Committed Dietary Patterns and Mucosal Immune Tolerance: A Multimechanism Hypothesis with Bile Acid Signaling as a Testable Intermediate

Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) share a characteristic depletion of bile acid-transforming bacteria, undermining intestinal mucosal immune tolerance. These organisms convert lithocholic acid into immunomodulatory secondary bile acid species: 3-oxolithocholic acid, isoallolithocholic acid, and isolithocholic acid, which suppress Th17 differentiation and expand Foxp3⁺ regulatory T cells through RORγt binding and mitochondrial signaling. This paper proposes that committed dietary patterns at either metabolic pole, verified nutritional ketosis or traditional Mediterranean diet, restore coherent signaling across multiple interdependent receptor and metabolic sensing networks (FXR, TGR5, S1PR2, RORγt, and an intersecting oxysterol-LXR axis) and, through that coherence, support mucosal immune tolerance. Bile acid signaling is the best-characterized candidate mechanism for one arm of this network and the primary testable intermediate the experimental program interrogates. Under committed ketosis, lipoprotein remodeling is most directly attributable to malonyl-CoA depletion and CPT-1 disinhibition; bile acid pool restructuring is a parallel candidate for immune effects. Mediterranean diet co-directional lipid and immune improvements are supported by IBD-specific randomized controlled trials. The equivalent prediction for committed ketosis, that both domains improve simultaneously in the same subjects under BHB-verified conditions, has not been demonstrated; IBD-specific clinical evidence for the ketogenic pole currently rests on a ten-patient case series, making it the primary hypothesis under experimental test rather than an established parallel. Intermediate carbohydrate restriction, defined by the absence of verified ketosis, is hypothesized to produce oscillating rather than coherent receptor engagement, producing neither lipid nor immune improvement reliably. No study has simultaneously characterized dietary metabolic state, the bile acid metabolome, and Th17/Treg balance in the same IBD patients. A staged experimental program is proposed; a cross-sectional design in quiescent IBD patients constitutes the immediate test. The framework is directly falsified if committed and intermediate dietary groups do not differ in species-level immunomodulatory bile acid concentrations despite differing in lipid and immune outcomes; such a result would redirect Stage 3 design toward BHB-direct NLRP3 inhibition and Kbhb-mediated mTOR signaling as the primary mechanistic candidates. The Host-Microbe Counter-Regulation Index (HMCRI) — a candidate index requiring empirical validation, with no currently established reference ranges — is proposed as a systems-level index of signaling coherence whose reference ranges and dietary responsiveness constitute primary Stage 1 analytical objectives.