Sex differences in the gut microbiome–brain axis across the lifespan

Abstract

In recent years, the bidirectional communication between the gut microbiome and the brain has emerged as a factor that influences immunity, metabolism, neurodevelopment and behaviour. Cross-talk between the gut and brain begins early in life immediately following the transition from a sterile in utero environment to one that is exposed to a changing and complex microbial milieu over a lifetime. Once established, communication between the gut and brain integrates information from the autonomic and enteric nervous systems, neuroendocrine and neuroimmune signals, and peripheral immune and metabolic signals. Importantly, the composition and functional potential of the gut microbiome undergoes many transitions that parallel dynamic periods of brain development and maturation for which distinct sex differences have been identified. Here, we discuss the sexually dimorphic development, maturation and maintenance of the gut microbiome–brain axis, and the sex differences therein important in disease risk and resilience throughout the lifespan.

Multifaceted origins of sex differences in the brain

“…Surprisingly, the gut microbiome differs in males and females, and in a direct tie-in to sexual differentiation, the male microbiome appears to stimulate androgen production that protects against autoimmune disorders [92]. Bale and co-workers [91] provide a different angle in the discovery that stress during pregnancy alters the vaginal microbiota, which is a primary source seeding the newborn infant gut microbiome. The impact seems to be sex-specific as evidenced by opposite changes in amino acid profiles in the paraventricular nucleus of neonates [93].…”

“…In this issue, Jašarević et al [91] shine a light on the microbiome as a source of sexually dimorphic disease risk. The coevolution of gut bacteria and the metabolic demands of the brain are postulated to have created a critical alliance that must be tightly orchestrated across the lifespan as both components in this partnership mature.…”

“…The paraventricular nucleus is a key component of the stress axis, and so sex-specific changes in the development of this brain region could have enduring consequences for later life stress management. Bale et al [91] speculate that changes in stress responsivity, both physiologically and behaviourally, may have origins in the microbiota and that sex differences in the latter may impact the former. Again, there is much work to be done.…”

Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder

“…In particular in this study we paralleled GM profiles, behavioral characteristics such as social interaction, stereotyped and repetitive behavior, intestinal integrity and immunological features of colon tissues in adult male and female BTBR mice. Furthermore because sex differences in the majority of mouse models of psychiatric disorders have been frequently overlooked31, and because sex differences have been reported in gut microbiota composition32, we analyzed sex-related profiles of GM and correlated them with specific pathological traits, separately in male and female BTBR. Interestingly, we studied if specific bacterial taxa drive dysbiosis in BTBR females and males, and their relationship with the aleration of behavior, gut integrity and colon immunological state.…”

Propelling the paradigm shift from reductionism to systems nutrition

“…Many investigators have studied the gut microbial community because of the obvious involvement in gastrointestinal disorders such as inflammatory bowel disease [52]. The microbial ecosystem, however, plays a key role in metabolizing and producing nutrients (e.g., [63]), modulating the immune system [96], and producing signaling molecules affecting the gut–brain axis [40]. A primer for researchers for conducting a microbiome study has recently been published [27] and refinements in standards are likely to be developed as this field matures.…”