Family 15: Gut-Microbiome-Immune Axis
Family overview. The gut microbiome influences systemic immunity, metabolism, and neuroendocrine function via microbial metabolites (short-chain fatty acids, secondary bile acids, tryptophan metabolites), barrier integrity, and neural signalling through the enteric nervous system and vagus nerve.
Concrete mechanisms and ME/CFS evidence:
Gut dysbiosis. Reduced alpha diversity; depletion of butyrate-producing species (Faecalibacterium prausnitzii, Roseburia); increased pro-inflammatory Enterobacteriaceae; replicated across multiple independent cohorts (Giloteaux et al. 2016).
Butyrate depletion. Loss of butyrate impairs colonocyte energy supply, intestinal barrier integrity (tight junction regulation), and regulatory T cell induction — amplifying systemic immune activation.
Intestinal hyperpermeability (“leaky gut”). Elevated IgA/IgM against LPS in 40–67% of ME/CFS patients versus 0% of controls; elevated serum LPS-binding protein (LBP) and sCD14 (Lacerda et al. 2018).
LPS and PAMP systemic translocation. Bacterial lipopolysaccharide, flagellin, and peptidoglycans translocate through the compromised epithelial barrier, providing continuous TLR stimulation and innate immune activation that feeds Family 4.
Microbiome-tryptophan axis dysregulation. Gut microbiota regulate tryptophan availability via enterochromaffin cell serotonin synthesis and IDO activation; dysbiosis disrupts this, linking to Family 11.
Gut-brain axis signalling disruption. Reduced serotonergic and vagal signalling from gut to brain; impaired enteric nervous system function; gut-origin neuroinflammatory and metabolic signals.
D-lactic acidosis hypothesis. Bacterial overgrowth producing D-lactate has been proposed in ME/CFS as a contributor to cognitive symptoms via CNS D-lactate effects; awaits systematic confirmation.
Full discussion: Gastrointestinal and Microbiome Dysfunction.
Evidence status: Probable (dysbiosis and LPS translocation replicated; gut-brain and butyrate mechanisms biologically coherent; causal direction not yet established).