Although impaired intestinal
sodium transport has been described for decades as a ubiquitous feature of
inflammatory bowel disease (IBD), whether and how it plays a pivotal role in the ailment has remained uncertain. Our identification of dominant mutations in
receptor guanylyl cyclase 2C as a cause of IBD-associated familial
diarrhea syndrome brought a shift in the way we envision impaired
sodium transport. Is this just a passive collateral effect resulting from intestinal
inflammation, or is it a crucial regulator of IBD pathogenesis? This review summarizes the mutational spectrum and underlying mechanisms of monogenic IBD associated with congenital
sodium diarrhea. We constructed a model proposing that impaired
sodium transport is an upstream pathogenic factor in IBD. The review also synthesized emerging insights from microbiome and animal studies to suggest how
sodium malabsorption can serve as a unifying mediator of downstream pathophysiology. Further investigations into the mechanisms underlying
salt and water transport in the intestine will provide newer approaches for understanding the ion-microbiome-immune cross-talk that serves as a driver of IBD. Model systems, such as patient-derived enteroids or induced pluripotent stem cell models, are warranted to unravel the role of individual genes regulating
sodium transport and to develop more effective epithelial rescue and repair
therapies.