Alcohol and gut-brain axis and the role of butyrate on neuroinflammation and pain sensitivity

ABSTRACT Chronic pain lasts for months or years which negatively impacts quality of life. Alcohol, an effective analgesic, is commonly used to self-medicate for pain, and strongest analgesia occurs for alcohol levels exceeding World Health Organization guidelines for low-risk drinking, which could explain alcohol misuse in those with persistent pain. The gut microbiota regulates many neurological disorders, including chronic pain. Both alcohol use disorder (AUD) and many pain disorders are associated with a disruption in microbiome composition and function (gut dysbiosis), neuroinflammation, neuronal damage, and behavioral alterations. Gut microbial- derived short-chain fatty acids (SCFA: e.g., butyrate) are important in regulating the gut barrier, modulating immune and inflammatory responses, and gene expression due to their histone deacetylase (HDAC) inhibitor activity and/or interactions with G-protein coupled receptors (GPCR). Epigenetic modulation of gene expression has emerged as a key regulator of the alcohol withdrawal state, and HDAC inhibitors are proposed as therapeutic targets for the treatment of emotional dysregulations associated with alcohol withdrawal and chronic pain. Butyrate crosses the blood brain barrier and is detected in the cerebrospinal fluid. Butyrate delivery improved cognitive impairments and neuronal plasticity induced by drugs of abuse via modifying HDAC activity. Butyrate is also anti-inflammatory as a ligand for GPR43, which is expressed on many cell types including intestinal epithelial cells and peripheral blood mononuclear cells. In unpublished studies, we have found chronic ethanol exposure and withdrawal in mice caused gut dysbiosis, depleted butyrate- producing bacteria and luminal butyrate, and induced plasma endotoxin. Concurrently, there was evidence of microglial activation, increased levels of proinflammatory cytokines, and heightened HDAC activity and reduced GPR43 expression in the brain, leading to increased pain sensitivity during ethanol withdrawal. Our prior studies show butyrate supplementation normalized intestinal epithelial barrier, systemic endotoxin levels and liver injury in mice exposed to ethanol. Our central hypothesis is that two butyrate targets, HDAC and GPR43 activity, are altered in the brain during chronic ethanol exposure due to depleted gut luminal butyrate and this contributes to neuroinflammation and alters pain sensitivity. We will test 3 specific aims: 1) Determine whether butyrate-targeted oral supplementation inhibits HDAC activity, neuroinflammation, and pain sensitivity in mice exposed to chronic ethanol exposure and withdrawal; 2) Determine the role of butyrate and GPR43 on astrocyte reactivity, neuroinflammation and pain sensitivity during chronic ethanol exposure and withdrawal; and 3) Define the link between gut microbiome, butyrate levels, peripheral immune and inflammatory profile, and pain sensitivity in chronic pain patients consuming alcohol. Completion of these studies will increase our knowledge to uncover therapeutic targets for future drug discovery and development for alcohol use and chronic pain syndromes.