Neonatal exposure to androgens dynamically alters gut microbiota architecture

Abstract

Gonadal steroids strongly contribute to the metabolic programming that shapes the susceptibility to manifestation of diseases later in life, and the affect is often sexually dimorphic. Microbiome signatures, together with metabolic traits and sex steroid levels, were analyzed at adulthood in neonatally androgenized female rats, and compared with those of control male and female rats. Exposure of female rats to high doses of androgens on early postnatal life resulted in persistent alterations of the sex steroid profile later on life, namely lower progesterone and higher estradiol and estrone levels, with no effect on endogenous androgens. Neonatally androgenized females were heavier (10% at early adulthood and 26% at adulthood) than controls and had impaired glucose homeostasis observed by higher AUC of glucose in GTT and ITT when subjected to obesogenic manipulations. Androgenized female displayed overt alterations in gut microbiota, indicated especially by higher Bacteriodetes and lower Firmicutes abundance at early adulthood, which disappeared when animals were concurrently overfed or at adulthood. Notably, these changes in gut microbiota were related with the intestinal expression of several miRNAs, such as miR-27a-3p, miR-29a-5p, and miR-100-3p. Our results suggest that nutritional and hormonal disruption at early developmental periods not only alters the metabolic programming of the individual later in life but also perturbs the architecture of gut microbiota, which may interact with the host by a cross-talk mediated by intestinal miRNAs; phenomena that may contribute to amplify the metabolic derangement caused by obesity, as seen in neonatally androgenized female rats.

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex

“…In contrast, increases in Lactobacillus , Lacnospiraceae NK4A136 , Eisenbergiella , Roseburia , Bacteroides , the Eubacterium xylanophilum group, and Parasutterella were reported for male and female GDX rats, Blautia and Alloprevotella for male GDX rats, and uncharacterized UCG-008 in female GDX rats. Altogether, this set of analyses confirmed and extended the previous literature data indicating sex differences in gut microbiota [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and the role of sex steroid hormones [ 9 , 12 , 14 , 15 , 16 ]. As described above, the gut exhibits sexual dimorphism in both its steroidogenic capability and microbial composition.…”

“…Among several factors which can influence the composition of the gut microbiota, sex is a major contributor [ 7 ]. Both human and animal studies, mainly performed in mice, have reported sex-related differences in the gut microbiota [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], and a role has been proposed for sex steroid hormones in contributing to this sexual dimorphism [ 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Additionally, inhibition of key enzymes in steroidogenesis, such as 5-alpha-reductase (5α-R), alters gut microbiota populations in rodents and humans [ 20 , 21 ].…”

A Novel Identified Peptide Hormone “Metabolitin” Attenuates Lipid Absorption in the Small Intestine of Diabetic Mice with Nonalcoholic Fatty Liver Disease by Regulating Neurotensin and AMPK Signaling Pathway

“…GLP-1 has been well established in reducing body weight and lowering blood sugar through inhibiting gastrointestinal peristalsis and gastric juice secretion and enhancing insulin secretion [ 24 ]. A variety of studies have confirmed that impaired glucose homeostasis was reflected by higher AUC of GTT and ITT [ 25 , 26 ]. Furthermore, the concentration of TG and TC in the feces of all mice was detected to confirm the regulation of metabolitin on lipid metabolism.…”

Salivary microbiome differences in prepubertal children with and without adrenal androgen excess

“… 10 - 15 There is a bidirectional relationship between steroid hormones and gut microbial communities, 16 , 17 with studies showing that prenatal and neonatal exposure to androgens can lead to gut dysbiosis in rats. 18 - 20 Several studies have shown that women with PCOS show taxonomical differences in their gut microbiomes and further signs of dysbiosis, including a reduced α-diversity that negatively correlates with serum testosterone levels in both healthy and obese PCOS subjects. 21 - 24 Imbalances in the gut microbiome can lead to the compromise of intestinal epithelial cell connections and a “leaky” gut, increasing the permeability of the gut lining to inflammatory mediators such as lipopolysaccharides.…”