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) sharea characteristic depletion of bile acid-transforming bacteria, undermining intestinal mucosalimmune tolerance. These organisms convert lithocholic acid into immunomodulatory secondarybile acid species through distinct enzymatic pathways: 3-oxolithocholic acid and isolithocholicacid suppress Th17 differentiation through RORγt binding, while isoallolithocholic acidpromotes Foxp3⁺ regulatory T cell differentiation through mitochondrial reactive oxygen speciessignaling.This paper proposes that committed dietary patterns at either metabolic pole, verified nutritionalketosis or traditional Mediterranean diet, are hypothesized to restore coherent signaling acrossmultiple interdependent receptor and metabolic sensing networks (FXR, TGR5, S1PR2, RORγt,and an intersecting oxysterol-LXR axis) and thereby support mucosal immune tolerance. Bileacid signaling is the best-characterized candidate mechanism for one arm of this network and theprimary testable intermediate the experimental program interrogates. Under committed ketosis,lipoprotein remodeling is most directly attributable to malonyl-CoA depletion and CPT-1disinhibition; bile acid pool restructuring is a parallel candidate for immune effects.Mediterranean diet co-directional lipid and immune improvements are supported by IBD-specificrandomized controlled trials. The equivalent prediction for committed ketosis, that both domainsimprove simultaneously in the same subjects under BHB-verified conditions, has not beendemonstrated; 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 anestablished parallel. Intermediate carbohydrate restriction, defined by the absence of verifiedketosis, 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, andTh17/Treg balance in the same IBD patients. A staged experimental program is proposed; across-sectional design in quiescent IBD patients constitutes the immediate test. The framework isdirectly falsified if committed and intermediate dietary groups do not differ in species-levelimmunomodulatory 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 nocurrently established reference ranges — is proposed as a systems-level index of signalingcoherence whose reference ranges and dietary responsiveness constitute primary Stage 1analytical objectives.