Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut-Brain Axis.

The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT-receptor expression in the brain, and 5-HT-receptor-dependent behavior was evaluated using the marble burying test. B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium-secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT-receptor 2a in B dentium-treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT-receptor 2a. These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior.

Engevik MA ，Luck B ，Visuthranukul C ，Ihekweazu FD ，Engevik AC ，Shi Z ，Danhof HA ，Chang-Graham AL ，Hall A ，Endres BT ，Haidacher SJ ，Horvath TD ，Haag AM ，Devaraj S ，Garey KW ，Britton RA ，Hyser JM ，Shroyer NF ，Versalovic J ... -  《Cellular and Molecular Gastroenterology and Hepatology》

Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism.

Li K ，Wei W ，Xu C ，Lian X ，Bao J ，Yang S ，Wang S ，Zhang X ，Zheng X ，Wang Y ，Zhong S ... -  《-》

Neurotransmitter Profiles Are Altered in the Gut and Brain of Mice Mono-Associated with Bifidobacterium dentium.

Luck B ，Horvath TD ，Engevik KA ，Ruan W ，Haidacher SJ ，Hoch KM ，Oezguen N ，Spinler JK ，Haag AM ，Versalovic J ，Engevik MA ... -  《Biomolecules》

The metabolic profile of Bifidobacterium dentium reflects its status as a human gut commensal.

Engevik MA ，Danhof HA ，Hall A ，Engevik KA ，Horvath TD ，Haidacher SJ ，Hoch KM ，Endres BT ，Bajaj M ，Garey KW ，Britton RA ，Spinler JK ，Haag AM ，Versalovic J ... -  《BMC MICROBIOLOGY》

Vinegar-processed Schisandra Chinensis enhanced therapeutic effects on colitis-induced depression through tryptophan metabolism.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by its incurable nature and undefined etiology, which is often accompanied by a high prevalence of comorbid depression. The gut-brain axis has emerged as a promising treatment target in recent years. This study aimed to investigate how vinegar-processed Schisandra Chinensis (VSC) enhances therapeutic effects on depressive behavior in chronic UC mice. A chronic UC model was induced in mice using dextran sulfate sodium. The therapeutic effects of both raw and vinegar-processed Schisandra Chinensis on UC and associated depressive symptoms were assessed. Colonic mucosal damage was evaluated using hematoxylin and eosin (H&E) and Alcian blue staining. The integrity of the blood-brain barrier (BBB) and synaptic structures was visualized via transmission electron microscopy (TEM). Enzyme-linked immunosorbent assay (ELISA) was employed to quantify inflammatory cytokine levels in the colon, serum, and brain, while western blotting was performed for protein expression analysis. Additionally, metagenomic analysis was conducted to investigate gut microbiota composition. Nissl staining and immunofluorescence were used to assess hippocampal neuronal damage, and behavioral assessments including the morris water maze, open field test, forced swimming test and tail suspension test, were implemented to evaluate depressive states. Serum metabolites were analyzed using UPLC-MS/MS. Both raw and vinegar-processed Schisandra Chinensis significantly upregulated aryl hydrocarbon receptor (AhR), inhibited NF-κB p-p65 activation, and reduced levels of pro-inflammatory cytokine. These treatments also enhanced the expression of tight junction proteins, restored colonic mucosal and BBB integrity, alleviated damage to hippocampal neurons, and improved synaptic structure. Behavioral assessments indicated that VSC was particularly effective in ameliorating depressive-like behaviors in chronic UC mice. In the gut, both treatments reshaped the gut microbial composition, restoring the relative abundance of Duncaniella, Candidatus_Amulumruptor, Alistipes, Parabacteroides, Lachnospiraceae_bacterium, uncultured_Bacteroides_sp., Candidatus_Amulumruptor_caecigallinarius, with VSC showing more pronounced effects. Serum metabolomics revealed an increase in tryptophan levels and a decrease in kynurenine and xanthurenic acid levels with VSC, indicating that tryptophan metabolism shifted from the kynurenine pathway to the 5-HT or indole pathway. However, this phenomenon did not occur with Schisandra Chinensis (SC). This study demonstrated that the disruption of tryptophan metabolic balance served as a biological mechanism underlying the occurrence of depressive behaviors induced by UC. The application of SC following vinegar processing enhanced its regulatory effects on gut microbiota and tryptophan metabolism. This findings provided a new insight for the clinical management of gut-brain comorbidities.

Zhang J ，Gao T ，Chen G ，Liang Y ，Nie X ，Gu W ，Li L ，Tong H ，Huang W ，Lu T ，Bian Z ，Su L ... -  《-》