Maternal microbiota-derived metabolic profile in fetal murine intestine, brain and placenta

Abstract

Background The maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. To reveal the spectrum of these molecular mediators of the earliest host-microbe interactions, we compared placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. Results One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. More than half of these were more abundant in the SPF organs, suggesting their microbial origin or a metabolic response of the host to the presence of microbes. The clearest separation was observed in the placenta, but most of the molecular features showed significantly different levels also in the fetal intestine and/or brain. Metabolites that were detected in lower amounts in the GF fetal organs included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also less abundant in the absence of microbiota. Ninety-nine molecular features were detected only in the SPF mice. We also observed several molecular features which were more abundant in the GF mice, possibly representing precursors of microbial metabolites or indicators of a metabolic response to the absence of microbiota. Conclusions The maternal microbiota has a profound impact on the fetal metabolome. Our observations suggest the existence of a multitude of yet unidentified microbially modified metabolites which pass through the placenta into the fetus and potentially influence fetal development.

Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders

“…A balanced gut-microbiota is involved directly or indirectly in maintaining the microenvironment to support the process of neuronal development ( Sarubbo et al, 2022 ). A recent comparative study between GF and SPF mice outlines a range of gut microbial metabolites that can cross through the placenta into the foetal compartment, with the ability to induce and regulate the prenatal developmental process ( Pessa-Morikawa et al, 2022 ). In addition, PG, a bacterial cell wall component, gets crossed through the placenta to reach the foetal brain, there it activates Toll-like receptor 2 (TLR2), triggering an increase in FOXG1 expression, a crucial transcription factor in regulating the development and neurogenesis, thereby inducing neuronal proliferation in the forebrain area ( Kaul et al, 2012 ; Humann et al, 2016 ).…”

The human microbial exposome: expanding the Exposome-Explorer database with gut microbial metabolites

“…3. Concentrations of microbial metabolites are lower in germ-free animals when compared with conventional animals [9]. Concentrations are increased by transplantation of faecal samples or gut bacterial strains to germ-free animals [17,18].…”

“…Some metabolites like colibactin, a genotoxin known for its oncogenic role in colon cancer pathogenesis, or equol, a metabolite of soy daidzein with estrogenic properties, are known as metabolites exclusively formed by bacteria [16,22]. However, in a recent comparison of germ-free and conventionalized mice through metabolomics, only 5 of the 61 metabolites showing a reduction of concentrations in three different tissues in germ-free animals were absent in conventionalized mice [9].…”

“…Many of them were used as substrates in experiments described in Exposome-Explorer (e.g. vitexin, rutin, quercetin, daidzein, (+)-catechin, rosmarinic acid, thymol, resveratrol, deoxycholic acid), and more microbial metabolites will be found as more substrates are tested [9].…”

“…Gut microbial metabolites exert local effects on the gut mucosa or, after absorption through the intestinal barrier, distal effects on inner tissues. Many of them are found in the systemic circulation and in inner tissues [9]. Importantly, gut microbial metabolites can also be seen as a read out of microbiota functionalities and dysbiosis [2].…”