The gut microbiota (GM) significantly influences host physiology, impacting immunity, metabolism, mood, and behavior. GM metabolites, reaching high concentrations in the serum and organs, communicate with the brain through the gut-brain axis, a neural circuit enabling sensory transduction of nutrients. The GM's role in neurodegenerative diseases like Alzheimer's and Parkinson's disease is increasingly recognized, highlighting its potential as a therapeutic target. Diets high in sugar and low in fiber cause gut dysbiosis, increasing intestinal permeability, impairing immunity and glucolipid metabolism, and altering bacterial dominance (e.g., reduced Bifidobacterium and Bacillus, increased Gram-negative bacteria). Intestinal barrier dysfunction, even without obesity, can be driven by hyperglycemia, increasing pathogen entry and shifts in fecal microbiota. Certain bacteria produce bioactive neurotransmitters that regulate the nervous system and host behavior. While various gut-brain axis communication pathways exist (immune system, vagus nerve, microbiota modulation of neuroactive compounds), how bacteria activate the brain remains unclear. This study uses an HSHF diet to induce GM dysbiosis in mice, monitoring effects on pathology, neurotransmitters, metabolism, and circRNA transcription to identify associations between GM function, neurotransmitters, and brain function, ultimately expanding the "microbiome-transcriptome" linkage library and informing therapeutic strategies.

Extensive research demonstrates the gut microbiota's profound impact on host physiology, including its role in regulating immunity, metabolism, and even behavior. Studies have highlighted the gut-brain axis, a complex communication network where gut metabolites influence brain function. The importance of the gut microbiota in neurodegenerative diseases such as Alzheimer's and Parkinson's disease is gaining increasing attention, with potential therapeutic interventions targeting the gut microbiota or its metabolites being explored. The negative impacts of high-sugar, high-fat diets on the gut microbiota, leading to dysbiosis and increased intestinal permeability, are well-documented. The ability of certain gut bacteria to produce neuroactive compounds and influence host behavior is also an active area of research, although the precise mechanisms of communication between the gut and the brain remain to be fully elucidated.

The study utilized three mouse models. First, adult male KM mice were randomly assigned to control (standard diet) and model (HSHF diet) groups for three months. The HSHF diet consisted of 20% sucrose, 15% fat, 12% cholesterol, 0.2% bile acid sodium, 10% casein, 0.6% calcium hydrogen phosphate, 0.4% stone powder, 0.4% premix, and 52.5% basal feed. Second, Sprague-Dawley rats were divided into a normal group and a trimethylamine (TMA)-induced group (2 mL/kg of 2.5% TMA). Third, C57 mice were divided into four groups: normal, C. albicans-treated, K. pneumoniae-treated, and C. albicans + K. pneumoniae-treated. Physiological and biochemical indices (body weight, blood glucose, triglycerides, cholesterol, HDL-C, TMAO, neurotransmitters) were measured. Histopathology and immunostaining (H&E, silver, Nissl, TUNEL) were performed on brain, liver, kidney, spinal cord, spleen, and adipose tissue. Gut microbiota composition was analyzed via 16S rRNA gene sequencing. Metabolomics analysis of brain and intestinal content was performed using UPLC-MS/MS. CircRNA expression was assessed using RNA sequencing and RT-qPCR. Data analysis included differential gene expression analysis (edgeR) and pathway analysis (KEGG).

The HSHF diet induced gut dysbiosis, intestinal damage, and altered neurotransmitter metabolism in both the intestine and brain, leading to changes in brain function and circRNA profiles. TMAO, a gut microbial metabolite, was found to degrade certain circRNAs. The basal level of the gut microbiota influenced the conversion rate of choline to TMAO. Altering the abundance of a single bacterial strain impacted neurotransmitter secretion. Specific bacteria, such as C. albicans and K. pneumoniae, were shown to influence the cholinergic system. These findings demonstrate a novel link between metabolism, brain circRNAs, and the gut microbiota, expanding our understanding of the gut-brain axis.

This study provides strong evidence for a direct link between diet-induced gut dysbiosis, altered neurotransmitter metabolism, and changes in brain function and circRNA profiles. The identification of TMAO as a regulator of circRNA degradation adds a new layer of complexity to the gut-brain axis communication. The findings highlight the importance of the gut microbiota in maintaining brain health and suggest potential therapeutic targets for neurological disorders. Further research is needed to fully elucidate the mechanisms involved and to translate these findings into clinical applications.

This research reveals a previously unknown connection between dietary habits, gut microbiota composition, neurotransmitter metabolism, and brain function, mediated by alterations in brain circRNA profiles. The study highlights the importance of the gut microbiome in modulating brain health and identifies potential therapeutic targets and mechanistic pathways for neurological disorders. Future research should focus on translating these findings into effective clinical interventions.

The study utilized animal models, which may not fully reflect the complexity of human systems. Further research is needed to validate these findings in human populations. The specific mechanisms underlying the observed interactions between the gut microbiota, neurotransmitters, and circRNAs require further investigation.