Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways

Abstract

BackgroundInhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits.MethodsWe studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics.ResultsAn interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor’s bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient’s mice.ConclusionThese results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.

Gut Microbiome, Inflammation, and Cerebrovascular Function: Link Between Obesity and Cognition

“…Interestingly, when mice on a standard chow diet received microbiota from HFD-induced obese mice, they showed increased inflammation, gut permeability, blood-brain barrier (BBB) permeability, anxiety and decreased memory performance ( Bruce-Keller et al, 2015 ). Furthermore, mice that received microbiota from humans experiencing obesity, showed decreased inhibition, just like the human donors, compared to lean human donors and mice who received their microbiota ( Arnoriaga-Rodriguez et al, 2021 ). Altogether, this indicates the importance of a healthy gut microbiota for optimal cognitive function in animals.…”

“…Firmicutes bacteria are positively associated with memory performance, whereas Bacteroidetes and Proteobacteria are inversely associated with memory ( Arnoriaga-Rodriguez et al, 2020 ). Adults with obesity showed lower scores in a Stroop test, which was positively associated with Eubacterium and Firmicutes bacterium abundance, and inversely associated with Bacteroidetes abundance ( Arnoriaga-Rodriguez et al, 2021 ). One way the gut microbiota may influence cognition is through inflammation: Kreutzer et al (2017) found increased inflammation in the mediobasal hypothalamus in adults with obesity, which was inversely correlated to Parasutterella sp.…”

Obesity influences composition of salivary and fecal microbiota and impacts the interactions between bacterial taxa

“…D-Glutamine concentrations were shown to be decreased in obese individuals and glutamine supplementation may alleviate obesity symptoms [133, 134]. Metabolic pathways enriched in the microbiota of obese individuals included one-carbon metabolism, which was previously shown to contribute to the development of obesity[135]. In addition, steatosis was shown to be associated with one carbon metabolism’s gene expression [136].…”

Microbiota and Metabolite Profiling as Markers of Mood Disorders: A Cross-Sectional Study in Obese Patients

“…Among microbiota-derived metabolites, several are thought to exert neuroactive properties including short chain fatty acids (SCFA) or bile acids [ 12 , 13 ]. Recent studies highlighted that some gut-derived metabolites originating from aromatic amino acids metabolism are able to modulate cognition and brain function in obesity [ 14 , 15 ]. Since a crosstalk exists between the gut microbiota and the brain, the circulating metabolome is susceptible to play an important role in psychiatric disorders.…”