Pub Date : 2024-09-17DOI: 10.1080/19490976.2024.2402543
Theresa Neuper,Tobias Frauenlob,Hieu-Hoa Dang,Peter W Krenn,Gernot Posselt,Christof Regl,Nikolaus Fortelny,Veronika Schäpertöns,Michael S Unger,Gunda Üblagger,Daniel Neureiter,Iris Mühlbacher,Michael Weitzendorfer,Franz Singhartinger,Klaus Emmanuel,Christian G Huber,Silja Wessler,Fritz Aberger,Jutta Horejs-Hoeck
Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.
复杂的免疫逃避策略使幽门螺杆菌（H. pylori）得以在全球约一半人口的胃黏膜上定植。持续感染和由此引起的慢性炎症是导致胃癌的主要原因。为了了解幽门螺杆菌与宿主免疫之间错综复杂的相互作用，研究人员利用空间图谱监测幽门螺杆菌感染胃组织中的免疫细胞。在胃有机体/免疫细胞共培养物中进一步研究了树突状细胞（DC）和T细胞的表型，并通过人类DC的蛋白质组学研究获得了机制方面的见解。在这里，我们发现 ADP-庚糖--一种最初被报道为真正的 PAMP 的细菌代谢产物--降低了幽门螺杆菌诱导的 DC 成熟和随后的 T 细胞反应。从机理上讲，我们报告了幽门螺杆菌摄取ADP-庚糖缺陷的幽门螺杆菌菌株以及随后的DC活化依赖于TLR2。此外，在幽门螺杆菌感染的情况下，ADP-庚糖会通过影响 I 型 IFN 信号转导来减弱原代人类 DC 的全面激活。这项研究揭示了ADP-庚糖在幽门螺杆菌感染过程中减轻宿主免疫力的作用。
{"title":"ADP-heptose attenuates Helicobacter pylori-induced dendritic cell activation.","authors":"Theresa Neuper,Tobias Frauenlob,Hieu-Hoa Dang,Peter W Krenn,Gernot Posselt,Christof Regl,Nikolaus Fortelny,Veronika Schäpertöns,Michael S Unger,Gunda Üblagger,Daniel Neureiter,Iris Mühlbacher,Michael Weitzendorfer,Franz Singhartinger,Klaus Emmanuel,Christian G Huber,Silja Wessler,Fritz Aberger,Jutta Horejs-Hoeck","doi":"10.1080/19490976.2024.2402543","DOIUrl":"https://doi.org/10.1080/19490976.2024.2402543","url":null,"abstract":"Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"27 1","pages":"2402543"},"PeriodicalIF":12.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1080/19490976.2024.2399360
J Buttar,E Kon,A Lee,G Kaur,G Lunken
The gut microbiome is a complex, unique entity implicated in the prevention, pathogenesis, and progression of common gastrointestinal diseases. While largely dominated by bacterial populations, advanced sequencing techniques have identified co-inhabiting fungal communities, collectively referred to as the mycobiome. Early studies identified that gut inflammation is associated with altered microbial composition, known as gut dysbiosis. Altered microbial profiles are implicated in various pathological diseases, such as inflammatory bowel disease (IBD), though their role as a cause or consequence of systemic inflammation remains the subject of ongoing research. Diet plays a crucial role in the prevention and management of various diseases and is considered to be an essential regulator of systemic inflammation. This review compiles current literature on the impact of dietary modulation on the mycobiome, showing that dietary changes can alter the fungal architecture of the gut. Further research is required to understand the impact of diet on gut fungi, including the metabolic pathways and enzymes involved in fungal fermentation. Additionally, investigating whether dietary modulation of the gut mycobiome could be utilized as a therapy in IBD is essential.
{"title":"Effect of diet on the gut mycobiome and potential implications in inflammatory bowel disease.","authors":"J Buttar,E Kon,A Lee,G Kaur,G Lunken","doi":"10.1080/19490976.2024.2399360","DOIUrl":"https://doi.org/10.1080/19490976.2024.2399360","url":null,"abstract":"The gut microbiome is a complex, unique entity implicated in the prevention, pathogenesis, and progression of common gastrointestinal diseases. While largely dominated by bacterial populations, advanced sequencing techniques have identified co-inhabiting fungal communities, collectively referred to as the mycobiome. Early studies identified that gut inflammation is associated with altered microbial composition, known as gut dysbiosis. Altered microbial profiles are implicated in various pathological diseases, such as inflammatory bowel disease (IBD), though their role as a cause or consequence of systemic inflammation remains the subject of ongoing research. Diet plays a crucial role in the prevention and management of various diseases and is considered to be an essential regulator of systemic inflammation. This review compiles current literature on the impact of dietary modulation on the mycobiome, showing that dietary changes can alter the fungal architecture of the gut. Further research is required to understand the impact of diet on gut fungi, including the metabolic pathways and enzymes involved in fungal fermentation. Additionally, investigating whether dietary modulation of the gut mycobiome could be utilized as a therapy in IBD is essential.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"2 1","pages":"2399360"},"PeriodicalIF":12.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1080/19490976.2024.2402544
Torsten P M Scheithauer,Roy C Montijn,Arnout Mieremet
Post-COVID syndrome (PCS) patients have reported a wide range of symptoms, including fatigue, shortness of breath, and diarrhea. Particularly, the presence of gastrointestinal symptoms has led to the hypothesis that the gut microbiome is involved in the development and severity of PCS. The objective of this review is to provide an overview of the role of the gut microbiome in PCS by describing the microbial composition and microbial metabolites in COVID-19 and PCS. Moreover, host-microbe interactions via the microbiota-gut-brain (MGB) and the microbiota-gut-lung (MGL) axes are described. Furthermore, we explore the potential of therapeutically targeting the gut microbiome to support the recovery of PCS by reviewing preclinical model systems and clinical studies. Overall, current studies provide evidence that the gut microbiota is affected in PCS; however, diversity in symptoms and highly individual microbiota compositions suggest the need for personalized medicine. Gut-targeted therapies, including treatments with pre- and probiotics, have the potential to improve the quality of life of affected individuals.
{"title":"Gut microbe-host interactions in post-COVID syndrome: a debilitating or restorative partnership?","authors":"Torsten P M Scheithauer,Roy C Montijn,Arnout Mieremet","doi":"10.1080/19490976.2024.2402544","DOIUrl":"https://doi.org/10.1080/19490976.2024.2402544","url":null,"abstract":"Post-COVID syndrome (PCS) patients have reported a wide range of symptoms, including fatigue, shortness of breath, and diarrhea. Particularly, the presence of gastrointestinal symptoms has led to the hypothesis that the gut microbiome is involved in the development and severity of PCS. The objective of this review is to provide an overview of the role of the gut microbiome in PCS by describing the microbial composition and microbial metabolites in COVID-19 and PCS. Moreover, host-microbe interactions via the microbiota-gut-brain (MGB) and the microbiota-gut-lung (MGL) axes are described. Furthermore, we explore the potential of therapeutically targeting the gut microbiome to support the recovery of PCS by reviewing preclinical model systems and clinical studies. Overall, current studies provide evidence that the gut microbiota is affected in PCS; however, diversity in symptoms and highly individual microbiota compositions suggest the need for personalized medicine. Gut-targeted therapies, including treatments with pre- and probiotics, have the potential to improve the quality of life of affected individuals.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"34 1","pages":"2402544"},"PeriodicalIF":12.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1080/19490976.2024.2402547
Ning Li,Xinyan Han,Ming Ruan,Fei Huang,Liu Yang,Tianhao Xu,Huijun Wang,Hui Wu,Songshan Shi,Yongjun Wang,Xiaojun Wu,Shunchun Wang
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination occurring in the central nervous system (CNS). Inulin is a common prebiotic that can improve metabolic disorders by modulating the gut microbiota. However, its capacity to affect CNS autoimmunity is poorly recognized. Experimental autoimmune encephalomyelitis (EAE) is a classical mouse model of MS. Herein, we found that oral administration of inulin ameliorated the severity EAE in mice, accompanied by reductions in inflammatory cell infiltration and demyelination in the CNS. These reductions were associated with decreased proportion and numbers of Th17 cells in brain and spleen. Consistent with the findings, the serum concentrations of IL-17, IL-6, and TNF-α were reduced in inulin treated EAE mice. Moreover, the proliferation of auto-reactive lymphocytes, against MOG35-55 antigen, was attenuated ex vivo. Mechanistically, inulin treatment altered the composition of gut microbiota. It increased Lactobacillus and Dubosiella whereas decreased g_Prevotellaceae_NK3B31_group at the genus level, alongside with elevated concentration of butyric acid in fecal content and serum. In vitro, butyrate, but not inulin, could inhibit the activation of MOG35-55 stimulated lymphocytes. Furthermore, fecal microbiota transplantation assay confirmed that fecal contents of inulin-treated normal mice had an ameliorative effect on EAE mice. In contrast, antibiotic cocktail (ABX) treatment diminished the therapeutic effect of inulin in EAE mice as well as the reduction of Th17 cells, while supplementation with Lactobacillus reuteri restored the amelioration effect. These results confirmed that the attenuation of inulin on Th17 cells and inflammatory demyelination in EAE mice was dependent on its modulation on gut microbiota and metabolites. Our findings provide a potential therapeutic regimen for prebiotic inulin supplementation in patients with multiple sclerosis.
{"title":"Prebiotic inulin controls Th17 cells mediated central nervous system autoimmunity through modulating the gut microbiota and short chain fatty acids.","authors":"Ning Li,Xinyan Han,Ming Ruan,Fei Huang,Liu Yang,Tianhao Xu,Huijun Wang,Hui Wu,Songshan Shi,Yongjun Wang,Xiaojun Wu,Shunchun Wang","doi":"10.1080/19490976.2024.2402547","DOIUrl":"https://doi.org/10.1080/19490976.2024.2402547","url":null,"abstract":"Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination occurring in the central nervous system (CNS). Inulin is a common prebiotic that can improve metabolic disorders by modulating the gut microbiota. However, its capacity to affect CNS autoimmunity is poorly recognized. Experimental autoimmune encephalomyelitis (EAE) is a classical mouse model of MS. Herein, we found that oral administration of inulin ameliorated the severity EAE in mice, accompanied by reductions in inflammatory cell infiltration and demyelination in the CNS. These reductions were associated with decreased proportion and numbers of Th17 cells in brain and spleen. Consistent with the findings, the serum concentrations of IL-17, IL-6, and TNF-α were reduced in inulin treated EAE mice. Moreover, the proliferation of auto-reactive lymphocytes, against MOG35-55 antigen, was attenuated ex vivo. Mechanistically, inulin treatment altered the composition of gut microbiota. It increased Lactobacillus and Dubosiella whereas decreased g_Prevotellaceae_NK3B31_group at the genus level, alongside with elevated concentration of butyric acid in fecal content and serum. In vitro, butyrate, but not inulin, could inhibit the activation of MOG35-55 stimulated lymphocytes. Furthermore, fecal microbiota transplantation assay confirmed that fecal contents of inulin-treated normal mice had an ameliorative effect on EAE mice. In contrast, antibiotic cocktail (ABX) treatment diminished the therapeutic effect of inulin in EAE mice as well as the reduction of Th17 cells, while supplementation with Lactobacillus reuteri restored the amelioration effect. These results confirmed that the attenuation of inulin on Th17 cells and inflammatory demyelination in EAE mice was dependent on its modulation on gut microbiota and metabolites. Our findings provide a potential therapeutic regimen for prebiotic inulin supplementation in patients with multiple sclerosis.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"197 1","pages":"2402547"},"PeriodicalIF":12.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1080/19490976.2024.2393270
Kallie E Hays,Jacob M Pfaffinger,Rebecca Ryznar
Short-chain fatty acids (SCFAs) - acetate, propionate, and butyrate - are important bacterial fermentation metabolites regulating many important aspects of human physiology. Decreases in the concentrations of any or multiple SCFAs are associated with various detrimental effects to the host. Previous research has broadly focused on gut microbiome produced SCFAs as a group, with minimal distinction between acetate, propionate, and butyrate independently, each with significantly different host effects. In this review, we comprehensively delineate the roles of these SCFAs with emphasis on receptor affinity, signaling pathway involvement, and net host physiologic effects. Butyrate is highlighted due to its unique role in gastrointestinal-associated functions, especially maintaining gut barrier integrity. Butyrate functions by promoting epithelial tight junctions, serving as fuel for colonocyte ATP production, and modulating the immune system. Interaction with the immune system occurs locally in the gastrointestinal tract and systemically in the brain. Investigation into research conducted on butyrate production pathways and specific bacterial players involved highlights a unique risk associated with use of gram-positive targeted antibiotics. We review and discuss evidence showing the relationship between the butyrate-producing gram-positive genus, Roseburia, and susceptibility to commonly prescribed, widely used gram-positive antibiotics. Considering gut microbiome implications when choosing antibiotic therapy may benefit health outcomes in patients.
短链脂肪酸（SCFA）--醋酸酯、丙酸酯和丁酸酯--是重要的细菌发酵代谢产物，对人体生理的许多重要方面起着调节作用。任何一种或多种 SCFAs 浓度的降低都会对宿主产生各种不利影响。以往的研究主要集中于肠道微生物组产生的 SCFAs，而很少区分独立的乙酸盐、丙酸盐和丁酸盐，它们对宿主的影响大不相同。在这篇综述中，我们全面阐述了这些 SCFAs 的作用，重点是受体亲和力、信号通路参与和对宿主生理的净影响。丁酸盐因其在胃肠道相关功能中的独特作用，尤其是在维持肠道屏障完整性方面的作用而受到重视。丁酸盐通过促进上皮紧密连接、作为结肠细胞产生 ATP 的燃料以及调节免疫系统来发挥作用。丁酸盐与免疫系统的相互作用发生在胃肠道局部和大脑系统。对丁酸盐产生途径和所涉及的特定细菌参与者进行的调查显示，使用革兰氏阳性靶向抗生素会带来独特的风险。我们回顾并讨论了一些证据，这些证据显示了产生丁酸盐的革兰氏阳性菌属罗斯伯菌与对常用处方、广泛使用的革兰氏阳性抗生素的敏感性之间的关系。在选择抗生素治疗时考虑肠道微生物组的影响可能会有利于患者的健康结果。
{"title":"The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease.","authors":"Kallie E Hays,Jacob M Pfaffinger,Rebecca Ryznar","doi":"10.1080/19490976.2024.2393270","DOIUrl":"https://doi.org/10.1080/19490976.2024.2393270","url":null,"abstract":"Short-chain fatty acids (SCFAs) - acetate, propionate, and butyrate - are important bacterial fermentation metabolites regulating many important aspects of human physiology. Decreases in the concentrations of any or multiple SCFAs are associated with various detrimental effects to the host. Previous research has broadly focused on gut microbiome produced SCFAs as a group, with minimal distinction between acetate, propionate, and butyrate independently, each with significantly different host effects. In this review, we comprehensively delineate the roles of these SCFAs with emphasis on receptor affinity, signaling pathway involvement, and net host physiologic effects. Butyrate is highlighted due to its unique role in gastrointestinal-associated functions, especially maintaining gut barrier integrity. Butyrate functions by promoting epithelial tight junctions, serving as fuel for colonocyte ATP production, and modulating the immune system. Interaction with the immune system occurs locally in the gastrointestinal tract and systemically in the brain. Investigation into research conducted on butyrate production pathways and specific bacterial players involved highlights a unique risk associated with use of gram-positive targeted antibiotics. We review and discuss evidence showing the relationship between the butyrate-producing gram-positive genus, Roseburia, and susceptibility to commonly prescribed, widely used gram-positive antibiotics. Considering gut microbiome implications when choosing antibiotic therapy may benefit health outcomes in patients.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"5 1","pages":"2393270"},"PeriodicalIF":12.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1080/19490976.2024.2399215
Jinglin Ma,Leen Hermans,Matthias Dierick,Hans Van der Weken,Eric Cox,Bert Devriendt
Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal illness in humans and animals, induced by enterotoxins produced by these pathogens. Despite the crucial role of neutrophils in combatting bacterial infections, our understanding of how enterotoxins impact neutrophil function is limited. To address this knowledge gap, we used heat-labile enterotoxin (LT) and heat-stable enterotoxin a (STa) to investigate their impact on the effector functions of neutrophils. Our study reveals that pSTa does not exert any discernible effect on the function of neutrophils. In contrast, LT altered the migration and phagocytosis of neutrophils and induced the production of inflammatory factors via activation of cAMP/PKA and ERK1/2 signaling. LT also attenuated the release of neutrophil extracellular traps by neutrophils via the PKA signaling pathway. Our findings provide novel insights into the impact of LT on neutrophil function, shedding light on the underlying mechanisms that govern its immunoregulatory effects. This might help ETEC in subverting the immune system and establishing infection.
{"title":"Enterotoxigenic Escherichia coli heat labile enterotoxin affects neutrophil effector functions via cAMP/PKA/ERK signaling.","authors":"Jinglin Ma,Leen Hermans,Matthias Dierick,Hans Van der Weken,Eric Cox,Bert Devriendt","doi":"10.1080/19490976.2024.2399215","DOIUrl":"https://doi.org/10.1080/19490976.2024.2399215","url":null,"abstract":"Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal illness in humans and animals, induced by enterotoxins produced by these pathogens. Despite the crucial role of neutrophils in combatting bacterial infections, our understanding of how enterotoxins impact neutrophil function is limited. To address this knowledge gap, we used heat-labile enterotoxin (LT) and heat-stable enterotoxin a (STa) to investigate their impact on the effector functions of neutrophils. Our study reveals that pSTa does not exert any discernible effect on the function of neutrophils. In contrast, LT altered the migration and phagocytosis of neutrophils and induced the production of inflammatory factors via activation of cAMP/PKA and ERK1/2 signaling. LT also attenuated the release of neutrophil extracellular traps by neutrophils via the PKA signaling pathway. Our findings provide novel insights into the impact of LT on neutrophil function, shedding light on the underlying mechanisms that govern its immunoregulatory effects. This might help ETEC in subverting the immune system and establishing infection.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"23 1","pages":"2399215"},"PeriodicalIF":12.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.
胆汁淤积性肝脏损伤是有毒胆汁酸在肝脏中蓄积的结果，这给治疗带来了挑战，迄今为止尚无有效的治疗方法。穿心莲内酯（AP）具有治疗胆汁淤积性肝病的潜力。然而，其有限的口服生物利用度对利用其强大的治疗特性构成了重大障碍，并限制了其临床实用性。这一限制可能是由于肠道微生物群参与了 AP 的代谢。在我们的研究中，我们采用了假无胚胎、无菌和菌株定植动物模型，并结合 16S rRNA 和散弹枪元基因组测序分析，阐明了肠道微生物群在 AP 的 C-磺酸盐代谢过程中发挥的关键作用，这一过程对 AP 的生物利用率和抗胆汁淤积功效产生了深远影响。随后的研究确定了一种特殊的酶--5'-磷酸腺苷（APS）还原酶，它主要由皮格脱硫弧菌产生，能催化SO42-还原成HSO3-。HSO3- 随后与 AP 相互作用，以其 C=C 不饱和双键为目标，形成 C-磺酸盐代谢物 14-deoxy-12(R)-sulfo andrographolide (APM)。抑制 APS 还原酶可显著提高 AP 的生物利用率和抗胆汁淤积功效。此外，利用 RNA 测序分析和法尼类固醇 X 受体（FXR）基因敲除小鼠，我们的研究结果表明，AP 可能通过激活 FXR 途径来促进胆汁酸外流，从而发挥抗胆汁淤积作用。总之，我们的研究揭示了肠道微生物群在 AP 的丙磺酸盐代谢过程中的重要作用，并强调了抑制 APS 还原酶以增强其治疗效果的潜在益处。这些发现为提高 AP 的临床适用性提供了宝贵的见解，是治疗胆汁淤积性肝损伤的一种有前途的方法。
{"title":"Gut microbiota-mediated C-sulfonate metabolism impairs the bioavailability and anti-cholestatic efficacy of andrographolide.","authors":"Dafu Tang,Wanyu Hu,Bingxuan Fu,Xiaojie Zhao,Guoquan You,Cong Xie,Hong Yu Wang,Xueni Guo,Qianbing Zhang,Zhongqiu Liu,Ling Ye","doi":"10.1080/19490976.2024.2387402","DOIUrl":"https://doi.org/10.1080/19490976.2024.2387402","url":null,"abstract":"Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"15 1","pages":"2387402"},"PeriodicalIF":12.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1080/19490976.2024.2395907
Tao Wang,Ling Hao,Kexin Yang,Wenjing Feng,Zhiting Guo,Miao Liu,Rong Xiao
Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.
{"title":"Fecal microbiota transplantation derived from mild cognitive impairment individuals impairs cerebral glucose uptake and cognitive function in wild-type mice: Bacteroidetes and TXNIP-GLUT signaling pathway.","authors":"Tao Wang,Ling Hao,Kexin Yang,Wenjing Feng,Zhiting Guo,Miao Liu,Rong Xiao","doi":"10.1080/19490976.2024.2395907","DOIUrl":"https://doi.org/10.1080/19490976.2024.2395907","url":null,"abstract":"Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"14 1","pages":"2395907"},"PeriodicalIF":12.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1080/19490976.2024.2401939
Jiushuang Zhu, Zhuoting Zhong, Lijie Shi, Ling Huang, Chunqiao Lin, Yan He, Xiuwen Xia, Tiane Zhang, Weijun Ding, Youjun Yang
Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in earl...
{"title":"Gut microbiota mediate early life stress-induced social dysfunction and anxiety-like behaviors by impairing amino acid transport at the gut","authors":"Jiushuang Zhu, Zhuoting Zhong, Lijie Shi, Ling Huang, Chunqiao Lin, Yan He, Xiuwen Xia, Tiane Zhang, Weijun Ding, Youjun Yang","doi":"10.1080/19490976.2024.2401939","DOIUrl":"https://doi.org/10.1080/19490976.2024.2401939","url":null,"abstract":"Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in earl...","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"20 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1080/19490976.2024.2398126
Harithaa Anandakumar,Ariana Rauch,Moritz I Wimmer,Alex Yarritu,Gudrun Koch,Victoria McParland,Hendrik Bartolomaeus,Nicola Wilck
The intestine exhibits distinct characteristics along its length, with a substantial immune cell reservoir and diverse microbiota crucial for maintaining health. This study investigates how anatomical location and regional microbiota influence intestinal immune cell abundance. Using conventionally colonized and germ-free mice, segment-specific immune cell composition and microbial communities were assessed. Metagenomic sequencing analyzed microbiome variations, while flow cytometry and immunofluorescence examined immune cell composition. Microbiome composition varied significantly along the intestine, with diversity and abundance increasing from upper to lower segments. Immune cells showed distinct segment-specific patterning influenced by microbial colonization and localization. T cell subsets displayed varied dependence on microbiome presence and anatomical location. This study highlights locoregional differences in intestinal immune cell and microbiome composition, identifying immune subsets susceptible to microbiota presence. The findings provide context for understanding immune cell alterations in disease models.
{"title":"Segmental patterning of microbiota and immune cells in the murine intestinal tract.","authors":"Harithaa Anandakumar,Ariana Rauch,Moritz I Wimmer,Alex Yarritu,Gudrun Koch,Victoria McParland,Hendrik Bartolomaeus,Nicola Wilck","doi":"10.1080/19490976.2024.2398126","DOIUrl":"https://doi.org/10.1080/19490976.2024.2398126","url":null,"abstract":"The intestine exhibits distinct characteristics along its length, with a substantial immune cell reservoir and diverse microbiota crucial for maintaining health. This study investigates how anatomical location and regional microbiota influence intestinal immune cell abundance. Using conventionally colonized and germ-free mice, segment-specific immune cell composition and microbial communities were assessed. Metagenomic sequencing analyzed microbiome variations, while flow cytometry and immunofluorescence examined immune cell composition. Microbiome composition varied significantly along the intestine, with diversity and abundance increasing from upper to lower segments. Immune cells showed distinct segment-specific patterning influenced by microbial colonization and localization. T cell subsets displayed varied dependence on microbiome presence and anatomical location. This study highlights locoregional differences in intestinal immune cell and microbiome composition, identifying immune subsets susceptible to microbiota presence. The findings provide context for understanding immune cell alterations in disease models.","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"24 1","pages":"2398126"},"PeriodicalIF":12.2,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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