Influences of the gastrointestinal tract on mood and mental health have been recognized for centuries, and accumulating results over the past decade have supported a key role for gut bacteria (collectively known as the gut microbiome) in many aspects of brain health and disease [1]. While the mechanistic underpinnings of microbiome-brain interactions are complex, emerging evidence suggests that gut microbiota produce multiple brain-penetrant metabolites with gene regulatory potential, such as co-factors for epigenetic modifications [2,3,4]. This observation has the potential to link differences in gut microbiota to dysregulated gene expression and chromatin patterns that are observed in multiple neuropsychiatric disorders, including major depression, stress-related conditions, and substance abuse [5]. Although bacterial metabolites have recently been implicated in the orchestration of gut-brain interactions [2], evidence supporting a direct role for specific factors in complex motivated behaviors and drug-induced transcriptional reprogramming remains limited.

In this issue of Neuropsychopharmacology, Hofford et al. [6] explored the contribution of gut microbiome diversity and composition in morphine conditioned place preference (CPP) and locomotor sensitization using an oral antibiotic knockdown model (Abx; an antibiotic cocktail delivered via drinking water). The authors first show that oral antibiotic administration reduced bacterial complexity and altered the relative proportion of bacterial phyla, including decreases in Firmicutes bacteria. This common gut microbiome phylum is found in healthy individuals and is known to generate short-chain fatty acids (SCFAs) (such as butyrate), which act both as histone deacetylase inhibitors and are further metabolized into co-factors for acetylation of histone proteins. Notably, loss of bacterial diversity was associated with decreased levels of at least two SCFAs produced by gut bacteria—butyrate and propionate. Next, the manuscript reports that microbiome depletion blunts morphine locomotor sensitization and abolishes morphine CPP, commonly used measures of behavioral effects of drugs. Even more strikingly, morphine CPP was completely restored when drinking water was supplemented with SCFAs, demonstrating reversible control of morphine reward as well as necessity for SCFAs in this process.

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