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A murine model of pediatric inflammatory bowel disease causes microbiota-gut-brain axis deficits in adulthood.
Inflammatory bowel diseases (IBDs) are chronic intestinal diseases, frequently associated with comorbid psychological and cognitive deficits. These neuropsychiatric effects include anxiety, depression, and memory impairments that can be seen both during active disease and following remission and are more frequently seen in pediatric patients. The mechanism(s) through which these extraintestinal deficits develop remain unknown, and the study of these phenomenon is hampered by a lack of murine pediatric IBD models. Herein we describe microbiota-gut-brain (MGB) axis deficits following induction of colitis in a pediatric setting. Acute colitis was induced by administration of 2% dextran sodium sulfate (DSS) for 5 days starting at weaning [postnatal day (P)21] causing reduced weight gain, colonic shortening, and colonic inflammation by 8 days post-DSS (P29), which were mostly resolved in adult (P56) mice. Despite resolution of acute disease, cognitive deficits (novel object recognition task) and anxiety-like behavior (light/dark box) were identified in the absence of changes in exploratory behavior (open field test) in P56 mice previously treated with DSS at weaning. Behavioral deficits were found in conjunction with neuroinflammation, decreased neurogenesis, and altered expression of pattern recognition receptor genes in the hippocampus. Additionally, persistent alterations in the gut microbiota composition were observed at P56, including reduced butyrate-producing species. Taken together, these results describe for the first time the presence of MGB axis deficits following induction of colitis at weaning, which persist in adulthood.NEW & NOTEWORTHY Here we describe long-lasting impacts on the microbiota-gut-brain (MGB) axis following administration of low-dose dextran sodium sulfate (DSS) to weaning mice (P21), including gut dysbiosis, colonic inflammation, and brain/behavioral deficits in adulthood (P56). Early-life DSS leads to acute colonic inflammation, similar to adult mice; however, it results in long-lasting deficits in the MGB axis in adulthood (P56), in contrast to the transient deficits seen in adult DSS. This model highlights the unique features of pediatric inflammatory bowel disease.
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Gut Microbiota Alterations in Patients with Panic Disorder: A Case-Control Study.
Background/Objectives: Recent evidence suggests that gut microbiota plays an important role in anxiety and stress-related disorders through interactions along the gut-brain axis. Our aim was to determine the microbiological diversity of intestinal microorganisms in individuals with acute and remission phases of PD when compared to healthy individuals. Another aim was also to analyze the differences in the metabolic pathways occurring in the intestinal microbiota of individuals from the three analyzed groups. Methods: A diagnosis was established using the Mini-International Neuropsychiatric Interview (M.I.N.I). The gut's microbiota composition was analyzed through bacterial 16S rRNA gene sequencing (V1-V2 regions). The clinical evaluations included a BMI measurement, Short Form-36 Health Survey (SF-36), Hamilton Anxiety Scale (HAM-A), Montgomery-Åsberg Depression Rating Scale (MADRS), Columbia-Suicide Severity Rating Scale (C-SSRS), and State-Trait Anxiety Inventory (STAI). Results: We recruited 62 participants (31 PD and 31 controls). After conducting quality control filtering, data from 54 participants were analyzed (25 PD, 11 acute, 14 remission, and 29 controls). Observed richness was lower in the acute PD (63) group than in the control (74) and remission (66) (p = 0.038) groups, whereas the Shannon and Simpson indices and beta diversity (PERMANOVA) were not significantly different. The Ruminococcus gnavus group was enriched in acute PD; no other deconfounded differences in microbial composition were detected. Predicted functional differences were detected by edgeR only and included the pathways that are related to steroid biosynthesis and innate immune signaling. Conclusions: Distinct gut microbial signatures were associated with PD, implicating both the metabolic and inflammatory pathways in disease pathophysiology.
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Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge.
BACKGROUND: Long coronavirus disease 2019 (COVID-19) in recovered patients (RPs) is gradually recognized by more people. However, how long it will last and the underlining mechanism remains unclear. METHODS: We conducted a prospective follow-up study to evaluate the long-term symptoms and clinical indices of RPs at one-year after discharge from Union Hospital, Wuhan, China between December 2020 to May 2021. We also performed the 16S rRNA sequencing of stool samples from RPs and healthy controls (HCs) and analyzed the correlation between the gut microbiota and long COVID-19. RESULTS: In total, 187 RPs were enrolled, among them, 84 (44.9%) RPs reported long COVID-19 symptoms at one-year after discharge. The most common long-term symptoms were cardiopulmonary symptoms, including chest tightness after activity (39/187, 20.9%), palpitations on exercise (27/187, 14.4%), sputum (21/187, 11.2%), cough (15/187, 8.0%) and chest pain (13/187, 7.0%), followed by systemic symptoms including fatigue (34/187, 18.2%) and myalgia (20/187, 10.7%), and digestive symptoms including constipation (14/187, 7.5%), anorexia (13/187, 7.0%), and diarrhea (8/187, 4.3%). Sixty-six (35.9%) RPs presented either anxiety or depression (42/187 [22.8%] and 53/187 [28.8%] respectively), and the proportion of anxiety or depression in the long symptomatic group was significantly higher than that in the asymptomatic group (41/187 [50.6%] vs. 25/187 [24.3%]). Compared with the asymptomatic group, scores of all nine 36-Item Short Form General Health Survey domains were lower in the symptomatic group (all P < 0.05). One hundred thirty RPs and 32 HCs (non-severe acute respiratory syndrome coronavirus 2 infected subjects) performed fecal sample sequencing. Compared with HCs, symptomatic RPs had obvious gut microbiota dysbiosis including significantly reduced bacterial diversities and lower relative abundance of short-chain fatty acids (SCFAs)-producing salutary symbionts such as Eubacterium_hallii_group, Subdoligranulum, Ruminococcus, Dorea, Coprococcus, and Eubacterium_ventriosum_group. Meanwhile, the relative abundance of Eubacterium_hallii_group, Subdoligranulum, and Ruminococcus showed decreasing tendencies between HCs, the asymptomatic group, and the symptomatic group. CONCLUSION: This study demonstrated the presence of long COVID-19 which correlates with gut microbiota dysbiosis in RPs at one-year after discharge, indicating gut microbiota may play an important role in long COVID-19.
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Behavioural adaptations after antibiotic treatment in male mice are reversed by activation of the aryl hydrocarbon receptor.
The intestinal microbiota plays an important role in regulating brain functions and behaviour. Microbiota-dependent changes in host physiology have been suggested to be key contributors to psychiatric conditions. However, specific host pathways modulated by the microbiota involved in behavioural control are lacking. Here, we assessed the role of the aryl hydrocarbon receptor (Ahr) in modulating microbiota-related alterations in behaviour in male and female mice after antibiotic (Abx) treatment. Mice of both sexes were treated with Abx to induce bacterial depletion. Mice were then tested in a battery of behavioural tests, including the elevated plus maze and open field tests (anxiety-like behaviour), 3 chamber test (social preference), and the tail suspension and forced swim tests (despair behaviour). Behavioural measurements in the tail suspension test were also performed after microbiota reconstitution and after administration of an Ahr agonist, β-naphthoflavone. Gene expression analyses were performed in the brain, liver, and colon by qPCR. Abx-induced bacterial depletion did not alter anxiety-like behaviour, locomotion, or social preference in either sex. A sex-dependent effect was observed in despair behaviour. Male mice had a reduction in despair behaviour after Abx treatment in both the tail suspension and forced swim tests. A similar alteration in despair behaviour was observed in Ahr knockout mice. Despair behaviour was normalized by either microbiota recolonization or Ahr activation in Abx-treated mice. Ahr activation by β-naphthoflavone was confirmed by increased expression of the Ahr-target genes Cyp1a1, Cyp1b1, and Ahrr. Our results demonstrate a role for Ahr in mediating the behaviours that are regulated by the crosstalk between the intestinal microbiota and the host. Ahr represents a novel potential modulator of behavioural conditions influenced by the intestinal microbiota.
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Features of gut microbiota in patients with anorexia nervosa.
BACKGROUND: Anorexia nervosa (AN) is a psychological disorder, which is characterized by the misunderstanding of body image, food restriction, and low body weight. An increasing number of studies have reported that the pathophysiological mechanism of AN might be associated with the dysbiosis of gut microbiota. The purpose of our study was to explore the features of gut microbiota in patients with AN, hoping to provide valuable information on its pathogenesis and treatment. METHODS: In this cross-sectional study, from August 2020 to June 2021, patients with AN who were admitted into Peking University Third Hospital and Peking University Sixth Hospital ( n = 30) were recruited as the AN group, and healthy controls (HC) were recruited from a middle school and a university in Beijing ( n = 30). Demographic data, Hamilton Depression Scale (HAMD) scores of the two groups, and length of stay of the AN group were recorded. Microbial diversity analysis of gut microbiota in stool samples from the two groups was analyzed by 16S ribosomal RNA (rRNA) gene sequencing. RESULTS: The weight (AN vs. HC, [39.31 ± 7.90] kg vs. [56.47 ± 8.88] kg, P < 0.001) and body mass index (BMI, AN vs. HC, [14.92 ± 2.54] kg/m 2vs. [20.89 ± 2.14] kg/m 2 , P < 0.001) of patients with AN were statistically significantly lower than those of HC, and HAMD scores in AN group were statistically significantly higher than those of HC. For alpha diversity, there were no statistically significant differences between the two groups; for beta diversity, the two groups differed obviously regarding community composition. Compared to HC, the proportion of Lachnospiraceae in patients with AN was statistically significantly higher (AN vs. HC, 40.50% vs. 31.21%, Z = -1.981, P = 0.048), while that of Ruminococcaceae was lower (AN vs. HC, 12.17% vs. 19.15%, Z = -2.728, P = 0.007); the proportion of Faecalibacterium (AN vs. HC, 3.97% vs. 9.40%, Z = -3.638, P < 0.001) and Subdoligranulum (AN vs. HC, 4.60% vs. 7.02%, Z = -2.369, P = 0.018) were statistically significantly lower, while that of Eubacterium_hallii_group was significantly higher (AN vs. HC, 7.63% vs. 3.43%, Z = -2.115, P = 0.035). Linear discriminant effect (LEfSe) analysis (LDA score >3.5) showed that o_Lachnospirales, f_Lachnospiraceae, and g_Eubacterium_hallii_group (o, f and g represents order, family and genus respectively) were enriched in patients with AN. Microbial function of nutrient transport and metabolism in AN group were more abundant ( P > 0.05). In AN group, weight and BMI were significantly negatively correlated with the abundance of Bacteroidota and Bacteroides , while positively correlated with Subdoligranulum . BMI was significantly positively correlated with Firmicutes; HAMD scores were significantly negatively correlated with Faecalibacterium. CONCLUSIONS: The composition of gut microbiota in patients with AN was different from that of healthy people. Clinical indicators have correlations with the abundance of gut microbiota in patients with AN.
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Association between blood omega-3 polyunsaturated fatty acids and the gut microbiota among breast cancer survivors.
Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients demonstrated to have health benefits, such as decreasing the risk of coronary heart disease, improving parameters associated with metabolic syndrome, and decreasing anxiety symptoms and depression risk. Previous intervention studies indicated the association between blood or tissue PUFA levels and the gut microbiota; however, the details remain incompletely elucidated. We conducted a cross-sectional study to examine the association between PUFAs and the gut microbiota among breast cancer survivors. Adults who had been diagnosed with invasive breast cancer more than one year ago and were not currently undergoing chemotherapy were enrolled. Capillary blood and faecal samples were obtained to assess the blood PUFA levels and gut microbiota compositions. The mean age (n=124) was 58.7 years, and 46% of the participants had a history of chemotherapy. Multiple regression analysis controlling for possible confounders indicated that an increased relative abundance of Actinobacteria was significantly associated with increased levels of docosahexaenoic acid (DHA, beta=0.304, q<0.01). At the genus level, the abundance of Bifidobacterium was positively associated with the level of DHA (beta=0.307, q<0.01). No significant association between omega-6 PUFAs and the relative abundances of gut microbiota members was observed. In addition, analyses stratified by the history of chemotherapy indicated significant associations of PUFA levels with the abundance of some bacterial taxa, including the phylum Actinobacteria (DHA, beta=0.365, q<0.01) and Bacteroidetes (EPA, beta=-0.339, q<0.01) and the genus Bifidobacterium (DHA, beta=0.368, q<0.01) only among participants without a history of chemotherapy. These findings provide the first evidence of positive associations between the abundances of Bifidobacterium among the gut microbiota and the levels of omega-3 PUFAs in the blood. Further studies are required to gain additional insight into these associations in healthy subjects as well as into the causality of the relationship.
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Resveratrol alleviates IBD-associated neuropsychiatric comorbidities via microbiota-dependent arginine metabolism reprogramming and microglial M2 polarization through gut-brain axis.
Inflammatory bowel disease (IBD) is intricately linked to neuropsychiatric comorbidities through gut-brain axis dysregulation. This study demonstrates that resveratrol (RSV), a natural polyphenol, alleviates DSS-induced colitis-associated anxiety and depression by reprogramming the microbiota─metabolite-barrier network. RSV (100 mg/kg/day) ameliorated DSS-associated anxiety-like behaviors in open field tests (peripheral zone time ↓12.6%, P< 0.0001) and depression-like phenotypes (TST immobility ↓31.0%, P = 0.0004). It restored colonic barrier integrity via ZO-1 mRNA upregulation (↑80.4%, P < 0.0001) and PAS score recovery (↑29.6%, P < 0.0001), while reducing systemic inflammation (serum LPS ↓31.9%, TNF-α ↓29.9%; P < 0.0001) vs. DSS. Crucially, RSV attenuated neuroinflammation by enhancing brain ZO-1 protein expression (↑146.1%, P = 0.0016), suppressing TLR4/MyD88/NF-κB signaling (TLR4 mRNA ↓68.8%, MyD88 protein ↓48.8%; P < 0.05), and promoting M2 microglial polarization (CD206 protein ↑171.9%, P = 0.0003) vs. DSS. Multi-omics integration revealed RSV’s dual regulatory mechanism: ① Suppression of the pro-inflammatory Turicibacter4-guanidinobutanoic acid axis (↓42% and ↓37%, respectively; P < 0.01), disrupting LPS─TLR4─MyD88 cascades; ② Enrichment of barrier-protective Muribaculum (↑419%) and Dubosiella (↑208%), driving polyamine synthesis (spermidine ↑92%, spermine ↑38%) vs. DSS to reinforce gut-brain barriers. Spearman correlations confirmed Turicibacter-4-guanidinobutanoic acid-LPS-MyD88 interactions(r = 0.658-0.865) and Dubosiella-spermine-ZO-1 associations (r = 0.539-0.725). Conclusions: These findings establish RSV as a microbiota-metabolite modulator that redirects arginine metabolism from a pro-inflammatory bypass to polyamine-mediated barrier repair, offering novel therapeutic strategies for IBD-related neuropsychiatric complications. The integrated "microbe-metabolite-neuroimmune" axis provides mechanistic insights into gut-brain crosstalk, emphasizing dual-barrier restoration as a critical intervention node.
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Alcohol-fluoxetine co-treatment drives gut dysbiosis and intestinal barrier disruption with consequences for neuroimmune signaling in male rats.
Alcohol consumption and depression frequently co-occur, but little is known about how alcohol and antidepressant medication interact along the gut-brain axis. We examined the independent and combined effects of chronic alcohol exposure and fluoxetine on gut microbiota, intestinal structure, peripheral endotoxin-related and inflammatory markers, and neuroinflammatory gene expression in male rats. Animals received alcohol for 14 days and fluoxetine for 7 days, resulting in four groups: control-vehicle, control-fluoxetine, alcohol-vehicle, and alcohol-fluoxetine. Fecal microbiota was analyzed using 16S rRNA sequencing, functional prediction, and culturable bacteria under antibiotic selection. Ileal morphology, extracellular matrix organization, plasma LPS and cytokines, and neuroinflammation-related gene expression in the amygdala and medial prefrontal cortex (mPFC) were also evaluated. Both alcohol and fluoxetine modified the gut microbiota, with their combination producing the most pronounced alterations, including the loss of several short-chain fatty acid-producing taxa. Fluoxetine alone increased alpha diversity and altered the abundance of genera linked to metabolic activity. Alcohol impaired intestinal integrity by reducing villus width, increasing goblet cell density, and decreasing collagen content. In animals with prior alcohol exposure, reduced plasma LPS and TNF-α levels were observed at the time of sample collection. Neuroimmune gene expression changes differed between the amygdala and mPFC, indicating region-specific central responses. Together, these findings reveal that fluoxetine treatment can modulate the gut-brain axis differently depending on prior alcohol exposure, supporting further investigation of microbiota-related mechanisms in alcohol use and psychiatric comorbidity.
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Gualou-Xiebai-Banxia-Tang regulates liver-gut axis to ameliorate Metabolic Syndrome in HFD-fed mice.
BACKGROUND: Metabolic syndrome (MetS), characterized by obesity, hyperglycemia, and abnormal blood lipid levels, is the pathological basis of many cardiovascular diseases. Gualou-Xiebai-Banxia-Tang decoction (GT) was first described in the Synopsis of the Golden Chamber, the earliest traditional Chinese medicine (TCM) monograph on diagnosis and treatment of miscellaneous diseases in China. According to TCM precepts, based on its ability to activate yang to release stagnation, activate qi to reduce depression, remove phlegm, and broaden the chest, GT has been used for more than 2,000 years to treat cardiovascular ailments. However, the molecular bases of its therapeutic mechanisms remain unclear. PURPOSE: The aim of this study was to identify lipid- and glucose-related hepatic genes differentially regulated by GT, and to assess GT impact on gut microbiota composition, in mice with high-fat diet (HFD)-induced MetS. STUDY DESIGN AND METHODS: ApoE-/- mice were fed with an HFD for 24 weeks, with or without concurrent GT supplementation, to induce MetS. At the study's end, body weight, visceral fat weight, blood lipid levels, and insulin sensitivity were measured, and histopathological staining was used to evaluate hepatosteatosis and intestinal barrier integrity. Liver transcriptomics was used for analysis of differentially expressed genes in liver and prediction of relevant regulatory pathways. Hepatic lipid/glucose metabolism-related genes and proteins were detected by RT-qPCR and western blotting. Gut microbial composition was determined by 16S rRNA gene sequencing. RESULTS: GT administration reduced MetS-related liver steatosis and weight gain, promoted insulin sensitivity and lipid metabolism, and beneficially modulated gut microbiota composition by decreasing the relative abundance of g_Lachnospiraceae_NK4A136_group and increasing the relative abundance of g_Alistipes. Liver transcriptomics revealed that GT regulated the expression of genes related to lipid and glucose metabolism (Pparγ, Igf1, Gpnmb, and Trem2) and of genes encoding chemokines/chemokine receptors (e.g. Cxcl9 and Cx3cr1). Significant, positive correlations were found for Ccr2, Ccl4, Ccr1, and Cx3cr1 and the g_Lachnospiraceae_NK4A136_group, and between Cxcl9, Ccr2, Ccl4, and Cx3cr1 and g_Desulfovibrio. GT treatment downregulated the protein expressions of SCD1 and CX3CR1 and upregulated the expression of PCK1 protein. CONCLUSION: GT supplementation alleviates HFD-induced MetS in mice by improving hepatic lipid and glucose metabolism. The anti-metabolic syndrome effects of GT may be related to the regulation of the gut-liver axis.
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Jianchang No. 1 (1) formula alleviates irritable bowel syndrome with diarrhea improving gut microbiota and regulating toll-like receptors/nuclear factor-kappa B signaling pathway in bowel syndrome with diarrhea rats.
OBJECTIVE: To evaluate the therapeutic efficacy of Jianchang No. 1 (1) in treating irritable bowel syndrome with diarrhea (IBS-D) and to explore its underlying mechanisms of action. METHODS: IBS-D rat models were established through a combination of chronic restraint stress, water avoidance stress, and the administration of senna decoction. Body weight, fecal water content (FWC), and intestinal capacity threshold in IBS-D rats were monitored before and after treatment. Pathological alterations in colon tissue were examined using hematoxylin and eosin staining. Serum levels of lipopolysaccharide (LPS), along with LPS content in colon tissue were measured using the enzyme-linked immunosorbent assay. 16S rRNA sequencing technology was employed to assess the abundance and compositional shifts within the gut microbiota. Quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence were employed to determine gene and protein expression in colonic samples. RESULTS: Jianchang No. 1 treatment restored body weight, lowered FWC, and raised the intestinal capacity threshold in IBS-D rats. Meanwhile, Jianchang No. 1 enhanced both the richness and composition of the gut microbiota. Moreover, Jianchang No. 1 markedly upregulated the tight-junction proteins zonula occludens-1 and occludin together with the anti-inflammatory cytokine interleukin-10, while simultaneously downregulating the LPS-toll-like receptor (TLR) 2/4- myeloid differentiation factor 88- nuclear factor kappa B (NF-κB) axis and the downstream pro-inflammatory mediators interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, together with interleukin-4 and interferon-gamma. CONCLUSIONS: Jianchang No. 1 maintains intestinal barrier integrity by reshaping gut-microbial diversity and composition, dampening the TLR/NF-κB signaling cascade, and thereby alleviating low-grade colonic inflammation and its attendant clinical symptoms in IBS-D rats.