The ileum is considered the primary site of inorganic
sulfate ([Formula: see text]) absorption. In the present study, we explored the contributions of the apical
chloride/
bicarbonate (Cl-/[Formula: see text]) exchangers downregulated in
adenoma (DRA; Slc26a3), and putative
anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial 35[Formula: see text] and 36Cl- fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma
sulfate. The WT distal ileum supported net
sulfate absorption [197.37 ± 13.61 (SE) nmol·cm-2·h-1], but neither DRA nor PAT1 directly contributed to the unidirectional mucosal-to-serosal flux ([Formula: see text]), which was sensitive to serosal (but not mucosal)
DIDS, dependent on Cl-, and regulated by cAMP. However, the absence of DRA significantly enhanced net
sulfate absorption by one-third via a simultaneous rise in [Formula: see text] and a 30% reduction to the secretory serosal-to-mucosal flux ([Formula: see text]). We propose that DRA, together with PAT1, contributes to [Formula: see text] by mediating
sulfate efflux across the apical membrane. Associated with increased ileal
sulfate absorption in vitro, plasma
sulfate was 61% greater, and urinary
sulfate excretion (USO4) 2.2-fold higher, in DRA-KO mice compared with WT controls, whereas USO4 was increased 1.8-fold in PAT1-KO mice. These alterations to
sulfate homeostasis could not be accounted for by any changes to renal
sulfate handling suggesting that the source of this additional
sulfate was intestinal. In summary, we characterized transepithelial
sulfate fluxes across the mouse distal ileum demonstrating that DRA (and to a lesser extent, PAT1) secretes
sulfate with significant implications for intestinal
sulfate absorption and overall homeostasis.NEW & NOTEWORTHY
Sulfate is an essential
anion that is actively absorbed from the small intestine involving members of the Slc26 gene family. Here, we show that the main intestinal
chloride transporter Slc26a3, known as downregulated in
adenoma (DRA), also handles
sulfate and contributes to its secretion into the lumen. In the absence of functional DRA (as in the disease
congenital chloride diarrhea), net intestinal
sulfate absorption was significantly enhanced resulting in substantial alterations to overall
sulfate homeostasis.