Secretion of bicarbonate into the adherent layer of mucus gel creates a pH gradient with a near-neutral pH at the epithelial surfaces in stomach and duodenum, providing the first line of mucosal protection against luminal acid. The continuous adherent mucus layer is also a barrier to luminal pepsin, thereby protecting the underlying mucosa from proteolytic digestion. In this article we review the present state of the gastroduodenal mucus bicarbonate barrier two decades after the first supporting experimental evidence appeared. The primary function of the adherent mucus gel layer is a structural one to create a stable, unstirred layer to support surface neutralization of acid and act as a protective physical barrier against luminal pepsin. Therefore, the emphasis on mucus in this review is on the form and role of the adherent mucus gel layer. The primary function of the mucosal bicarbonate secretion is to neutralize acid diffusing into the mucus gel layer and to be quantitatively sufficient to maintain a near-neutral pH at the mucus-mucosal surface interface. The emphasis on mucosal bicarbonate in this review is on the mechanisms and control of its secretion and the establishment of a surface pH gradient. Evidence suggests that under normal physiological conditions, the mucus bicarbonate barrier is sufficient for protection of the gastric mucosa against acid and pepsin and is even more so for the duodenum.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00102.2004

Gastroduodenal mucus bicarbonate barrier: Protection against acid and pepsin

NHE3 is the brush-border (BB) Na + /H + exchanger of small intestine, colon, and renal proximal tubule which is involved in large amounts of neutral Na + absorption. NHE3 is a highly regulated transporter, being both stimulated and inhibited by signaling that mimics the postprandial state. It also undergoes downregulation in diarrheal diseases as well as changes in renal disorders. For this regulation, NHE3 exists in large, multiprotein complexes in which it associates with at least nine other proteins. This review deals with short-term regulation of NHE3 and the identity and function of its recognized interacting partners and the multiprotein complexes in which NHE3 functions.

https://www.physiology.org/doi/pdf/10.1152/physrev.00030.2006

Regulatory Binding Partners and Complexes of NHE3

The gastroduodenal mucosa withstands injury from acid, drugs, foodstuffs, and other factors. Defense mechanisms include pre-epithelial and epithelial barriers, submucosal acid sensors, prostaglandin generation, endogenous protective gases, and other chemical mediators. Recent studies have focused on proteinase-activated receptors and their linkage to prostaglandin formation, as well as on antioxidants targeted to reduce harmful reactive oxygen species. Investigation continues into the protective roles of calcitonin gene-related peptide, hydrogen sulfide, annexin-1, survivin, and methylnicotinamide. This article also summarizes some new findings on the genetics of ulcer formation and the effects of age and gender on mucosal defense and touches on current developments in drugs, including considerations for future therapeutic agents.

Gastroduodenal Mucosal Defense

Na(+) and Cl(-) movement across the intestinal epithelium occurs by several interconnected mechanisms: (a) nutrient-coupled Na(+) absorption, (b) electroneutral NaCl absorption, (c) electrogenic Cl(-) secretion by CFTR, and (d) electrogenic Na(+) absorption by ENaC. All these transport modes require a favorable electrochemical gradient maintained by the basolateral Na(+)/K(+)-ATPase, a Cl(-) channel, and K(+) channels. Electroneutral NaCl absorption is observed from the small intestine to the distal colon. This transport is mediated by apical Na(+)/H(+) (NHE2/3) and Cl(-)/HCO(3)(-) (Slc26a3/a6 and others) exchangers that provide the major route of NaCl absorption. Electroneutral NaCl absorption and Cl(-) secretion by CFTR are oppositely regulated by the autonomic nerve system, the immune system, and the endocrine system via PKAα, PKCα, cGKII, and/or SGK1. This integrated regulation requires the formation of macromolecular complexes, which are mediated by the NHERF family of scaffold proteins and involve internalization of NHE3. Through use of knockout mice and human mutations, a more detailed understanding of the integrated as well as subtle regulation of electroneutral NaCl absorption by the mammalian intestine has emerged.

/pdf/regulation-of-electroneutral-nacl-absorption-by-the-small-3ykrzrxfoh.pdf

Regulation of Electroneutral NaCl Absorption by the Small Intestine

We hypothesized that duodenal HCO3− secretion alkalinizes the microclimate surrounding intestinal alkaline phosphatase (IAP), increasing its activity. We measured AP activity in rat duodenum in sit...

Duodenal brush border intestinal alkaline phosphatase activity affects bicarbonate secretion in rats

We examined the effect of inhibition of Na+/H+ exchange (NHE) on duodenal bicarbonate secretion (DBS) in rats to further understand DBS regulation. DBS was measured by using the pH-stat method and ...

NHE3 inhibition activates duodenal bicarbonate secretion in the rat

The proximal duodenum is exposed to extreme elevations of Pco2 because of the continuous mixture of secreted HCO3− with gastric acid. These elevations (up to 80 kPa) are likely to place the mucosal...

Mechanism of augmented duodenal HCO3− secretion after elevation of luminal CO2

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NHE3 inhibition activates duodenal bicarbonate secretion in the rat

Mechanism of augmented duodenal HCO3− secretion after elevation of luminal CO2