Table.
Potential Causes and Consequences of Increased Enteric Short-chain Fatty Acid Production and/or Decreased Breakdown and Their Relation to Autism Spectrum Disordera
| Causes | Consequences of SCFAs |
|---|---|
| Long-term antibiotics for routine infection (maternal/infant) treatment of maternal ß hemolytic strep | Gut dysmotility/inflammation/carbohydrate malabsorption/altered gut permeability (tight junction impairment) |
| Hospitalization (colonization of nosocomial bacteria), ie, Cesarean section, neonatal distress | Active uptake of SCFA to CNS (monocarboxylate transporters) |
| Prenatal drugs (valproate, ethanol) | pH-dependent intracellular concentration of SCFA |
| Opportunistic infection (Clostridium spp, Desulfovibrio spp) | Neurotransmitter synthesis and release (catecholamines, enkephalins) CNS/sympathetic nervous system |
| Maternal/infant gut dysbiosis | Receptor activity (+NMDA, -GABA) SCFA G protein coupled receptors/Ca++ influx |
| Organic acidemias (propionic/methylmalonic, biotinidase/holocarboxylase deficiency) | Gap junction closure, altered neurodevelopment, neuroinflammation |
| B12/biotin deficiency | Impaired mitochondrial function/increased oxidative stress |
| Genetic/acquired impaired carnitine synthesis/absorption (TMLHE/OCTN2 genes, ß-lactam antibiotics) | Reduced glutathione/increased sensitivity to xenobiotics (ie, acetaminophen) |
| Mitochondrial disorder/dysfunction (inherited/acquired) | Decreased carnitine/altered lipid metabolism/membrane fluidity |
| Colitis (impaired barrier/SCFA metabolism), ie, celiac disease, Met-receptor tyrosine kinase mutation | Altered gene expression (CREB activation, histone deacetylase inhibition) |
| Increased refined carbohydrate consumption—substrate for bacterial fermentation | Antisocial/perseverative/anxiety-like behavior, seizure/movement disorder, restrictive food interests/carbohydrate craving |
Abbreviations: CNS, central nervous system; CREB, cAMP response element-binding protein; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate; OCTN2, organic cation transporter; SCFA, short-chain fatty acid; TMLHE, trimethyllysine hydroxylase, epsilon.
a
These findings, which are not mutually exclusive, may contribute to the pathophysiology, behavioral symptoms, and comorbidities of autism. Modified with permission from MacFabe (2012), Microbial Ecology in Health and Disease.