Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals

Abstract

Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of steroid hormones in the periphery. However, the influence of the gut microbiota on levels of steroids acting and present in the brain (i.e., neuroactive steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several neuroactive steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the neuroactive steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning.

Comparative biology of germ-free and conventional poultry

“…The entire body of work from 1950 to 2022 (approximately 40 independent studies) on germ-free chickens gives considerable insight into the role of the microbiome in development of the intestine and support organs, the ability of the chick to extract nutrients from the feed, development of immune function, retention of protein and nonprotein nitrogen ( N ), energy metabolism, metabolic rate, and disease resilience. Additionally, complementary germ-free work in pigs and mice exploring differential gene expression, metagenomics and biomarkers ( Chowdhury et al, 2007 ; Tlaskalova-Hogenova et al, 2011 ; Sun et al, 2018 ; Mishima et al, 2020 ; Diviccaro et al, 2021 ; Yang et al, 2021 ) confirms several important observations around the central role of the microbiome in host immunity, growth, the gut-brain axis and N cycling. The present review will summarize key observations from germ-free research in poultry, supported with work in pigs and rodents, to create a foundational framework for ongoing initiatives to leverage microbiome modulatory technologies to achieve desirable end points in poultry nutrition, veterinary health, live production, and environmental sustainability.…”

“…Finally, Diviccaro et al (2021) explored the role of the microbiome on steroid hormones in mice. Higher allopregnanolone and lower 17β-diol levels were observed in plasma of GF vs. CV mice.…”

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex

“…In the context of gut physiology, and consequently of its local steroidogenesis, it is also important to consider the impact on the central nervous system, potentially through the gut-brain axis [ 31 , 35 , 36 ]. The nervous system can also locally synthesize steroids (i.e., neurosteroids) in a sexually dimorphic way [ 38 ], and it adapts its steroid levels in response to changes in gonadal steroid hormones [ 45 ]; however, the sexually dimorphic pattern of neurosteroids does not mirror that of the pattern noted in the gut.…”

“…On the other hand, gut microbes also regulate the availability of sex steroids in the gut environment, such as oestrogens [ 22 , 23 , 24 , 25 , 26 , 27 ] and androgens [ 26 , 28 , 29 ]. Microbiota and their derived metabolites actively participate in host homeostasis via the gut-brain axis, a bi-directional communication highway [ 26 , 30 , 31 , 32 , 33 , 34 ], which includes immune, endocrine, neural, and humoral routes [ 31 , 35 , 36 ].…”

Microbiota modulates the steroid response to acute immune stress in male mice

“…Chronic stress results in pronounced alterations of the gut microbial community ( 21 , 22 ), whereas acute stress results in transcriptional reprogramming of the bacteria with minimal changes in their relative abundance ( 23 ). Additionally, the gut microbiota impacts the metabolism of endogenous steroids ( 24 ) and the concentration of neuroactive steroids in the brain ( 25 ). Because these studies indicate a link between commensal bacteria, activity of the HPA axis and steroid metabolism, investigating whether activation of the HPA axis and corticosteroid metabolism depend on microbial colonization is worthwhile.…”