Nicotine Alters the Gut Microbiome and Metabolites of Gut–Brain Interactions in a Sex-Specific Manner

Abstract

As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut-brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown. In this study, we applied high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) to explore how nicotine exposure affects the gut microbiome and its metabolism in female and male C57BL/6J mice, with a focus on the chemical signaling involved in gut-brain interactions. 16S sequencing results indicated that the community composition of the gut microbiome was differentially perturbed by nicotine in females and males. Differential alterations of bacterial carbohydrate metabolic pathways are consistent with lower body weight gain in nicotine-treated males. Oxidative stress response and DNA repair genes were also specifically enriched in the nicotine-treated male gut microbiome. The fecal metabolome indicated that multiple neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), and glycine, were differentially altered in female and male mice. Some neuroactive metabolites, including leucine and uric acid, were also changed. This study demonstrates a sex-dependent effect of nicotine on gut microbiome community composition, functional bacterial genes, and the fecal metabolome.

Insular resting state functional connectivity is associated with gut microbiota diversity

“…Several published reports show that the gut microbiota likely plays a role in mood regulation, cognition and visceral pain Collins et al, 2012;Mayer et al, 2014). A major impetus for this research is the increasing evidence that many substance use and psychiatric disorders and animal models of these disorders are associated with substantial alterations in the gut microbiota, and the ready accessibility of microbiota for a broad range of therapeutic interventions using anti-bacterials and probiotics to induce specific microbiota changes (Cryan & Dinan, 2012;Leclercq et al, 2014;Chi et al, 2017).…”

Sexual Dimorphism in the Gut Microbiome

“…When C57BL/6J mice were exposed to nicotine, male mice showed an increase in F16, Turicicibacteraceae, and Peptococcaceae, Christensenellaceae and a decrease in Dehalobacteriaceae (Chi, Mahbub et al, 2017). On the other hand, female C57BL/6J mice exposed to nicotine showed a decrease in F16, Christensenellaceae, and Anaeroplasmataceae (Chi, Mahbub et al, 2017). In addition, male mice decreased in weight whereas females did not (Chi, Mahbub et al, 2017).…”

“…On the other hand, female C57BL/6J mice exposed to nicotine showed a decrease in F16, Christensenellaceae, and Anaeroplasmataceae (Chi, Mahbub et al, 2017). In addition, male mice decreased in weight whereas females did not (Chi, Mahbub et al, 2017). This may be explained by differences in the effect of nicotine on carbohydrate metabolism with the acetate synthesis genes up-regulated for males and the butyrate synthesis genes up-regulated for females (Chi, Mahbub et al, 2017).…”

“…Another substance that alters the gut microbiome in a sex-specific manner is nicotine (Chi, Mahbub, Gao, Bian, Tu, Ru & Lu, 2017). Nicotine can influence human behavior by directly passing through the blood-brain barrier, affecting the reward system in the brain by triggering dopamine release, and regulating many neurotransmitters involved in learning, memory, and cognition (Pogun & Yararbas, 2009;Rezvani & Levin, 2001;Singer et al, 2004;Toth, Sershen, Hashim, Vizi & Lajtha, 1992;Yu & Wecker, 1994).…”

“…Nicotine can influence human behavior by directly passing through the blood-brain barrier, affecting the reward system in the brain by triggering dopamine release, and regulating many neurotransmitters involved in learning, memory, and cognition (Pogun & Yararbas, 2009;Rezvani & Levin, 2001;Singer et al, 2004;Toth, Sershen, Hashim, Vizi & Lajtha, 1992;Yu & Wecker, 1994). When C57BL/6J mice were exposed to nicotine, male mice showed an increase in F16, Turicicibacteraceae, and Peptococcaceae, Christensenellaceae and a decrease in Dehalobacteriaceae (Chi, Mahbub et al, 2017). On the other hand, female C57BL/6J mice exposed to nicotine showed a decrease in F16, Christensenellaceae, and Anaeroplasmataceae (Chi, Mahbub et al, 2017).…”