What Actually Causes IBD? A Mechanistic Reading of Crohn's Disease and Ulcerative Colitis — The specific mechanisms producing colonocyte bioenergetic failure in IBD

Several specific mechanisms produce the colonocyte bioenergetic failure that drives IBD. They overlap. Most IBD patients have features of all of them. The SLC5A8 epigenetic silencing pathway SLC5A8 is the principal apical transporter for butyrate uptake into the colonocyte. It is epigenetically regulated. Its promoter is methylated under conditions of chronic mucosal inflammation, and the methylation silences the transporter. Multiple studies have documented SLC5A8 silencing in colorectal cancer, where the silencing is particularly well-characterized. The same silencing occurs in IBD, where it produces a functional decoupling: butyrate is present in the lumen but cannot enter the cell. This explains a clinical paradox. Butyrate supplementation, which has been studied extensively as a potential IBD treatment, produces inconsistent results across patients. Some respond. Many do not. Stool butyrate levels may correlate poorly with clinical response. The current explanation in the functional medicine literature is variable bioavailability or formulation issues. The more parsimonious explanation, supported by the SLC5A8 research, is that butyrate cannot enter cells whose transporter has been silenced. The substrate is present. The transporter is not. The functional outcome is the same as if the substrate were absent. This same mechanism is described in the recurrent SIBO article and