Gut Microbes May Shape Brain, Behavior Through Hidden Mutations

Summary: In a groundbreaking study with Merino sheep, researchers discovered that small genetic variations within gut microbes can influence brain-related behavior. By sequencing more than 5,000 microbial genomes, including 3,500 never before reported, they linked single nucleotide variations (SNVs) in microbes with neurobehavioral traits and plasma metabolites linked to brain function.

These SNVs, primarily within Firmicutes and Bacteroidetes, were found to alter metabolites that affect neuroactive regulation and oxidative stress. The findings suggest that microbial genetics can subtly fine-tune host metabolism and cognition, offering new insights into the microbiome-metabolism-brain connection.

Key facts:

Microbial genome discovery: Researchers reconstructed 5,253 gut microbial genomes, including 3,548 new species-level genomes. Microbe-brain link: Variations in microbial DNA (SNV) were associated with changes in metabolites and exploratory behavior. Behavioral Perspective: A mutation of a microbial gene was correlated with the synthesis of brain-derived neurotrophic factor (BDNF). affecting curiosity and exploration.

Source: Chinese Scientific Press

The researchers used Merino sheep as an animal model, systematically collecting samples of their ruminal and hindgut microbiota, plasma metabolites, and neurocognitive behavioral phenotype data.

Based on metagenomic sequencing data from fecal and ruminal samples, the authors reconstructed 5,253 metagenomically assembled genomes (MAGs) at the species level, including 3,548 previously unreported novel genomes, significantly expanding the microbial genome resources of ruminant digestive tracts.

Based on this database, the study characterized approximately 140 million single nucleotide variation (SNV) sites from 790 species.

By associating the phylogenetic evolutionary distances of the 790 species with 21 neurobehavioral trait phenotypes, the study found that hosts harboring different potential strains within the same species exhibited neurobehavioral differences.

Subsequently, by performing an association analysis between microbial SNVs and host plasma metabolites, the study identified 34 significant associations between SNVs and metabolites, mainly enriched in the phyla Firmicutes and Bacteroidetes, many of which are potential new species.

Metabolites associated with microbial SNVs are mainly related to key physiological processes, such as neuroactive regulation and oxidative stress. The authors further integrated the associations between SNVs, metabolites, and microbial phenotypes, identifying five metabolites significantly associated with specific SNVs and exploratory behavior.

For example, at position 828 in the bamb gene of Phocaeicola new416, the cytosine base was significantly different from the thymine base in plasma 4-anisic acid levels, and 4-anisic acid showed the strongest correlation with sheep exploratory duration. This mutation can alter protein structure, affecting the biosynthesis of brain-derived neurotrophic factor (BDNF), thus regulating host exploratory behavior.

This study suggests that microbial genomic SNVs may be important drivers of host phenotypic differences, revealing that microbial genetic variation can influence host neurocognitive behavior by regulating host metabolism.

This finding expands our understanding of the “microbiome-metabolism-brain” axis and provides a theoretical basis for the development of interventions targeting the gut microbiome.

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About this news about research in genetics and behavior.

Author: Bei Yan
Source: Chinese Scientific Press
Contact: Bei Yan – Science China Press
Image: Image is credited to Neuroscience News.

Original research: Open access.
“Gut microbial genetic variations are associated with exploratory behavior through SNV-driven metabolic regulation in a sheep model” by Lianmin Chen et al. Chinese Science Life Sciences

Abstract

Gut microbial genetic variations are associated with exploratory behavior through SNV-driven metabolic regulation in a sheep model

Host neurocognitive functions are influenced by the gut microbiome, but the role of microbial genetic variation in shaping host neuronal behavior remains unexplored.

Here, we profile multi-omics data and neurobehavioral phenotypes in a model of 200 Merino sheep.

Genomic reconstruction of deeply sequenced fecal and ruminal samples generated 5,253 metagenomically assembled genomes at the species level, of which 3,548 were identified as new species compared to existing sheep databases.

The association between strain-level genetic differences and host neurobehavioral traits showed that phylogenetic differences in 85% of species were associated with exploratory behavior (FDR < 0.05).

Furthermore, we associated 146 million microbial single nucleotide variations (SNVs) with 953 plasma metabolites and identified 34 significant associations across the entire study (P < 2.9 × 10−8), implicating possible microbial genetic regulation of host neuroactivity and oxidative stress-related metabolites, including 4-anisic acid and D-galacturonate.

Integrated analysis revealed that microbial SNVs can regulate host cognitive exploration by regulating metabolites through structural modulation of encoded proteins.

For example, we found that the entry of a new time zone was associated with 4-anisic acid, which was determined by SNV through structural regulation of membrane transporters.

Our findings suggest that microbial genetic variation plays a critical role in modulating host neurocognition, possibly through metabolite regulation, providing novel insights for targeted interventions in neurometabolic disorders.