Sulfate ions in mammalian physiology: lessons from sulfate transporter null mice

Abstract

The NaS1 sulfate transporter maintains serum sulfate levels. Several polymorphisms (SNPs) exist in human NaS1, including R12X and N174S. NaS1 null (Nas1–/–) mice exhibit hyposulfatemia and a decreased sulfate content of intestinal mucins. This is relevant to gastrointestinal (GI) physiology because sulfate plays a role in protecting mucins from degradation. Our aims were to functionally characterise human NaS1 SNPs and to determine the effects of hyposulfatemia in Nas1–/– mice on GI physiology. Compared to wild-type NaS1, R12X and N174S led to 100% & 60% loss of function, respectively. Nas1–/– and Nas1+/+ mice were challenged orally with C. jejuni bacteria or dextran sodium sulfate (DSS), a model for inducing colitis. C. jejuni colonised stomach and intestines of Nas1–/– (n=16) and Nas1+/+ (n=16) mice. One Nas1+/+ and 9 Nas1–/– mice developed systemic infection. DSS treatment (2.5% 7 days) led to shorter intestines (by 15% P<0.01) and decreased hematocrit (by 25% P<0.05) in Nas1–/– mice, suggesting hyposulfatemia enhances DSS-induced colitis and intestinal bleeding. In summary, we characterized 2 loss of function SNPs in human NaS1 and showed that Nas1–/– mice have reduced defence from mucosal bacterial infection, and are more susceptible to DSS-induced colitis. These findings underline the importance of sulfated mucins in intestinal barrier function, and prompt studies of GI mucins in humans with NaS1 SNPs.