Antibiotic Exposure Has Sex-Dependent Effects on the Gut Microbiota and Metabolism of Short-Chain Fatty Acids and Amino Acids in Mice

Abstract

The gut microbiota has the capability to regulate homeostasis of the host metabolism. Since antibiotic exposure can adversely affect the microbiome, we hypothesized that antibiotic effects on the gut microbiota and host metabolism are sex dependent. In this study, we examined the effects of antibiotic treatments, including vancomycin (Vanc) and ciprofloxacin-metronidazole (CiMe), on the gut microbiome and metabolome in colonic contents and tissues in both male and female mice. We found that the relative abundances and structural composition of Firmicutes were significantly reduced in female mice after both Vanc and CiMe treatments but in male mice only after treatment with Vanc. However, Vanc exposure considerably altered the relative abundances and structural composition of representatives of the Proteobacteria especially in male mice. The levels of short-chain fatty acids (SCFAs; acetate, butyrate, and propionate) in colonic contents and tissues were significantly decreased in female mice after both antibiotic treatments, while these reductions were detected in male mice only after Vanc treatment. However, another SCFA, formate, exhibited the opposite tendency in colonic tissues. Both antibiotic exposures significantly decreased the levels of alanine, branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and aromatic amino acids (AAAs; phenylalanine and tyrosine) in colonic contents of female mice but not in male mice. Additionally, female mice had much greater correlations between microbe and metabolite than male mice. These findings suggest that sex-dependent effects should be considered for antibiotic-induced modifications of the gut microbiota and host metabolism. IMPORTANCE Accumulating evidence shows that the gut microbiota regulates host metabolism by producing a series of metabolites, such as amino acids, bile acids, fatty acids, and others. These metabolites have a positive or negative effect on host health. Antibiotic exposure can disrupt the gut microbiota and thereby affect host metabolism and physiology. However, there are a limited number of studies addressing whether antibiotic effects on the gut microbiota and host metabolism are sex dependent. In this study, we uncovered a sex-dependent difference in antibiotic effects on the gut microbiota and metabolome in colonic contents and tissues in mice. These findings reveal that sex-dependent effects need to be considered for antibiotic use in scientific research or clinical practice. Moreover, this study will also give an important direction for future use of antibiotics to modify the gut microbiome and host metabolism in a sex-specific manner.

Consumption of a Western-Style Diet Modulates the Response of the Murine Gut Microbiome to Ciprofloxacin

“…First, our study was performed only in female mice. It is now understood that sex-dependent differences exist in diet metabolism, mucosal immunity, and gut microbiome antibiotic responses, and as such our findings may not be generalizable to males (96,99,100). Another critical drawback is that the analytical pipelines used to analyze microbiome data are reliant on existing databases that are largely incomplete: approximately half of all genes within the human gut microbiome are hypothesized to have no functional annotation, limiting the ability to accurately profile the transcriptional activity of these communities (101).…”

Dysbiosis of the gut and lung microbiome has a role in asthma

“…Most logically, antibiotics affect significantly and with immediate and sustained effect the gut microbiota composition, supporting subsequent development of various diseases. In a mouse model, this effect was explained by a change not only of phylotypes and diversity, but also of bacterial metabolites with positive or negative effect on health, even in a gender-dependent manner [93]. Interestingly, antibiotics-like social stress-affect the microbiota composition and lead to microbial translocation into the mesenteric lymph nodes [94].…”

Sex-Dependent Effects of Intestinal Microbiome Manipulation in a Mouse Model of Alzheimer’s Disease

“…These differential effects of treatments in male and female animals could be due to the high abundance of distinct intestinal bacterial genera, such as Prevotella , Parabacteroides , Clostridium , and Alistipes , and low abundance of Lactobacillus in males versus females. Another study also showed sex-specific effects of vancomycin and ciprofloxacin-metronidazole in male versus female mice [ 41 ]. Our data indicate that although both sexes demonstrated Aβ plaque deposition, female App NL-G-F mice had a more robust memory deficit at this age compared to males.…”