Pub Date : 2024-01-01Epub Date: 2024-05-08DOI: 10.1080/19490976.2024.2338947
Jiaqi Wang, Xiufeng Zhao, Xianhe Li, Xuemin Jin
The gut microbiota has coevolved with the host for hundreds of millions of years, playing a beneficial role in host health. Human parasitic helminths are widespread and pose a pervasive global public health issue. Although Type 2 immunity provides partial resistance to helminth infections, the composition of the gut microbiota can change correspondingly. Therefore, it raises the question of what role the gut microbiota plays during helminth infection. Akkermansia muciniphila has emerged as a notable representative of beneficial microorganisms in the gut microbiota. Recent studies indicate that A. muciniphila is not merely associated with helminth infection but is also causally linked to infection. Here, we provide an overview of the crosstalk between A. muciniphila and enteric helminth infection. Our goal is to enhance our understanding of the interplay among A. muciniphila, helminths, and their hosts while also exploring the potential underlying mechanisms.
{"title":"<i>Akkermansia muciniphila</i>: a deworming partner independent of type 2 immunity.","authors":"Jiaqi Wang, Xiufeng Zhao, Xianhe Li, Xuemin Jin","doi":"10.1080/19490976.2024.2338947","DOIUrl":"10.1080/19490976.2024.2338947","url":null,"abstract":"<p><p>The gut microbiota has coevolved with the host for hundreds of millions of years, playing a beneficial role in host health. Human parasitic helminths are widespread and pose a pervasive global public health issue. Although Type 2 immunity provides partial resistance to helminth infections, the composition of the gut microbiota can change correspondingly. Therefore, it raises the question of what role the gut microbiota plays during helminth infection. <i>Akkermansia muciniphila</i> has emerged as a notable representative of beneficial microorganisms in the gut microbiota. Recent studies indicate that <i>A. muciniphila</i> is not merely associated with helminth infection but is also causally linked to infection. Here, we provide an overview of the crosstalk between <i>A. muciniphila</i> and enteric helminth infection. Our goal is to enhance our understanding of the interplay among <i>A. muciniphila</i>, helminths, and their hosts while also exploring the potential underlying mechanisms.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.
{"title":"<i>Prevotella copri</i> promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.","authors":"Qing-Yun Hao, Jing Yan, Jin-Tao Wei, Yu-Hong Zeng, Li-Yun Feng, Dong-Dong Que, Shi-Chao Li, Jing-Bin Guo, Ying Fan, Yun-Fa Ding, Xiu-Li Zhang, Ping-Zhen Yang, Jing-Wei Gao, Ze-Hua Li","doi":"10.1080/19490976.2024.2351532","DOIUrl":"10.1080/19490976.2024.2351532","url":null,"abstract":"<p><p>Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of <i>Prevotella copri</i> (<i>P. copri</i>) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of <i>P. copri</i> and aortic calcification scores. Moreover, oral administration of live <i>P. copri</i> aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells <i>in vivo</i>, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. <i>In vitro</i> and <i>ex vivo</i> experiments consistently demonstrated that <i>P. copri</i>-derived LPS (<i>Pc</i>-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, <i>Pc</i>-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated <i>Pc</i>-LPS-induced VSMC calcification. Our study clarifies a novel role of <i>P. copri</i> in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including <i>Pc</i>-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight <i>P. copri</i> and its-derived LPS as potential therapeutic targets for VC in CKD.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
High-fat diets alter gut barrier integrity, leading to endotoxemia by impacting epithelial functions and inducing endoplasmic reticulum (ER) stress in intestinal secretory goblet cells. Indeed, ER stress, which is an important contributor to many chronic diseases such as obesity and obesity-related disorders, leads to altered synthesis and secretion of mucins that form the protective mucus barrier. In the present study, we investigated the relative contribution of omega-3 polyunsaturated fatty acid (PUFAs)-modified microbiota to alleviating alterations in intestinal mucus layer thickness and preserving gut barrier integrity. Male fat-1 transgenic mice (exhibiting endogenous omega-3 PUFAs tissue enrichment) and wild-type (WT) littermates were fed either an obesogenic high-fat diet (HFD) or a control diet. Unlike WT mice, HFD-fed fat-1 mice were protected against mucus layer alterations as well as an ER stress-mediated decrease in mucin expression. Moreover, cecal microbiota transferred from fat-1 to WT mice prevented changes in the colonic mucus layer mainly through colonic ER stress downregulation. These findings highlight a novel feature of the preventive effects of omega-3 fatty acids against intestinal permeability in obesity-related conditions.
{"title":"The transplantation of the gut microbiome of fat-1 mice protects against colonic mucus layer disruption and endoplasmic reticulum stress induced by high fat diet.","authors":"Amina Bourragat, Quentin Escoula, Sandrine Bellenger, Olivier Zemb, Martin Beaumont, Killian Chaumonnot, Jean-Pierre Farine, Emmanuel Jacotot, Aline Bonnotte, Laure Avoscan, Jeanine Lherminier, Kangjia Luo, Michel Narce, Jérôme Bellenger","doi":"10.1080/19490976.2024.2356270","DOIUrl":"10.1080/19490976.2024.2356270","url":null,"abstract":"<p><p>High-fat diets alter gut barrier integrity, leading to endotoxemia by impacting epithelial functions and inducing endoplasmic reticulum (ER) stress in intestinal secretory goblet cells. Indeed, ER stress, which is an important contributor to many chronic diseases such as obesity and obesity-related disorders, leads to altered synthesis and secretion of mucins that form the protective mucus barrier. In the present study, we investigated the relative contribution of omega-3 polyunsaturated fatty acid (PUFAs)-modified microbiota to alleviating alterations in intestinal mucus layer thickness and preserving gut barrier integrity. Male fat-1 transgenic mice (exhibiting endogenous omega-3 PUFAs tissue enrichment) and wild-type (WT) littermates were fed either an obesogenic high-fat diet (HFD) or a control diet. Unlike WT mice, HFD-fed fat-1 mice were protected against mucus layer alterations as well as an ER stress-mediated decrease in mucin expression. Moreover, cecal microbiota transferred from fat-1 to WT mice prevented changes in the colonic mucus layer mainly through colonic ER stress downregulation. These findings highlight a novel feature of the preventive effects of omega-3 fatty acids against intestinal permeability in obesity-related conditions.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-06-11DOI: 10.1080/19490976.2024.2363021
Edward C Deehan, Zhengxiao Zhang, Nguyen K Nguyen, Maria Elisa Perez-Muñoz, Janis Cole, Alessandra Riva, David Berry, Carla M Prado, Jens Walter
Dietary fiber supplements are a strategy to close the 'fiber gap' and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; n = 15) relative to non-fermentable microcrystalline cellulose (MCC; n = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (p < 0.05, Mann-Whitney tests), but subjects 'adapted' with symptoms reverting to baseline levels toward the end of treatment. Symptom adaptations were individualized and correlated with the relative abundance of Bifidobacterium longum at baseline (rs = 0.74, p = 0.002), within the bacterial community that utilized AX (rs = 0.69, p = 0.006), and AX-induced shifts in acetate (rs = 0.54, p = 0.039). Lower baseline consumption of animal-based foods and higher whole grains associated with less severity and better adaptation. These findings suggest that humans do 'adapt' to tolerate efficacious fiber doses, and this process is linked to their microbiome and dietary factors known to interact with gut microbes, providing a basis for the development of strategies for improved tolerance of dietary fibers.
{"title":"Adaptation to tolerate high doses of arabinoxylan is associated with fecal levels of <i>Bifidobacterium longum</i>.","authors":"Edward C Deehan, Zhengxiao Zhang, Nguyen K Nguyen, Maria Elisa Perez-Muñoz, Janis Cole, Alessandra Riva, David Berry, Carla M Prado, Jens Walter","doi":"10.1080/19490976.2024.2363021","DOIUrl":"10.1080/19490976.2024.2363021","url":null,"abstract":"<p><p>Dietary fiber supplements are a strategy to close the 'fiber gap' and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; <i>n</i> = 15) relative to non-fermentable microcrystalline cellulose (MCC; <i>n</i> = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (<i>p</i> < 0.05, Mann-Whitney tests), but subjects 'adapted' with symptoms reverting to baseline levels toward the end of treatment. Symptom adaptations were individualized and correlated with the relative abundance of <i>Bifidobacterium longum</i> at baseline (r<sub>s</sub> = 0.74, <i>p</i> = 0.002), within the bacterial community that utilized AX (r<sub>s</sub> = 0.69, <i>p</i> = 0.006), and AX-induced shifts in acetate (r<sub>s</sub> = 0.54, <i>p</i> = 0.039). Lower baseline consumption of animal-based foods and higher whole grains associated with less severity and better adaptation. These findings suggest that humans do 'adapt' to tolerate efficacious fiber doses, and this process is linked to their microbiome and dietary factors known to interact with gut microbes, providing a basis for the development of strategies for improved tolerance of dietary fibers.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11174067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-06-11DOI: 10.1080/19490976.2024.2363012
Pyoung Hwa Park, Kelsey Keith, Gennaro Calendo, Jaroslav Jelinek, Jozef Madzo, Raad Z Gharaibeh, Jayashri Ghosh, Carmen Sapienza, Christian Jobin, Jean-Pierre J Issa
The intestinal microbiota is an important environmental factor implicated in CRC development. Intriguingly, modulation of DNA methylation by gut microbiota has been reported in preclinical models, although the relationship between tumor-infiltrating bacteria and CIMP status is currently unexplored. In this study, we investigated tumor-associated bacteria in 203 CRC tumor cases and validated the findings using The Cancer Genome Atlas datasets. We assessed the abundance of Bacteroides fragilis, Escherichia coli, Fusobacterium nucleatum, and Klebsiella pneumoniae through qPCR analysis and observed enrichment of all four bacterial species in CRC samples. Notably, except for E. coli, all exhibited significant enrichment in cases of CIMP. This enrichment was primarily driven by a subset of cases distinguished by high levels of these bacteria, which we labeled as "Superhigh". The bacterial Superhigh status showed a significant association with CIMP (odds ratio 3.1, p-value = 0.013) and with MLH1 methylation (odds ratio 4.2, p-value = 0.0025). In TCGA CRC cases (393 tumor and 45 adj. normal), bacterial taxa information was extracted from non-human whole exome sequencing reads, and the bacterial Superhigh status was similarly associated with CIMP (odds ratio 2.9, p < 0.001) and MLH1 methylation (odds ratio 3.5, p < 0.001). Finally, 16S ribosomal RNA gene sequencing revealed high enrichment of Bergeyella spp. C. concisus, and F. canifelinum in CIMP-Positive tumor cases. Our findings highlight that specific bacterial taxa may influence DNA methylation, particularly in CpG islands, and contribute to the development and progression of CIMP in colorectal cancer.
{"title":"Association between gut microbiota and CpG island methylator phenotype in colorectal cancer.","authors":"Pyoung Hwa Park, Kelsey Keith, Gennaro Calendo, Jaroslav Jelinek, Jozef Madzo, Raad Z Gharaibeh, Jayashri Ghosh, Carmen Sapienza, Christian Jobin, Jean-Pierre J Issa","doi":"10.1080/19490976.2024.2363012","DOIUrl":"10.1080/19490976.2024.2363012","url":null,"abstract":"<p><p>The intestinal microbiota is an important environmental factor implicated in CRC development. Intriguingly, modulation of DNA methylation by gut microbiota has been reported in preclinical models, although the relationship between tumor-infiltrating bacteria and CIMP status is currently unexplored. In this study, we investigated tumor-associated bacteria in 203 CRC tumor cases and validated the findings using The Cancer Genome Atlas datasets. We assessed the abundance of <i>Bacteroides fragilis</i>, <i>Escherichia coli</i>, <i>Fusobacterium nucleatum</i>, and <i>Klebsiella pneumoniae</i> through qPCR analysis and observed enrichment of all four bacterial species in CRC samples. Notably, except for <i>E. coli</i>, all exhibited significant enrichment in cases of CIMP. This enrichment was primarily driven by a subset of cases distinguished by high levels of these bacteria, which we labeled as \"Superhigh\". The bacterial Superhigh status showed a significant association with CIMP (odds ratio 3.1, p-value = 0.013) and with <i>MLH1</i> methylation (odds ratio 4.2, p-value = 0.0025). In TCGA CRC cases (393 tumor and 45 adj. normal), bacterial taxa information was extracted from non-human whole exome sequencing reads, and the bacterial Superhigh status was similarly associated with CIMP (odds ratio 2.9, <i>p</i> < 0.001) and <i>MLH1</i> methylation (odds ratio 3.5, <i>p</i> < 0.001). Finally, 16S ribosomal RNA gene sequencing revealed high enrichment of <i>Bergeyella spp</i>. <i>C. concisus</i>, and <i>F. canifelinum</i> in CIMP-Positive tumor cases. Our findings highlight that specific bacterial taxa may influence DNA methylation, particularly in CpG islands, and contribute to the development and progression of CIMP in colorectal cancer.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11174071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-06-11DOI: 10.1080/19490976.2024.2363880
Yongguo Zhang, Yinglin Xia, Jun Sun
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.
肌萎缩性脊髓侧索硬化症(ALS)是一种神经肌肉疾病。表达人突变型转录反应 DNA 结合蛋白 43 kDa(hmTDP43)的 ALS 小鼠在出现神经肌肉症状之前就表现出肠道功能障碍。我们推测,用细菌代谢物或益生菌恢复肠道和微生物的平衡可延缓 ALS 发病。我们研究了 ALS 进展过程中肠道和神经元、肠道和血脑屏障以及炎症的病理生理变化。然后,我们培养了从 TDP43 小鼠体内分离出来的肠胶质细胞(EGCs),进行机理研究。与年龄匹配的野生型小鼠相比,TDP43 小鼠的肠道流动性明显降低,渗透性增加,肌肉变弱。我们在 TDP43 小鼠的结肠、脊髓和大脑中观察到 hmTDP43 和神经胶质纤维酸性蛋白(GFAP)增加,α-平滑肌肌动蛋白(α-SMA)、紧密连接蛋白(ZO-1 和 Claudin-5)表达减少。与 WT 小鼠相比,TDP43 小鼠的丁酰辅酶 A CoA 转移酶减少,丁酸菌 Butyrivibrio fibrisolvens 减少,脆弱拟杆菌 Bacteroides 增加。TDP43小鼠的血清炎症细胞因子(IL-6、IL-17和IFN-γ)和LPS升高。TDP43小鼠的EGCs显示出hmTDP43的聚集,并伴有GFAP和电离钙结合适配分子(IBA1,一种小胶质细胞标记物)的增加。与未治疗组相比,接受丁酸盐或益生菌 VSL#3 治疗的 TDP43 小鼠的转体时间明显增加,肠道流动性增加,渗透性降低。丁酸盐或益生菌治疗可减少结肠、脊髓和大脑中 GFAP 和 TDP43 的表达,增加 α-SMA、ZO-1 和 Claudin-5 的表达。此外,丁酸盐或益生菌处理还能增强丁酰辅酶 A CoA 转移酶、丁酸纤维梭菌,并减少 TDP43 小鼠体内的炎性细胞因子。用丁酸盐或益生菌处理的 TDP43 EGCs 显示出 GFAP、IBA1 和 TDP43 聚集减少。通过有益菌和代谢产物恢复肠道和微生物的平衡为治疗渐冻人症提供了一种潜在的治疗策略。
{"title":"Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.","authors":"Yongguo Zhang, Yinglin Xia, Jun Sun","doi":"10.1080/19490976.2024.2363880","DOIUrl":"10.1080/19490976.2024.2363880","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria <i>Butyrivibrio fibrisolvens</i>, and increased <i>Bacteroides fragilis</i>, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, <i>Butyrivibrio fibrisolvens</i>, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11174066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-08-27DOI: 10.1080/19490976.2024.2392877
Kaitlyn Grando, Shingo Bessho, Kayla Harrell, Kathrine Kyrylchuk, Alejandro M Pantoja, Sophia Olubajo, Francisco J Albicoro, Andres Klein-Szanto, Çagla Tükel
Salmonella enterica serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA; activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1α branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. In vivo, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA.
{"title":"Bacterial amyloid curli activates the host unfolded protein response via IRE1α in the presence of HLA-B27.","authors":"Kaitlyn Grando, Shingo Bessho, Kayla Harrell, Kathrine Kyrylchuk, Alejandro M Pantoja, Sophia Olubajo, Francisco J Albicoro, Andres Klein-Szanto, Çagla Tükel","doi":"10.1080/19490976.2024.2392877","DOIUrl":"10.1080/19490976.2024.2392877","url":null,"abstract":"<p><p><i>Salmonella enterica</i> serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA; activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1α branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. <i>In vivo</i>, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic diarrhea has a considerable impact on quality of life. This randomized, double-blind, placebo-controlled crossover intervention trial was conducted with 69 participants (36 in Group A, 33 in Group B), aiming to investigate the potential of postbiotics in alleviating diarrhea-associated symptoms. Participants received postbiotic Probio-Eco® and placebo for 21 days each in alternating order, with a 14-day washout period between interventions. The results showed that postbiotic intake resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety. Moreover, the postbiotic intervention increased beneficial intestinal bacteria, including Dysosmobacter welbionis and Faecalibacterium prausnitzii, while reducing potential pathogens like Megamonas funiformis. The levels of gut Microviridae notably increased. Non-targeted metabolomics analysis revealed postbiotic-driven enrichment of beneficial metabolites, including α-linolenic acid and p-methoxycinnamic acid, and reduction of diarrhea-associated metabolites, including theophylline, piperine, capsaicin, and phenylalanine. Targeted metabolomics confirmed a significant increase in fecal butyric acid after postbiotic intervention. The levels of aromatic amino acids, phenylalanine and tryptophan, and their related metabolites, 5-hydroxytryptophan and kynurenine, decreased after the postbiotic intervention, suggesting diarrhea alleviation was through modulating the tryptophan-5-hydroxytryptamine and tryptophan-kynurenine pathways. Additionally, chenodeoxycholic acid, a diarrhea-linked primary bile acid, decreased substantially. In conclusion, postbiotics have shown promise in relieving chronic diarrhea.
{"title":"Effects of postbiotics on chronic diarrhea in young adults: a randomized, double-blind, placebo-controlled crossover trial assessing clinical symptoms, gut microbiota, and metabolite profiles.","authors":"Shuai Guo, Teng Ma, Lai-Yu Kwok, Keyu Quan, Bohai Li, Huan Wang, Heping Zhang, Bilige Menghe, Yongfu Chen","doi":"10.1080/19490976.2024.2395092","DOIUrl":"10.1080/19490976.2024.2395092","url":null,"abstract":"<p><p>Chronic diarrhea has a considerable impact on quality of life. This randomized, double-blind, placebo-controlled crossover intervention trial was conducted with 69 participants (36 in Group A, 33 in Group B), aiming to investigate the potential of postbiotics in alleviating diarrhea-associated symptoms. Participants received postbiotic Probio-Eco® and placebo for 21 days each in alternating order, with a 14-day washout period between interventions. The results showed that postbiotic intake resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety. Moreover, the postbiotic intervention increased beneficial intestinal bacteria, including <i>Dysosmobacter welbionis</i> and <i>Faecalibacterium prausnitzii</i>, while reducing potential pathogens like <i>Megamonas funiformis</i>. The levels of gut <i>Microviridae</i> notably increased. Non-targeted metabolomics analysis revealed postbiotic-driven enrichment of beneficial metabolites, including α-linolenic acid and p-methoxycinnamic acid, and reduction of diarrhea-associated metabolites, including theophylline, piperine, capsaicin, and phenylalanine. Targeted metabolomics confirmed a significant increase in fecal butyric acid after postbiotic intervention. The levels of aromatic amino acids, phenylalanine and tryptophan, and their related metabolites, 5-hydroxytryptophan and kynurenine, decreased after the postbiotic intervention, suggesting diarrhea alleviation was through modulating the tryptophan-5-hydroxytryptamine and tryptophan-kynurenine pathways. Additionally, chenodeoxycholic acid, a diarrhea-linked primary bile acid, decreased substantially. In conclusion, postbiotics have shown promise in relieving chronic diarrhea.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-08-21DOI: 10.1080/19490976.2024.2391505
Femke M Prins, Iwan J Hidding, Marjolein A Y Klaassen, Valerie Collij, Johannes P D Schultheiss, Werna T C Uniken Venema, Amber Bangma, Jurne B Aardema, Bernadien H Jansen, Wout G N Mares, Ben J M Witteman, Eleonora A M Festen, Gerard Dijkstra, Marijn C Visschedijk, Herma H Fidder, Arnau Vich Vila, Bas Oldenburg, Ranko Gacesa, Rinse K Weersma
Emerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.
{"title":"Limited predictive value of the gut microbiome and metabolome for response to biological therapy in inflammatory bowel disease.","authors":"Femke M Prins, Iwan J Hidding, Marjolein A Y Klaassen, Valerie Collij, Johannes P D Schultheiss, Werna T C Uniken Venema, Amber Bangma, Jurne B Aardema, Bernadien H Jansen, Wout G N Mares, Ben J M Witteman, Eleonora A M Festen, Gerard Dijkstra, Marijn C Visschedijk, Herma H Fidder, Arnau Vich Vila, Bas Oldenburg, Ranko Gacesa, Rinse K Weersma","doi":"10.1080/19490976.2024.2391505","DOIUrl":"10.1080/19490976.2024.2391505","url":null,"abstract":"<p><p>Emerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phages are the most diversified and dominant members of the gut virobiota. They play a crucial role in shaping the structure and function of the gut microbial community and consequently the health of humans and animals. Phages are found mainly in the mucus, from where they can translocate to the intestinal organs and act as a modulator of gut microbiota. Understanding the vital role of phages in regulating the composition of intestinal microbiota and influencing human and animal health is an emerging area of research. The relevance of phages in the gut ecosystem is supported by substantial evidence, but the importance of phages in shaping the gut microbiota remains unclear. Although information regarding general phage ecology and development has accumulated, detailed knowledge on phage-gut microbe and phage-human interactions is lacking, and the information on the effects of phage therapy in humans remains ambiguous. In this review, we systematically assess the existing data on the structure and ecology of phages in the human and animal gut environments, their development, possible interaction, and subsequent impact on the gut ecosystem dynamics. We discuss the potential mechanisms of prophage activation and the subsequent modulation of gut bacteria. We also review the link between phages and the immune system to collect evidence on the effect of phages on shaping the gut microbial composition. Our review will improve understanding on the influence of phages in regulating the gut microbiota and the immune system and facilitate the development of phage-based therapies for maintaining a healthy and balanced gut microbiota.
{"title":"Role of bacteriophages in shaping gut microbial community.","authors":"Md Rayhan Mahmud, Sanjida Khanam Tamanna, Sharmin Akter, Lincon Mazumder, Sumona Akter, Md Rakibul Hasan, Mrityunjoy Acharjee, Israt Zahan Esti, Md Saidul Islam, Md Maksudur Rahman Shihab, Md Nahian, Rubaiya Gulshan, Sadia Naser, Anna Maria Pirttilä","doi":"10.1080/19490976.2024.2390720","DOIUrl":"10.1080/19490976.2024.2390720","url":null,"abstract":"<p><p>Phages are the most diversified and dominant members of the gut virobiota. They play a crucial role in shaping the structure and function of the gut microbial community and consequently the health of humans and animals. Phages are found mainly in the mucus, from where they can translocate to the intestinal organs and act as a modulator of gut microbiota. Understanding the vital role of phages in regulating the composition of intestinal microbiota and influencing human and animal health is an emerging area of research. The relevance of phages in the gut ecosystem is supported by substantial evidence, but the importance of phages in shaping the gut microbiota remains unclear. Although information regarding general phage ecology and development has accumulated, detailed knowledge on phage-gut microbe and phage-human interactions is lacking, and the information on the effects of phage therapy in humans remains ambiguous. In this review, we systematically assess the existing data on the structure and ecology of phages in the human and animal gut environments, their development, possible interaction, and subsequent impact on the gut ecosystem dynamics. We discuss the potential mechanisms of prophage activation and the subsequent modulation of gut bacteria. We also review the link between phages and the immune system to collect evidence on the effect of phages on shaping the gut microbial composition. Our review will improve understanding on the influence of phages in regulating the gut microbiota and the immune system and facilitate the development of phage-based therapies for maintaining a healthy and balanced gut microbiota.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":null,"pages":null},"PeriodicalIF":12.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}