Sex-Dependent Effects of Inhaled Nicotine on the Gut Microbiome

Abstract

Introduction The impact of nicotine, the addictive component of both traditional cigarettes and e-cigarettes, on many physiological processes remains poorly understood. To date, there have been few investigations into the impact of nicotine on the gut microbiome, and these studies utilized oral administration rather than inhalation. This study aimed to establish if inhaled nicotine alters the gut microbiome and the effect of sex as a biological variable. Methods Female (n=8 air; n=10 nicotine) and male (n=10 air; n=10 nicotine) C57BL6/J mice were exposed to air (control) or nicotine vapor (12 hour/day) for 13 weeks. A fecal sample was collected from each mouse at the time of sacrifice, and the gut microbiome was analyzed by 16S rRNA gene sequencing. QIIME2, PICRUSt, and STAMP were used to detect gut bacterial differences and functional metabolic pathways. Results Sex-specific differences were observed in both alpha and beta diversities in the absence of nicotine. While nicotine alters microbial community structure in both male and female mice as revealed by the beta diversity metric, nicotine significantly reduced alpha diversity only in female mice. A total of 42 bacterial taxa from phylum to species were found to be significantly different among the treatment groups. Finally, analysis for functional genes revealed significant differences in twelve metabolic pathways in female mice and ten in male mice exposed to nicotine compared to air controls. Conclusions Nicotine inhalation alters the gut microbiome and reduces bacterial diversity in a sex-specific manner, which may contribute to the overall adverse health impact of nicotine. Implications The gut microbiota plays a fundamental role in the well-being of the host, and traditional cigarette smoking has been shown to affect the gut microbiome. The effects of nicotine alone, however, remain largely uncharacterized. Our study demonstrates that nicotine inhalation alters the gut microbiome in a sex-specific manner, which may contribute to the adverse health consequences of inhaled nicotine. This study points to the importance of more detailed investigations into the influence of inhaled nicotine on the gut microbiota.

Potential Roles of Cigarette Smoking on Gut Microbiota Profile among Chinese Men

“…A mouse study revealed a potentially time-dependent effect of smoking exposure on the increase in Turicibacter[g] abundance [57]. Nevertheless, two other mice studies have reported con icting ndings on this matter [58,59]. In any case, our study contributes new evidence to this ongoing debate from a population perspective.…”

Butyrate protects and synergizes with nicotine against iron- and manganese-induced toxicities in cell culture: Implications for neurodegenerative diseases

“…Finally, interaction of Fe, Mn, butyrate, and nicotine with gut microbiota have been recently highlighted ( Tinkov et al 2021 ; Whitehead et al 2022 ; Nicese et al 2023 ; Xiao et al 2023 ). Hence, potential exploits of the gut-brain axis in amelioration of heavy metal toxicities and/or prevention or delay of neurodegenerative diseases is worth consideration.…”

Sex Differences in E-Cigarette Use and Related Health Effects

“…Not surprisingly, sexdependent effects were found, whereby female adolescent rats displayed lower anxiolytic effects and were more sensitive to the rewarding effect of nicotine than their male counterparts [93,139,140], although others did not find sex differences [107]. Interestingly, the gut microbiome was found to mediate sex-dependent effects related to nicotine metabolism in chronic e-cigarette exposure, and nicotine exposure was found to decrease alpha diversity in females and beta diversity in both sexes [92]. A history of vaping was also associated with stroke, with higher odds for females [109].…”