rajendran, Vazhaikkurichi M.; Kumar, Navalpur S. Nanda; Tse, Chung Ming; Binder, Henry J.

doi:10.1074/jbc.m115.654277

Cited by 15 publications

(20 citation statements)

References 42 publications

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“…Physiologically these findings may be interpreted to compromise the absorption of NaCl and water hence contribute to the development of diarrhea in the present model of colitis. Furthermore, we have not measured the uptake of Na + or water in this condition as this is a well-known fact that the electrolyte uptake is impaired in inflamed enterocytes which is a contributory factor to the development of diarrhea in these animals [ 20 – 21 , 33 – 34 ]. This has been reported that in DSS model, suppression of NHE-3 activity is accompanied by an induction of the NHE-2 activity as a counter act mechanism [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of down regulation of Na-H exchanger-2 in experimental colitis

2017

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BackgroundThe Na-H exchanger [NHE] performs an electroneutral uptake of NaCl and water from the lumen of the gastrointestinal tract. There are several distinct NHE isoforms, some of which show an altered expression in the inflammatory bowel diseases (IBD). In this study, we examined a role of NHE-2 in experimental colitis.MethodsColitis was induced in male Sprague-Dawley rats by intra-rectal administration of trinitrobenzenesulphonic acid (TNBS). On day 6 post-TNBS, the animals were sacrificed, colonic and ileal segments were taken out, cleaned with phosphate buffered saline and used in this study.ResultsThere was a significant decrease in the level of NHE-2 protein as measured by ECL western blot analysis and confocal immunofluorescence microscopy. The levels of NHE-2 mRNA and heteronuclear RNA measured by an end-point RT-PCR and a real time PCR were also decreased significantly in the inflamed colon. However, there was no change in the level of NHE-2 protein in response to in vitro TNF-α treatment of uninflamed rat colonic segment. These changes were selective and localized to the colon as actin, an internal control, remained unchanged. Confocal immunofluorescence microscopy revealed co-localization of NHE-2 and NHE-3 in the brush borders of colonic epithelial cells. Inflamed colon showed a significant increase in myeloperoxidase activity and colon hypertrophy. In addition, there was a significant decrease in body weight and goblet cells’ mucin staining in the TNBS treated colon. These changes were not conspicuous in the non-inflamed ileum.ConclusionsThese findings demonstrate suppression of NHE-2 expression on the brush borders in the colonic epithelial cells which is regulated transcriptionally. However a role of TNF-α in the regulation of NHE-2 is discounted in the present model of colitis. This decrease in the NHE-2 expression will lead to a loss of electrolyte and water uptake thus contributing to the symptoms associated with IBD.

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Section: Discussionmentioning

confidence: 99%

Mechanism of down regulation of Na-H exchanger-2 in experimental colitis

2017

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“…(10,11,25) While it has been shown that diarrhea associated with ulcerative colitis (UC) occurs primarily as the result of inhibition of NHE-mediated Na + absorption in UC, (30) …”

Section: Ibd As a Consequence Of Loss Of Nhe3 Functionmentioning

confidence: 99%

Congenital Sodium Diarrhea

Janecke

Heinz‐Erian

Müller

2016

J. pediatr. gastroenterol. nutr.

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Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.

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“…SCFAs are generated in the colon as end products of bacterial fermentation where the primary ones are acetate, propionate, and butyrate (98). In colon, SCFAs play critical roles as predominant source of metabolic energy, maintenance of epithelial integrity, fluid absorption and have important anti-inflammatory and anti-cancer effects (66, 87, 156, 178, 187, 193, 194). These SCFAs specifically also affect important cellular processes such as proliferation, differentiation, apoptosis, hormonal secretion, and immune responses in the gut, and in part via activation of FFA2 and FFA3 (5, 31, 52, 92, 111, 116, 154, 165, 181, 196), as outlined later.…”

Section: Introductionmentioning

confidence: 99%

Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology

Priyadarshini

Kotlo

Dudeja

et al. 2018

Comprehensive Physiology

147

115

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Nutrient sensing is a mechanism for organisms to sense their environment. In larger animals, including humans, the intestinal tract is a major site of nutrient sensing for the body, not surprisingly, as this is the central location where nutrients are absorbed. In the gut, bacterial fermentation results in generation of short chain fatty acids (SCFAs), a class of nutrients, which are sensed by specific membrane bound receptors, FFA2, FFA3, GPR109a, and Olfr78. These receptors are expressed uniquely throughout the gut and signal through distinct mechanisms. To date, the emerging data suggests a role of these receptors in normal and pathological conditions. The overall function of these receptors is to regulate aspects of intestinal motility, hormone secretion, maintenance of the epithelial barrier, and immune cell function. Besides in intestinal health, a prominent role of these receptors has emerged in modulation of inflammatory and immune responses during pathological conditions. Moreover, these receptors are being revealed to interact with the gut microbiota. This review article updates the current body of knowledge on SCFA sensing receptors in the gut and their roles in intestinal health and disease as well as in whole body energy homeostasis. © 2017 American Physiological Society. Compr Physiol 8:1091-1115, 2018.

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Na-H Exchanger Isoform-2 (NHE2) Mediates Butyrate-dependent Na+ Absorption in Dextran Sulfate Sodium (DSS)-induced Colitis

Abstract: Background: Defective Na ϩ absorption is the primary cause of diarrhea in inflamed colon such as ulcerative colitis (UC).

Cited by 15 publications

References 42 publications

Mechanism of down regulation of Na-H exchanger-2 in experimental colitis

Mechanism of down regulation of Na-H exchanger-2 in experimental colitis

Congenital Sodium Diarrhea

Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology

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