JOURNAL OF MEDICAL VIROLOGY
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2025
·Vol. 97
·期 5
·e70395
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IF 4.6
Qiuhong You,Kaifeng Wang,Zhou Zhao,Heqi Zhou,Zhixian Lan,Hongyan Liang,Rui Deng,Wanying Li,Sheng Shen,Routing Wang,Kaikai Zhang,Dekai Zheng,Jian Sun
In chronic hepatitis B (CHB) patients under antiviral treatment, liver injury, as evidenced by elevated alanine transaminase (ALT), is associated with unfavorable outcomes and needs effective treatment. The interaction between gut microbiota and liver injury in CHB patients remains unclear. Using a case-control design, 28 cases with elevated ALT and 28 matched controls with normal ALT were randomly selected from CHB patients with viral control. Clinical characteristics were comparable between groups. Metagenomic sequencing revealed that Bacteroides fragilis was decreased in cases and exhibited the greatest disparity between cases and controls. Mice colonized by gut microbiota from cases exhibited more severe liver damage in both LPS-induced and MCD diet-induced liver injury models, and had a lower abundance of B. fragilis compared to mice colonized by gut microbiota from controls. Oral gavage of B. fragilis improved both LPS-induced and MCD diet-induced liver injury. Metabolomics analysis revealed that the levels of 7-Ketolithocholic acid (7-Keto-LCA) were positively correlated with B. fragilis and significantly increased in the cultural supernatant of B. fragilis . Consistently, 7-Keto-LCA exerted protective effects against both LPS-induced and MCD diet-induced liver damage. Targeting gut microbiota might be a promising therapeutic treatment for alleviation residual liver inflammation in CHB patients with viral control.
研究领域:
医学
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微生物学
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代谢组学
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DOI
PubMed
高影响因子
Gut Microbes
·
2025
·
IF 11
Tong Jin,Si-Yuan Li,Hong-Li Zheng,Xiao-Dan Liu,Yue Huang,Gan Ma,Ya-Xuan Zhao,Xiao-Tian Zhao,Li Yang,Qi-Hui Wang,Hong-Jun Wang,Chengyong Gu,Zhiqiang Pan,Fuqing Lin
The gut microbiota has been linked to a number of neurological disorders. However, it is unclear whether the gut microbiota is involved in the genesis of chronic itch, a refractory condition that afflicts patients both physically and mentally. Here, we report that depletion of gut microbiota enhances tolerance to itch in mice orally administered with antibiotics (ABX) and mice free of germ. Of note, oral gavage with Bacteroides fragilis (B. fragilis), a prominent species of the genus Bacteroides with most differential change, corrected the ABX-induced itch dysfunction through its driven metabolite acetyl-l-carnitine (ALC). Mechanistically, gut microbiota or B. fragilis depletion caused a decrease in RNA N6-methyladenosine (m6A) demethylase FTO expression in the dorsal horn and a consequent increase in RNA m6A sites in Mas-related G protein-coupled receptor F (MrgprF) mRNA, leading to decreased MRGPRF protein. The downregulation of FTO was triggered by inactivation of ETS proto-oncogene 1 (ETS1), a transcription factor that binds to the Fto promoter. These findings support a gut microbe – spinal connection in modulation of itch sensation in RNA m6A epigenetic-dependent manner and highlight a critical role of ALC in linking the altered B. fragilis and itch dysfunction.
研究领域:
神经科学
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微生物学
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表观遗传学
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DOI
PubMed
高影响因子
NEURON
·
2026
·
IF 15
Yicong Jia,Hong Chen,Qianhui Zou,Sijing Chen,Jiahao Li,Yiming Chen,Liming Lu,Feng Hong,Shuhui Jia,Xiaoyuan Jing,Jiayan Ren,Fahim Muhammad,JiaYu Mi,Jing Duan,Jianxiang Liao,Qing Liu,Fuqiang Xu,Paul J. Kenny,Ming-Hu Han,Liping Wang,Zuxin Chen,Dezhi Cao,Xin-an Liu
Gut dysbiosis has been implicated in epilepsy, yet probiotic efficacy and mechanisms remain unclear. Here, we identify that Bacteroides fragilis ( B. fragilis ) is markedly reduced in children with epilepsy and show that oral B. fragilis administration suppresses seizures in both pentylenetetrazole- and kainic-acid-induced mouse models. Mechanistically, B. fragilis activates colonic choline acetyltransferase-positive (ChAT + ) cells and enhances gut-vagus-brain cholinergic signaling, as demonstrated by vagal recordings, pharmacological blockade, and chemogenetic manipulation, identifying a colonic ChAT + -nodose ganglion circuit mediating seizure suppression. Its antiseizure effects associate with enriched intestinal Lactobacillus colonization. A randomized clinical trial (CHiCTR2100042203) further confirms the therapeutic efficacy of B. fragilis in pediatric refractory epilepsy. These findings define a gut-brain cholinergic pathway through which B. fragilis exerts antiseizure effects and establish a mechanistic basis for microbiota-targeted therapies in epilepsy.
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PubMed
高影响因子
Cell Chemical Biology
·
2026
·Vol. 33
·期 1
·102-116
·
IF 7.2
Yucheng Guo,Zhenlin Ouyang,Wenbo He,Qian Qin,Jiaxin Zhang,Ting Yu,Min Jiao,Peter M. Hwang,Fang Zheng,Serge Muyldermans,Yurong Wen
Enterotoxigenic Bacteroides fragilis (ETBF) promotes colonic inflammation by secreting metalloenzyme toxins (BFTs). Understanding BFT mechanisms and developing neutralization strategies is critical. Here, we have solved the structures of BFT-1 and BFT-2, revealing that residue 357 in the active site of the catalytic domain explains the diversity of function observed in BFT subtypes. We demonstrate that BFTs can directly cleave human epithelial-cadherin at extracellular domain 4, with BFT-2 possessing the highest activity. Using an alpaca antibody library, we identified a single-domain antibody, Nb2.43, targeting the BFTs. Nb2.43 can neutralize all three subtypes of BFT by directly binding the metalloenzyme catalytic zinc ion with its CDR3 antigen-binding loop. Furthermore, Nb2.43 blocks cleavage of E-cadherin by BFT and prevents the damage caused by ETBF in vitro and in a mouse colitis model. This work provides structural insights into BFT diversity and delivers a therapeutic nanobody against ETBF-mediated inflammation.
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PubMed
高影响因子
Nature Microbiology
·
2026
·
IF 18.7
Zhang Yue,Zhao Ying,Zhang Lu,Xuan Baoqin,Wang Zhenyu,Yu Bin,Li Weixun,Huang Xiaowen,Zhou Yilu,Ning Lijun,Ding Jinmei,Jiang Yi,Hu Muni,Shao Yuqi,Li Lingxi,Gao Xiang,Chen Shengliang,Chen Haoyan,Wang Fei,Cui Zhe,Fang Jing-Yuan,Hong Jie
Gut dysmotility is a common long-term effect of enterotoxigenic Bacteroides fragilis (ETBF) colonization but the underlying mechanisms are not clear. Here, using mouse colonization models, we found that ETBF-secreted B. fragilis toxin (BFT) causes loss of colonic myenteric neurons, which are crucial regulators of intestinal motility. BFT induced apoptosis in these neurons through the NOD1–RIPK2–CASP9–CASP3 pathway, leading to gut dysmotility that persisted even after the clearance of ETBF. Analyses of human inflammatory bowel disease and colorectal cancer patient cohorts showed a positive correlation between ETBF and Fusobacterium nucleatum abundance. In mice, F. nucleatum -derived 2-hydroxybutyric acid enhanced BFT production in ETBF by alleviating RprY-mediated suppression and aggravated neurotoxicity and dysmotility. This enteric neuron loss and dysmotility enhanced susceptibility to dextran sulfate sodium-induced colitis in mice. Therapeutically, a Bifidobacterium -based probiotic attenuated neuron toxicity and improved intestinal motility. Our findings reveal bacterial interactions regulating intestinal function and a potential clinical therapeutic approach to preventing outcomes of ETBF colonization.
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高影响因子
PHARMACOLOGICAL RESEARCH
·
2022
·
IF 10.334
Suhang Guo,Yi Peng,Yan Lou,Lijuan Cao,Junqing Liu,Nengming Lin,Sheng Cai,Yu Kang,Su Zeng,Lushan Yu
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the world. The downregulation of farnesoid X receptor (FXR) is frequently founded in CRC patients. The current study found that the decreased expression of FXR in colorectal cancer leads to disorders of bile acids (BAs) metabolism. The altered BAs profile shaped distinct intestinal flora and positively regulated secretory immunoglobulin A (sIgA). The dual regulation of BAs and sIgA enhanced adhesion and biofilm formation of enterotoxigenic Bacteroides fragilis (ETBF), which has a colorectal tumorigenesis effect. The abundance of ETBF increased significantly in intestinal mucosa of colitis-associated cancer (CAC) mice, and finally promoted the development of colorectal cancer. This study suggests that downregulation of FXR in CRC results in BAs dysregulation, and BAs have strong effects on sIgA and gut flora. The elevated BAs concentration and altered gut microbiome are risk factors for CRC.
研究领域:
肿瘤学
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胃肠病学
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微生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Protein & Cell
·
2024
·
IF 13.6
Ma Wei,Zhang Lu,Chen Weilong,Chang Zhaoxia,Tu Juchuanli,Qin Yuanyuan,Yao Yuwen,Dong Mengxue,Ding Jiajun,Li Siqin,Li Fengkai,Deng Qiaodan,Yang Yifei,Feng Tingting,Zhang Fanrong,Shao Xiying,He Xueyan,Zhang Lixing,Hu Guohong,Liu Quentin,Jiang Yi-Zhou,Zhu Shu,Xiao Zhi,Su Dan,Liu Tong,Liu Suling
Tumor-resident microbiota in breast cancer promote cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increases the chemosensitivity of breast cancer by impairing BCSCs.
研究领域:
肿瘤学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
CELL CYCLE
·
2024
·
IF 3.4
Jian Yang,Xue Wang,Tao Hu,He Huang,Gang Chen,Bo Jin,Guilin Zeng,Jian Liu
Our previous findings confirmed the high enrichment of Bacteroides fragilis (BF) in fecal samples from patients with colorectal cancer (CRC). The intestinal mucosal barrier is the first defense of the organism against commensal flora and intestinal pathogens and is closely associated with the occurrence and development of CRC. Therefore, this study aimed to investigate the molecular mechanisms through which BF mediates intestinal barrier injury and CRC progression. SW480 cells and a Caco2 intestinal barrier model were treated with entero-toxigenic BF (ETBF), its enterotoxin (B. fragilis toxin, BFT), and non-toxigenic BF (NTBF). Cell counting kit-8, flow cytometry, wound healing and transwell assays were performed to analyze the proliferation, apoptosis, migration, and invasion of SW480 cells. Transmission electron microscopy, FITC-dextran, and transepithelial electrical resistance (TEER) were used to analyze damage in the Caco2 intestinal barrier model. The Azoxymethane/Dextran Sulfate Sodium (AOM/DSS) animal model was established to evaluate the effect of ETBF on intestinal barrier injury and CRC progression in vivo. ETBF and BFT enhanced the viability, wound healing ratio, invasion, and EMT of SW480 cells. In addition, ETBF and BFT disrupted the tight junctions and villus structure in the intestinal barrier model, resulting in increased permeability and reduced TEER. Similarly, the expression of intestinal barrier-related proteins (MUC2, Occludin and Zo-1) was restricted by ETBF and BFT. Interestingly, the STAT3/ZEB2 axis was activated by ETBF and BFT, and treatment with Brevilin A (a STAT3 inhibitor) or knockdown of ZEB2 limited the promotional effect of ETBF and BFT on the SW480 malignant phenotype. In vivo experiments also confirmed that ETBF colonization accelerated tumor load, carcinogenesis, and intestinal mucosal barrier damage in the colorectum of the AOM/DSS animal model, and that treatment with Brevilin A alleviated these processes. ETBF-secreted BFT accelerated intestinal barrier damage and CRC by activating the STAT3/ZEB2 axis. Our findings provide new insights and perspectives for the application of ETBF in CRC treatment.
研究领域:
胃肠病学
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肿瘤学
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微生物学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Zhenhui Chen,Huijuan Chen,Wanwen Huang,Xiaotong Guo,Lu Yu,Jiamin Shan,Xiaoshi Deng,Jiaxin Liu,Wendan Li,Wei Shen,Hongying Fan
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.
研究领域:
微生物学
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胃肠病学
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儿科
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代谢组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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