Bile Acid Signaling as a Mechanistic Link Between Committed Dietary Patterns and Mucosal Immune Tolerance: A Hypothesis with a Staged Experimental Program

Patients with inflammatory bowel disease and the allied cholangiopathy primary sclerosing cholangitis share a characteristic microbiome-metabolite signature: depletion of the secondary bile acid–producing bacteria responsible for generating immunomodulatory trace species — 3-oxolithocholic acid (3-oxoLCA), isoallolithocholic acid (isoalloLCA), isolithocholic acid (isoLCA), and isodeoxycholic acid (isoDCA). These species regulate the intestinal Th17/Treg balance through distinct mechanisms: 3-oxoLCA and isoLCA suppress Th17 differentiation through direct RORγt binding, while isoalloLCA promotes Foxp3+ Treg differentiation through mitochondrial reactive oxygen species signaling and Foxp3 CNS3 enhancer activation. Whether this depletion is a cause, consequence, or amplifier of mucosal inflammation remains incompletely resolved, but the convergence of microbiome, metabolomic, and immune data across independent IBD and PSC cohorts argues for a mechanistically important role. This paper proposes that committed dietary patterns — sustained ketosis (verified β-hydroxybutyrate ≥0.5 mM) and traditional Mediterranean diet — generate stable microbiome configurations capable of producing coherent multi-receptor bile acid signaling environments that coordinately promote mucosal immune tolerance. Intermediate carbohydrate restriction, defined by the absence of verified ketosis in individuals nominally following a low-carbohydrate approach, is proposed to generate signaling incoherence that defaults toward immunostimulation. The mechanistic framework operates through four primary receptor systems: hepatic FXR governing bile acid synthesis and lipogenesis; TGR5 stimulating GLP-1 secretion and suppressing NLRP3 inflammasome assembly in macrophages; S1PR2 mediating hepatic lipid metabolism gene regulation under dietary conditions; and RORγt responding to microbially generated 3-oxoLCA and isoLCA to suppress Th17 differentiation and expand Foxp3+ Treg populations. An oxysterol-LXR axis, operating through cholesterol oxidation products that modulate both Th17 and RORγt+ Treg subsets in an isoform-specific manner, is identified as a parallel sterol-immune regulatory system that intersects with the bile acid framework and provides a bidirectional link between cholesterol metabolism and mucosal immune tone. These receptor systems and sterol-derived signalling networks do not operate in isolation but form a coupled regulatory architecture in which the microbiome, bile acid pool, oxysterol landscape, hepatic lipid metabolism, and mucosal immune effectors are mutually constraining. The coherence of this network, this paper proposes, is the mechanism by which dietary commitment generates co-directional metabolic and immune outcomes.A staged experimental program is proposed — beginning with cross-sectional bile acid metabolomics across three dietary cohorts including patients with quiescent IBD — to test whether dietary pattern–specific bile acid profiles mediate co-directional immune outcomes and whether the intermediate zone represents a qualitatively distinct signaling environment relevant to IBD disease course.