Effects of ceftriaxone on the gut microbiome in rats following alcohol drinking

Ceftriaxone is a beta-lactam antibiotic that increases central nervous system (CNS) protein expression of the glutamate transporters GLT-1 and xCT, and correspondingly ameliorates pathological behaviors in multiple rodent models of neurological disease and substance use disorders. However, little ceftriaxone passes through the blood-brain-barrier, the CNS binding partner of ceftriaxone is unknown, and applying ceftriaxone to cell culture does not consistently upregulate GLT-1 and xCT. Ceftriaxone alters the gut microbiome composition in rodents and humans, and the gut microbiome-brain axis regulates drug-seeking. Thus, here we test the hypothesis that ceftriaxone reduces alcohol intake in male and female rats while ameliorating alcohol-induced disruption of gut microbiome composition. Male and female Sprague-Dawley rats received intermittent access to alcohol (IAA) in 24 hr 2-bottle choice sessions (20% alcohol v/v and water) alternating with alcohol-free 24-hr periods. Controls received access to water. Following 17 IAA sessions, ceftriaxone/vehicle treatment was given for 5 consecutive days spanning 2 IAA sessions; intake continued to be measured in 2 sessions following cessation of ceftriaxone/vehicle. Fecal samples were collected prior to IAA, prior to and immediately following ceftriaxone/vehicle treatment, and used for the analysis of the gut microbiome composition by 16S rRNA gene amplicon sequencing. This study therefore allows for the longitudinal characterization of the effects of ceftriaxone on the rat gut microbiome and its interaction with the effects of alcohol drinking.