Developmental Signatures of Microbiota-Derived Metabolites in the Mouse Brain

Abstract

The gut microbiome is recognized to exert a wide-ranging influence on host health and disease, including brain development and behavior. Commensal bacteria can produce bioactive molecules that enter the circulation and impact host physiology and homeostasis. However, little is known about the potential for these metabolites to cross the blood–brain barrier and enter the developing brain under normal physiological conditions. In this study, we used a liquid chromatography–mass spectrometry-based metabolomic approach to characterize the developmental profiles of microbial-derived metabolites in the forebrains of mice across three key postnatal developmental stages, co-occurring with the maturation of the gut microbiota. We demonstrate that direct metabolites of the gut microbiome (e.g., imidazole propionate) or products of the combinatorial metabolism between the microbiome and host (e.g., 3-indoxyl-sulfate, trimethylamine-N-oxide, and phenylacetylglycine) are present in the forebrains of mice as early as the neonatal period and remain into adulthood. These findings demonstrate that microbial-associated molecules can cross the BBB either in their detected form or as precursor molecules that undergo further processing in the brain. These chemical messengers are able to bind receptors known to be expressed in the brain. Alterations in the gut microbiome may therefore influence neurodevelopmental trajectories via the regulation of these microbial-associated metabolites.

Metabolomic signature of the maternal microbiota in the fetus

“…Phenylacetylglycine has been identified as a gut microbial metabolite of phenylalanine with associations to health and disease in humans (Nemet et al, 2020). It has also been detected in forebrain of mice from neonatal period into adulthood (Swann et al, 2020). Certain amino acids and small peptides, such as L-threonine and two tripeptides with unknown structure, had higher levels in the GF organs compared to SPF, suggesting that they were accumulated in the organs due to lack of microbial metabolism.…”

“…Decreased levels of hippuric acid have been reported in serum of GF mice and in urine of antibiotic-treated rats (Wikoff et al, 2009; Lee et al, 2012) and recently also in the brain of fetuses of GF or antibiotic-treated mice (Vuong et al, 2020). Hippuric acid is one of the metabolites reported to be present in neonatal mouse brain with amounts decreasing by age (Swann et al, 2020). Apart from participating in removal of benzoate, a metabolite potentially toxic to mitochondria (Badenhorst et al, 2014), hippuric acid has been suggested a role in regulation of blood glucose levels, insulin secretion by β-cells and glucose utilization in skeletal muscle (de Mello et al, 2017; Bitner et al, 2018).…”

“…Phenylacetylglycine has been identified as a gut microbial metabolite of phenylalanine with associations to health and disease in humans (Nemet et al, 2020). It has also been detected in forebrain of mice from neonatal period into adulthood (Swann et al, 2020).…”

The Role of the Gut Microbiota in the Gut–Brain Axis in Obesity: Mechanisms and Future Implications

“…Finally, imidazole propionate (ImP, derived from gut-microbiota-processed dietary histidine) results in insulin resistance and subsequent type 2 diabetes [ 132 , 133 ]. Moreover, recent data showed that ImP is present in the forebrains of mice, thus underscoring that it can pass the BBB and therefore affect neurodevelopmental trajectories, including the gut–brain axis [ 134 , 135 ]. Moreover, histidine, the precursor to ImP, has been suggested to affect GLP-1 secretion [ 136 ].…”

The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research

“…Animal models were crucial in highlighting and understanding the manifold impact of microbes on the nervous system in development, maturation, aging and homeostasis such as changes in expression of neurotrophic factors, NMDA receptor subunits in the hippocampus (Sudo et al, 2004;Bercik et al, 2011;Diaz Heijtz et al, 2011), impaired blood-brain barrier function, increased myelination in the prefrontal cortex (Braniste et al, 2014;Hoban et al, 2016) as well as learning and memory (Gareau et al, 2011;Neufeld et al, 2011;Clarke et al, 2013;Swann et al, 2020). Further, there is also some evidence for a role of microbiota in psychiatric disorders like depression and anxiety (Foster and McVey Neufeld, 2013), autism spectrum disorder (ASD) (Krajmalnik- Brown et al, 2015;Marrone and Coccurello, 2019), schizophrenia (Severance et al, 2016;Marrone and Coccurello, 2019) as well as neurological diseases such as Alzheimer's disease (AD) (Kowalski and Mulak, 2019), Parkinson's disease (PD) (Keshavarzian et al, 2015) and stroke (Durgan et al, 2019;Battaglini et al, 2020).…”