Role of PPAR-Allopregnanolone Signaling in Behavioral and Inflammatory Gut-Brain Axis Communications

The gut microbiome regulates emotional behavior, stress responses, and inflammatory processes by communicating with the brain. How and which neurobiological mediators underlie this communication remain poorly understood. PPAR-α (peroxisome proliferator-activated receptor α), a transcription factor susceptible to epigenetic modifications, regulates pathophysiological functions, including metabolic syndrome, inflammation, and behavior. Mood disorders, inflammatory processes, and obesity are intertwined phenomena that are associated with low blood concentrations of the anti-inflammatory and "endogenous tranquilizer" neurosteroid allopregnanolone and poor PPAR-α function. Stress and consumption of obesogenic diets repress PPAR function in brain, enterocytes, lipocytes, and immune modulatory cells favoring inflammation, lipogenesis, and mood instability. Conversely, micronutrients and modulators of PPAR-α function improve microbiome composition, dampen systemic inflammation and lipogenesis, and improve anxiety and depression. In rodent stress models of anxiety and depression, PPAR activation normalizes both PPAR-α expression downregulation and decreased allopregnanolone content and ameliorates depressive-like behavior and fear responses. PPAR-α is known to regulate metabolic and inflammatory processes activated by short-chain fatty acids; endocannabinoids and congeners, such as N-palmitoylethanolamide, drugs that treat dyslipidemias; and micronutrients, including polyunsaturated fatty acids. Both PPAR-α and allopregnanolone are abundantly expressed in the colon, and they exert potent anti-inflammatory actions by blocking the toll-like receptor-4-nuclear factor-κB pathway in peripheral immune cells, neurons, and glia. The perspective that PPAR-α regulation in the colon by gut microbiota or metabolites influences central allopregnanolone content after trafficking to the brain, thereby serving as a mediator of gut-brain axis communications, is examined in this review.