Host Responses to the Pathogen Mycobacterium avium subsp. paratuberculosis and Beneficial Microbes Exhibit Host Sex Specificity

Abstract

c Differences between microbial pathogenesis in male and female hosts are well characterized in disease conditions connected to sexual transmission. However, limited biological insight is available on variances attributed to sex specificity in host-microbe interactions, and it is most often a minimized variable outside these transmission events. In this work, we studied two gut microbes-a pathogen, Mycobacterium avium subsp. paratuberculosis, and a probiotic, Lactobacillus animalis NP-51-and the interaction between each agent and the male and female gastrointestinal systems. This trial was conducted in BALB/c mice (n ‫؍‬ 5 per experimental group and per sex at a given time point), with analysis at four time points over 180 days. Host responses to M. avium subsp. paratuberculosis and L. animalis were sensitive to sex. Cytokines that were significantly different (P < 0.05) between the sexes included interleukin-1␣/␤ (IL-1␣/␤), IL-17, IL-6, IL-10, IL-12, and gamma interferon (IFN-␥) and were dependent on experimental conditions. However, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and IL-13/23 showed no sex specificity. A metabolomics study indicated a 0.5-to 2.0-fold (log 2 scale) increase in short-chain fatty acids (butyrate and acetate) in males and greater increases in o-phosphocholine or histidine from female colon tissues; variances distinct to each sex were observed with age or long-term probiotic consumption. Two genera, Staphylococcus and Roseburia, were consistently overrepresented in females compared to males; other species were specific to one sex but fluctuated depending on experimental conditions. The differences observed suggest that male and female gut tissues and microbiota respond to newly introduced microorganisms differently and that gut-associated microorganisms with host immune system responses and metabolic activity are supported by biology distinct to the host sex.

Caesarean birth and adiposity parameters in 6‐ to 8‐year‐old urban Maya children from two cities of Yucatan, Mexico

“…Studies in humans and mice suggest that differences in endocrine and immune systems between sexes induce different gut microbiota profiles in males and females (Fransen et al, 2017). Studies have demonstrated sexual dimorphism in several aspects of gut microbiota, including their composition (Dominianni et al, 2015;Mueller et al, 2006;Li et al, 2008), their changes in response to factors such as diet (Bolnick et al, 2014;Karunasena, McMahon, Chang, & Brashears, 2014) and their diversity, structure and individual phylotype during the colonization in germ-free mice (Wang et al, 2016). Females have consistently shown lower abundance of Bacteroidetes in their microbiota, a group of bacteria with beneficial effects in metabolism (Dominianni et al, 2015;Mueller et al, 2006).…”

The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility

“…paratuberculosis (MAP) challenge in mice either fed the probiotic Lactobacillus animalis or control fed, circulating cytokines (e.g. IL-1α/β, IL-6, IFN-γ) differed between the sexes [91]. This suggests that Th1, Th2, Th17 and Tregs may all be regulated by sex-linked factors in the mouse GIT.…”

“…Furthermore, females show an increase in Firmicutes, including Staphylococcus and Roseburia, in all groups except controls [91] indicating that male and female microbiota respond differently to certain dietary organisms, and that the female microbiota may be more susceptible to dietary manipulation than males. In an extension of these studies, the same authors examined cytokine transcription levels and found that males have greater expression of Th2 and B cell factors, while females have decreased pro-inflammatory cytokine expression after MAP infection [91]. Further, male mice show increased Tgf-β, Il-10 and Foxp3 expression (indicative of Treg induction) and Il-17 and Il-23A (typical of Th17 responses).…”

Sex differences in colonization of gut microbiota from a man with short-term vegetarian and inulin-supplemented diet in germ-free mice

“…Probiotics also exerted dissimilar responses on female and male mice. After probiotic consumption, two genera Staphylococcus and Roseburia in Firmicutes were overrepresented in females, while butyrate and acetate were increased in males15. Deletion of Bmal1, a gene encoding a core molecular clock component, induced changes in the microbial composition based on sexes.…”

“…Intriguingly, the compositional and metabolic changes of gut microbiota response to diet, exogenous bacteria or genetic deletion also demonstrated sexual dimorphism13141516. Whether in wild and laboratory fish, laboratory mice or in human beings, the diet made different effects on gut microbiota composition between sexes13.…”