iMeta
·
2025
·
IF 33.2
Cunzheng Zhang,Yuzhu Chen,Ruqiao Duan,Yiming Zhang,Haonan Zheng,Jindong Zhang,Tao Zhang,Jingxian Xu,Kailong Li,Fei Pei,Liping Duan
Maternal health, specifically changes in the gut microbiota, can profoundly impact offspring health; however, our understanding of how gut microbiota alterations during the preconception period influence the offspring remains limited. In this study, we investigated the impact and mechanisms of preconception maternal gut dysbiosis on the development of the enteric nervous system (ENS) in mice. We found that preconception maternal exposure to antibiotics led to the abnormal development of the ENS in offspring, increasing their susceptibility to water avoidance stress at the adult stage. Metagenomic, targeted metabolomic, and transcriptomic analyses revealed that preconception antibiotic exposure disrupted the expression of genes crucial for embryonic ENS development by altering maternal gut microbiota composition. Multi-omics analysis combined with Limosilactobacillus reuteri and propionate gestational supplementation demonstrated that the maternal gut microbiota and metabolites may influence embryonic ENS development via the GPR41–GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota before conception to support normal ENS development in offspring. Graphical Preconception administration of antibiotics to female mice reduces the abundance of Limosilactobacillus reuteri in the maternal gut microbiota during pregnancy, subsequently affecting propionate levels. Decreased propionate levels downregulated the expression of Gdnf / Ret / Sox10 mediated by GPR41, leading to abnormal development of the enteric nervous system during the embryonic period. This dysplasia results in colonic dysmotility, impaired colonic epithelium, and increased susceptibility to water-avoidance stress in offspring. Highlights Preconception maternal antibiotic exposure results in the abnormal development of the enteric nervous system (ENS) and intestinal mucosa in mouse offspring, thereby increasing their susceptibility to water avoidance stress in adulthood. Preconception maternal antibiotic exposure alters the composition of the maternal gut microbiota, leading to abnormal embryonic ENS development via the modulation of gene expression. Multi-omics analysis and supplementation with Limosilactobacillus reuteri and propionate during pregnancy indicate that the maternal gut microbiota and metabolites affect embryonic ENS development through the GPR41–GDNF/RET/SOX10 signaling pathway.
研究领域:
微生物学
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发育生物学
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神经科学
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胃肠病学
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DOI
PubMed
高影响因子
KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY
·
2024
·
IF 1.6
Yan Sun,Hai Qu,Xiaohong Niu,Ting Li,Lijuan Wang,Hairui Peng
Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and dyslipidemia. Carvacrol (CAR) has demonstrated the potential to mitigate dyslipidemia. This study aims to investigate whether CAR can modulate blood glucose and lipid levels in a T2DM rat model by regulating short-chain fatty acids (SCFAs) and the GPR41/43 pathway. The T2DM rat model was induced by a high-fat diet combined with low-dose streptozocin injection and treated with oral CAR and/or mixed antibiotics. Fasting blood glucose, oral glucose tolerance, and insulin tolerance tests were assessed. Serum lipid parameters, hepatic and renal function indicators, tissue morphology, and SCFAs were measured. In vitro , high glucose (HG)-induced IEC-6 cells were treated with CAR, and optimal CAR concentration was determined. HG-induced IEC-6 cells were treated with SCFAs or/and GPR41/43 agonists. CAR significantly reduced blood lipid and glucose levels, improved tissue damage, and increased SCFA levels in feces and GPR41/43 expression in colonic tissues of T2DM rats. CAR also attenuated HG-induced apoptosis of IEC-6 cells and enhanced GPR41/43 expression. Overall, these findings suggest that CAR alleviates blood lipid and glucose abnormalities in T2DM rats by modulating SCFAs and the GPR41/43 pathway.
研究领域:
药理学
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内分泌学
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糖尿病研究
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代谢
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胃肠生理学
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细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Yang Huan-xin,Wang Bing-xin,Dong Xiao-liang,Sun Jia,Miao Zeng-li,Pan Li-long
Aortic dissection (AD) is a life-threatening condition with high morbidity. Its underlying pathogenesis remains poorly understood, yielding limited therapeutic options. In this study, we investigated the role of gut microbiota and its metabolite, butyrate, in AD development. Experimental AD was established in 3-week-old mice by administering of β-aminopropionitrile monofumarate (BAPN, 1 g·kg -1 ·d -1 ) in drinking water for 4 weeks. Microbiota composition analysis was conducted on fecal samples from of the mice. AD mice exhibited significant alterations in gut microbiota composition in particular a decrease in butyrate-producing bacteria, accompanied by markedly reduced serum and fecal butyrate levels. Supplementation with exogenous butyrate (200 mg·kg -1 ·d -1 , i.g., for 4 weeks) significantly attenuated the progression of AD by enhancing the expression of vascular smooth muscle cell (SMC) contractile markers. Moreover, butyrate alleviated AD-associated SMC phenotypic switching by suppressing NADPH oxidase 4 expression, thereby reducing reactive oxygen species production. Notably, the protective effects of butyrate were abolished in G-protein-coupled receptor 41 (GPR41) knockout mice, but not in GPR109A knockout mice, highlighting the critical role of GPR41 in mediating its therapeutic effects. These results provide new insights into the pathogenesis of AD and suggest that targeting gut microbiota and its metabolites, such as butyrate, may offer a promising strategy.
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高影响因子
npj Science of Food
·
2026
·
IF 9.7
Zhang Yuyu,Wang Da,Wang Chuhan,Li Yiju,Pang Jingxi,Liu Xuebo,Liu Zhigang,Yuan Tian
Diabetic kidney disease (DKD) is a major diabetes complication lacking effective dietary therapies. While amino-acid-targeted diets modulate metabolic health, their impact on renal outcomes via gut microbiota-derived metabolites remains unclear. Here, we investigated whether a 13-week methionine-restricted (MR) diet improves renal outcomes in db/db mice and alters gut-derived short-chain fatty acids (SCFAs) and their receptors. MR improved renal function and histopathology, restored colonic barrier markers (Claudin-1, ZO-1, MUC2), and reduced circulating endotoxin (LPS). 16S rRNA profiling revealed MR-induced gut microbiota remodeling, enriching SCFA-producing taxa like Clostridium spp. This coincided with increased fecal propionate and restored colonic propionate receptor GPR41 expression. Furthermore, fecal propionate and its associated taxa correlated positively with barrier integrity and negatively with systemic LPS, renal TLR4/JNK activation, inflammation, and oxidative stress. Collectively, MR confers renoprotection in db/db mice by modulating the gut–kidney axis via microbiota remodeling and enhanced propionate-GPR41 signaling, highlighting MR as a promising nutritional strategy for DKD management. The alternative text for this image may have been generated using AI.
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
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IF 5.4
Xinglishang He,Wanfeng Xu,Linzi Li,Xiaofeng Jiang,Yingjie Dong,Kun Liu,Xiaojie Feng,Jie Su,Bo Li,Guiyuan Lv,Suhong Chen
Ethnopharmacological relevance Polygonatum Rhizoma Ginseng Formula (HJRS) is a traditional Chinese medicine preparation commonly used to enhance immunity. Traditionally, it is believed to “moisten dryness and nourish yin, tonify the spleen, and benefit qi.” However, a systematic evaluation of its efficacy and mechanism of action is still lacking. Aim of the study To explore the pharmacodynamic effects and underlying mechanisms of HJRS in cyclophosphamide (CTX)-induced immunocompromised model mice. Method To explore the immunomodulatory effects of HJRS, we used cyberpharmacology combined with in vivo experiments. An immunocompromised mouse model was established using CTX, and different doses of HJRS were administered by gavage during the modeling period. The efficacy of HJRS was evaluated by assessing immune-related parameters, including body weight, heat pain threshold, and behavioral activity. Biochemical markers (acid phosphatase, total nitric oxide synthase, and lactate dehydrogenase), immune function indicators (C3, C4, secretory immunoglobulin A [sIgA]), and immune organ indices (spleen and thymus coefficients) were measured. Additionally, intestinal mucosal immunity (Peyer’s patches, sIgA, and IgM), cellular immunity (delayed-type hypersensitivity [DTH]), and humoral immunity (serum hemolysin, hemolysin, and IgM) were analyzed in the model mice. To further investigate the underlying mechanisms, we used 16S RNA sequencing, western blotting, gas chromatography-mass spectrometry, and other techniques to examine the intestinal microbiota, the short-chain fatty acids–G protein-coupled receptor 41 (SCFAs-GPR41) pathway, and the downstream mitogen-activated protein kinase (MAPK) signaling pathway. Result Network pharmacology analysis identified 34 active compounds and predicted 154 potential targets in HJRS that may regulate immune function by interacting with multiple targets (tumor-necrosis factor [TNF], PIK3CG, JUN, AKT1, and MAPK) and immune-related signaling pathways (MAPK and TNF-signaling pathway). Experimental validation demonstrated that HJRS alleviated symptoms of weakness and reduced behavioral activity in the model mice. It significantly enhanced the DTH response, elevated serum hemolysin levels, and restored the balance of white blood cells, lymphocytes, red blood cells, and hemoglobin percentages. HJRS also rebalanced the serum CD3 + CD4 + /CD3 + CD8 + ratio and increased C3 and C4 levels. Furthermore, it improved immune organ function by raising the thymus and spleen coefficients and increasing serum IgA, IgA, and IgM levels. Histopathological examination revealed that HJRS ameliorated CTX-induced pathological damage in the thymus, spleen, and intestines. HJRS regulated gut microbiota composition by enhancing the richness of Bacteroidetes and increasing the Firmicutes/Bacteroidetes ratio, while reducing the abundance of Firmicutes . It decreased the relative abundance of harmful genera, such as Bacteroides and Enterorhabdus , and promoted the growth of beneficial genera, including Muribaculaceae , Clostridia , and Alloprevotella . Additionally, HJRS increased the fecal acetic acid, propionic acid, hexanoic acid, and total SCFA levels in the model mice. It activated the SCFAs-GPR41 pathway and downstream MAPK signaling, thereby enhancing intestinal mucosal immune function. Conclusion HJRS effectively improved immune function in CTX-induced immunocompromised mice. Its mechanism of action may be associated with the regulation of intestinal microbiota dysbiosis, activation of the intestinal “SCFA-GPR41” pathway, and modulation of the downstream MAPK signaling pathway.
研究领域:
民族药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
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IF 8.2
Zhengqi Zha,Xiaoning Wang,Guoqing Wang,Hongping Yin,Hang Wang
Acetic acid has been shown to be effective in chronic kidney disease (CKD). However, it is a low-molecular-weight compound that allows it to be absorbed in the upper digestive tract so that it cannot function in colon. To overcome these deficiencies, an acetate-releasing xylan derivative, xylan acetate ester (XylA), was synthesized and selected in this study for its potential in the treatment of CKD. IR, NMR and HPGPC were used to characterize the structure of XylA and its antinephritic effects was evaluated in vivo. The results showed that acetate was successfully grafted onto the C-2 and C-3 positions of xylan and with a molecular weight at 69157 Da. XylA treatments could relieve the symptoms of CKD in an adenine-induced chronic renal failure (CRF) model and an adriamycin-induced focal segmental glomerulosclerosis (FSGS) model in SD rats. Further study indicated that XylA could upregulate the short-chain fatty acids (SCFAs) in vitro and vivo . Nevertheless, the relative abundance of Phascolarctobacterium in colon was increased after XylA treatment. XylA could upregulate G-protein-coupled receptor 41 (GPR41) expression, inhibit glomerular cell apoptosis and promoting proliferation. Our study expands the application of xylan and provides a new idea for the treatment of CKD with acetic acid.
研究领域:
药学
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肾脏生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·
IF 7.5
Xiaoying Ma,Weibo Shi,Zhen Wang,Shujin Li,Rufei Ma,Weihao Zhu,Lin Wu,Xiaowei Feng,Bin Cong,Yingmin Li
Background Depression is closely associated with stress-induced hippocampal damage and dysfunction. Emerging evidence demonstrates that the gut microbiota and its metabolites, acting as probiotics or prebiotics, can modulate brain structure and function via the gut-brain axis, thereby offering therapeutic potential for ameliorating related neurological and psychiatric disorders. This study delves into the contribution of the gut microbiota and its metabolites to stress-induced ferroptosis of hippocampal neurons and the associated molecular pathways. Methods This study used time-course stress paradigms combined with ferroptosis inhibitors to identify hippocampal neuronal ferroptosis. Fecal microbiota transplantation were conducted to analyze the role of gut microbiota in this process. Subsequently, 16 S rDNA sequencing and metabolomics techniques were applied to identify key gut microbiota and metabolites. Metabolites intervention were performed to examine their causal relationship with neuronal ferroptosis. Finally, we used histochemical and molecular assays to assess both intestinal and blood-brain barrier integrity as well as inflammation in peripheral blood and hippocampal tissue, along with GPR41/RhoA/Rock1 pathway changes, to preliminarily investigate the molecular mechanisms underlying stress-induced hippocampal neuronal ferroptosis. Results We demonstrated that stress triggered hippocampal neuronal ferroptosis and subsequent depressive-like behaviors in mice. Fecal microbiota transplantation successfully replicated the ferroptosis phenotype. Butyric acid and valeric acid were identified as key metabolites significantly reduced in the serum of acutely and chronically stressed mice, respectively. Intervention with these metabolites markedly alleviated ferroptosis. Furthermore, valerate intervention increased hippocampal GPR41 expression and significantly suppressed the pro-inflammatory RhoA/Rock1 pathway in chronically stressed mice, thereby reducing neuroinflammation and ameliorating neuronal ferroptosis. However, butyrate intervention showed no significant effect on the GPR41/RhoA/Rock1 pathway. Conclusion Stress induces ferroptosis in hippocampal neurons, where reduced abundance of short-chain fatty acid-producing bacteria plays a key role. Key metabolites butyric acid and valeric acid alleviate neuroinflammation to improve ferroptosis via the gut-brain axis in acute and chronic stress, respectively. Specifically, valeric acid exerts neuroprotective effect through the GPR41/RhoA/Rock1 pathway, whereas butyric acid-mediated protection likely operates through alternative mechanisms. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-06950-0.
研究领域:
神经科学
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精神病学
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微生物学
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代谢组学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2023
·Vol. 18
·期 4
·e0283105
·
IF 3.7
Guifang Yuan,Song Wen,Xuemei Zhong,Xiaotong Yang,Linrui Xie,Xiuli Wu,Xiaoyu Li
Technically, symptom of offspring asthma is also closely reliant on its maternal high-fiber diet as well as the intestinal microbiome. Fruits and vegetables are abundant in inulin, and this naturally soluble dietary fiber is endowed with a potential value on offspring asthma control through the maternal intake, but the mechanism now remains less studied. In this study, rats were given with inulin-included drinking water, whereas in normal group rats were allowed with normal water. Afterwards, we analyzed both the formations of the offspring intestinal microbiome ahead of asthma model establishment and of the maternal intestinal microbiome through high throughput sequence and the short-chain fatty acids (SCFAs) by metabolomic analysis. Subsequently, lung inflammation indexes were detected by Elisa, and the expression of short-chain fatty acid receptors (GPR41, GPR43) in the offspring of asthma models were evaluated through qPCR assay. Inulin intake resulted in altered maternal intestinal microbiome composition, with a significant increase in SCFAs-producing bacteria (mainly Bifidobacterium ), attenuating the asthmatic inflammatory response in the offspring. Meanwhile, inulin intake during pregnancy modulates the composition of the intestinal microbiome of the offspring, and this alteration appears before the onset of asthma, hence, there should be further studies onto the impacts of offspring’s intestinal microbiome on asthma procession.
研究领域:
免疫学
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微生物学
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营养学
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药理学
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产品关联
DOI
PubMed
高影响因子
EBioMedicine
·
2024
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IF 9.7
Harry Cheuk-Hay Lau,Xiang Zhang,Fenfen Ji,Yufeng Lin,Wei Liang,Qing Li,Danyu Chen,Winnie Fong,Xing Kang,Weixin Liu,Eagle Siu-Hong Chu,Queena Wing-Yin Ng,Jun Yu
Abstract
Background: Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC.
Methods: NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids.
Findings: L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC.
Interpretation: L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC.
研究领域:
微生物学
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肝病学
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癌症生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
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2023
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IF 5.2
Huan-Huan Chen,Qi-Jun Wu,Tie-Ning Zhang,Yu-Hong Zhao
Background The association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown. Methods Fecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins. Results Non-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae , and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases. Conclusion We revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.
研究领域:
肿瘤学
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微生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CURRENT MICROBIOLOGY
·
2025
·Vol. 82
·期 9
·1-18
·
IF 2.6
Xu Wenyi,Guan Yinghua,Tian Liping,Fu Yu,Zhang Yinghui,Liu Yanhong,Hu Yanfei,Zhao Bowen,Wu Chongming
The global prevalence of type 2 diabetes mellitus (T2DM) is currently surging, posing significant health and socioeconomic burdens. Probiotics have emerged as promising interventions due to their safety and potential metabolic benefits. Gut microbiota plays a critical role in the pathophysiology of metabolic diseases in humans, offering valuable insights for therapeutic strategies such as probiotics. Here, aiming to identify novel probiotics from the human gut microbes to combat T2DM, a total of 203 human intestinal bacterial strains were screened in vitro to evaluate their enzymatic inhibition of α-glucosidase and α-amylase, in which Lacticaseibacillus paracasei Glu-07 (= QH-142 = CGMCC 23796) exhibited the highest inhibitory efficacy (81.05% and 72.56% for α-glucosidase and α-amylase, respectively). In HepG2 cells, L. paracasei Glu-07 elevated glucose uptake and consumption by 22.4% and 85.8%. Oral administration of strain Glu-07 in diabetic mice significantly improved hyperglycemia, hyperlipidemia, and restored the structure and composition of gut microbiota toward a healthier profile. Mechanistically, strain Glu-07 activated the AMPK-AKT1-GSK3β/FOXO1 signaling pathways by modulating the expression of key genes, enhanced glycolysis and fatty acid ꞵ-oxidation, and inhibited gluconeogenesis and lipogenesis. It also stimulated GLP-1 secretion, potentially via triggering the GPR41/43-GLP-1 axis, and increased the abundance of beneficial gut microbes, such as Akkermansia muciniphila (~ threefold). The dual regulations synergistically support strain Glu-07 as a promising probiotic candidate for T2DM management.
研究领域:
微生物学
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糖尿病研究
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分子生物学
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药理学
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营养科学
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代谢性疾病
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
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