Question:

Epithelial pH_i regulation and HCO₃^- transport is of paramount importance for intestinal mucosal health. Accordingly, the intestinal mucosa expresses a multitude of HCO₃^- transporters in a polarity-, cell type- and segment-specific fashion. The electrogenic Na⁺HCO3^- cotransporter NBCe1 (Slc4a4) is strongly expressed in the basolateral enterocyte membrane. Its function has so far remained largely elusive, due to early death of the NBCe1-deficient mice. Thus, does NBCe1 play an important role in gut?

Methods:

We used miniaturized Ussing chambers and microdissected intestinal villi to study the importance of NBCe1 in pH_i control, HCO₃^- secretory rates and short circuit current (Isc) in duodenum and jejunum from 16-18 days old slc4a4-deficient (KO) and WT mice.

Results:

In CO₂/HCO₃^- buffer, steady state pH_i did not significantly differ between KO and WT enterocytes within microdissected fluorescent pH indicator-loaded duodenal and jejunal villli. pH_i recovery from an intracellular acid load, however, was significantly slower in KO than WT jejunal villi, whereas it was not different in duodenal villi, which also displayed high expression levels of the electroneutral NBCn1(Slc4a7). Basal HCO₃^- secretory rates were significantly lower in NBCe1-deficient jejunal but not duodenal mucosa, and in both segments, as well as different colonic segments, the HCO₃^- secretory response to forskolin was similar between WT and KO mucosa. In all intestinal segments, basal short circuit current (Isc) was more negative in KO than in WT, and this was completely amiloride-insensitive in small intestinal and only partially sensitive in the large intestine. The Isc response to FSK response was significantly reduced in KO compared to WT mucosa in all studied intestinal segments except the duodenum. Inhibition of carbonic anhydrases strongly decreased HCO₃^- secretory rate in KO but not WT duodenum and cecum/prox. colon (which also express NBCn1), whereas it reduced HCO₃^- secretory rate in KO and WT jejunum.(which expresses little NBCn1).

Conclusions:

In most parts of the intestine, the electrogenic NBCe1 is not essential for basal or stimulated HCO₃^- secretion as well as pH_i recovery from acid loads, because alternative mechanisms exist, such as the electroneutral NBCn1 and/or basolateral Na⁺/H⁺ exchange. A lack of NBCe1 reduces electrogenic Cl^- secretory response in jejunum and colon, however, either by the influence of NBCe1 on basolateral membrane potential or on supply of HCO₃^- for basolateral Cl^- uptake via Cl^-/HCO₃^- exchange.