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Nieves KM, Flannigan KL, Hughes E, Stephens M, Thorne AJ, Delanne-Cuménal A, Strayer K, Kola-Ilesanmi D, Wickramasinghe S, Mirzadzar N, Baruta G, McDonald B, Cobo ER, Petri B, Mani S, Hirota SA. Indole-3-propionic acid protects medium-diversity colitic mice via barrier enhancement preferentially over anti-inflammatory effects. Am J Physiol Gastrointest Liver Physiol 2025; 328:G696-G715. [PMID: 40257386 DOI: 10.1152/ajpgi.00256.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/18/2024] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate intestinal mucosal homeostasis in specific pathogen-free (SPF)-colonized animals through distinct receptor-mediated events. Interestingly, IPA levels are reduced in patients with inflammatory bowel disease (IBD). In the current study, we assessed whether IPA could improve colitis outcomes in the absence of its production by the microbiota. To do this, colitis was induced by dextran sulfate sodium (DSS) in gnotobiotic mice colonized with the 12-member stable defined moderately diverse microbiota mouse 2 (sDMDMm2) microbial consortium, which lacks the genes required for IPA generation. We found that these mice were exquisitely sensitive to DSS compared with SPF-colonized mice. However, IPA treatment significantly increased survival. Infiltrating immune cells in the colon were not altered by IPA treatment nor were there any remarkable changes in local and systemic inflammatory mediator levels. Nevertheless, IPA treatment changed the composition of the fecal microbiota and enhanced intestinal barrier function, demonstrated by a reduction in FITC-dextran flux and retainment of a bioluminescent Escherichia coli within the lumen of colitic mice. Together, our data suggest that IPA treatment in the context of its systemic depletion enhances barrier function and enhances survival in the presence of established inflammation. These data support continued assessment of IPA as a potential treatment for IBD.NEW & NOTEWORTHY Indole-3-propionic acid (IPA) is a metabolite produced by the intestinal microbiota that has been shown to elicit beneficial effects in the gastrointestinal (GI) tract that include regulating intestinal barrier function, reducing inflammation, and controlling immune responses that lead to fibrosis. In patients with inflammatory bowel disease (IBD), IPA levels are reduced. In the current study, we found that treating mice with IPA at the peak of intestinal inflammation improved clinical outcomes and disease.
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Affiliation(s)
- Kristoff M Nieves
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Kyle L Flannigan
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Elizabeth Hughes
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Matthew Stephens
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Andrew J Thorne
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Ameline Delanne-Cuménal
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Kathryn Strayer
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Darasimi Kola-Ilesanmi
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Senya Wickramasinghe
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Niloofar Mirzadzar
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Grace Baruta
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Braedon McDonald
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Eduardo R Cobo
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Björn Petri
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Sridhar Mani
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States
| | - Simon A Hirota
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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Ao RF, Yong HR, Hu YT, Huang YS, Gao JW, Tu C, Zhuang JS, Zhong ZM. Indolepropionic Acid Attenuates CFA-Induced Inflammatory Pain in Mice. J Pain Res 2025; 18:2643-2650. [PMID: 40433318 PMCID: PMC12109599 DOI: 10.2147/jpr.s525859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Background Chronic pain is a global health issue that affects as many as 20% of the population. Inflammatory pain, an important form of chronic pain, negatively impacts patients' quality of life. Indolepropionic acid (IPA), a metabolite derived from the gut microbiota, has anti-inflammatory properties. However, its effect on inflammatory pain has not yet been explored. This study aims to investigate the impact of IPA on CFA-induced inflammatory pain. Methods A mouse model of inflammatory pain was established by injection of Complete Freund's Adjuvant (CFA) into the hind paw, and treated with the IPA supplement. Behavioral assessments were conducted using the Von Frey test, cold or hot plate tests. The expression of pain-related transcripts, such as transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) was evaluated. Degree of inflammation was assessed by the thickness of paws, degree of inflammatory infiltration and the changes of serum tumor necrosis factor (TNF)-α, interleukin(IL)-6 and IL-1β. Results IPA supplement improved the CFA-induced decrease of the mechanical withdrawal threshold and cold and thermal withdrawal latency. Meanwhile, IPA inhibited the CFA-induced upregulation of TRPV1 and CGRP in DRGs. In addition, IPA treatment also suppressed the CFA-induced local and systemic inflammation, including the swelling and thickening of the paw, local infiltration of inflammatory cells, and increased serum levels of TNF-α, IL-6, and IL-1β. Conclusion Our results show that IPA can improve pain-related behavior and alleviate inflammation in the CFA-treated mice, which provides new insight into potential strategies for inflammatory pain management.
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Affiliation(s)
- Rui-Feng Ao
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Heng-Rui Yong
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Ying-Tao Hu
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yu-Sheng Huang
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jia-Wen Gao
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Chen Tu
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Orthopedics, Academy of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Jing-Shen Zhuang
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Zhao-Ming Zhong
- Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
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Feng Y, Kim JW, Xie W. The intestinal functions of PXR and CAR. Pharmacol Res 2025; 216:107779. [PMID: 40378938 DOI: 10.1016/j.phrs.2025.107779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2025] [Revised: 05/03/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are so-called xenobiotic nuclear receptors that play pivotal roles in xenobiotic metabolism and detoxification. Both receptors, highly expressed in the liver and intestine, also have endobiotic functions by regulating the homeostasis of endogenous chemicals. While their hepatic functions are well-documented, the functional roles of PXR and CAR in the gastrointestinal tract are less understood. This review highlights the intestinal functions of PXR and CAR, focusing on their involvement in colon cancer, host-microbiome interactions, inflammation, and gut barrier integrity. PXR exhibits dual roles in colon cancer, acting either as a tumor suppressor by inducing cell-cycle arrest or as a promoter of cancer aggressiveness through activating the FGF19 signaling. CAR, on the other hand, regulates intestinal barrier integrity and immune responses, particularly in the context of inflammatory bowel disease (IBD). Both PXR and CAR interact with gut microbiota, modulating microbial composition and the production of metabolites, such as indole-3-propionic acid (IPA) that influences the gut barrier function and inflammation. Activation of PXR also mitigates intestinal inflammation by antagonizing the NF-κB signaling, while CAR activation affects bile acid metabolism and T-cell homeostasis. These findings underscore the complex and context-dependent roles of PXR and CAR in the intestinal tracts, offering potential therapeutic targets for gastrointestinal diseases.
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Affiliation(s)
- Ye Feng
- Department of Endocrinology and Metabolic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Fang L, Peng H, Tan Z, Deng N, Peng X. The Role of Gut Microbiota on Intestinal Fibrosis in Inflammatory Bowel Disease and Traditional Chinese Medicine Intervention. J Inflamm Res 2025; 18:5951-5967. [PMID: 40357383 PMCID: PMC12067688 DOI: 10.2147/jir.s504827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the intestine, frequently complicated by intestinal fibrosis. As fibrosis progresses, it can result in luminal stricture and compromised intestinal function, significantly diminishing patients' quality of life. Emerging evidence suggests that gut microbiota and their metabolites contribute to the pathogenesis of IBD-associated intestinal fibrosis by influencing inflammation and modulating immune responses. This review systematically explores the mechanistic link between gut microbiota and intestinal fibrosis in IBD and evaluates the therapeutic potential of traditional Chinese medicine (TCM) interventions. Relevant studies were retrieved from PubMed, Web of Science, Embase, Scopus, CNKI, Wanfang, and VIP databases. Findings indicate that TCM, including Chinese herbal prescriptions and bioactive constituents, can modulate gut microbiota composition and microbial metabolites, ultimately alleviating intestinal fibrosis through anti-inflammatory, immunemodulatory, and anti-fibrotic mechanisms. These insights highlight the potential of TCM as a promising strategy for targeting gut microbiota in the management of IBD-associated fibrosis.
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Affiliation(s)
- Leyao Fang
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- The Domestic First-Class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Huiyi Peng
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- The Domestic First-Class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Zhoujin Tan
- The Domestic First-Class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Na Deng
- The Domestic First-Class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
| | - Xinxin Peng
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, People’s Republic of China
- The Domestic First-Class Discipline Construction Project of Chinese Medicine of Hunan University of Chinese Medicine, Changsha, People’s Republic of China
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Leroue MK, Maddux AB, Lehmann T, Niemiec S, Mancuso CA, Khailova L, Mourani PM, Klawitter J, Davidson JA. Alteration in Indole Metabolites After Cardiopulmonary Bypass Surgery in Neonates and Infants. Crit Care Explor 2025; 7:e1267. [PMID: 40327389 PMCID: PMC12055184 DOI: 10.1097/cce.0000000000001267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025] Open
Abstract
IMPORTANCE Cardiopulmonary bypass (CPB) surgery is associated with changes in the intestinal microbiome. Metabolism of tryptophan into the indole pathway is entirely facilitated by the intestinal microbiome, and indole metabolites play a critical role in intestinal epithelial integrity, intestinal and systemic vascular tone, and intestinal and systemic immune response. OBJECTIVES To evaluate the impact of CPB on microbial-derived indole metabolites and their association with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of neonates and infants younger than 6 months of age undergoing CPB at a quaternary children's hospital. MAIN OUTCOMES AND MEASURES Serum samples underwent quantitative pathway mapping via mass spectroscopy. Clinical outcomes of interest included cardiac ICU (CICU) length of stay and Vasoactive-Inotropic Score (VIS) at 48 hours. RESULTS Ninety patients between 2 and 169 days old were enrolled. Patients showed significant postoperative changes in seven of eight indole metabolites. A two-fold increase in preoperative levels of indole-3-carboxylic acid was associated with 0.63 odds of requiring vasoactive medications at 48 hours (p = 0.023) and among those subjects still requiring vasoactives at 48 hours, they had an average 7.1% decrease in VIS at 48 hours (p = 0.005), and a 12.25% reduction in CICU length of stay (p = 0.001). Higher levels of indole-3-carboxylic acid preoperatively and at 24 and 48 hours postoperatively were also significantly associated with decreased CICU length of stay. Conversely, increased levels of several metabolites, including indole-3-lactic acid, indole-3-carbaldhyde, indole-3-propionic acid, tryptamine, and tryptophol, in the preoperative and postoperative period were associated with higher VIS at 48 hours and increased CICU length of stay. CONCLUSIONS AND RELEVANCE CPB was associated with significant changes in indole metabolite levels postoperatively. Indole-3-carboxylic acid, which suppresses T-regulatory (Treg) differentiation, is associated with improved patient outcomes, whereas other metabolites, that promote Treg differentiation, were associated with worse outcomes.
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Affiliation(s)
- Matthew K. Leroue
- Section of Critical Care Medicine, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Aline B. Maddux
- Section of Critical Care Medicine, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Tanner Lehmann
- Section of Cardiology, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Sierra Niemiec
- Department of Biostatistics and Informatics, University of Colorado, Denver, CO
| | | | - Ludmila Khailova
- Section of Cardiology, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Peter M. Mourani
- Section of Critical Care Medicine, Department of Pediatrics, Arkansas Children’s Hospital and University of Arkansas for Medical Sciences, Little Rock, AR
| | - Jelena Klawitter
- Department of Anesthesiology, University of Colorado, Aurora, CO
| | - Jesse A. Davidson
- Section of Cardiology, Department of Pediatrics, University of Colorado, Aurora, CO
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Liu C, Li R, Nie J, He J, Lin Z, Wu X, Tan J, Liu Z, Zhou L, Li X, Zeng Z, Chen M, Hu S, Zhu Y, Mao R. Gut Microbiota as a Mediator Between Intestinal Fibrosis and Creeping Fat in Crohn's Disease. United European Gastroenterol J 2025. [PMID: 40312989 DOI: 10.1002/ueg2.70027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/27/2024] [Accepted: 01/12/2025] [Indexed: 05/03/2025] Open
Abstract
Intestinal stricture remains one of the most challenging complications in Crohn's disease, and its underlying mechanisms are poorly understood. Accumulating evidence suggests that gut microbiota is significantly altered in stenotic intestines and may play a key role in the development of fibrogenesis in Crohn's disease. Additionally, the presence of hypertrophic mesenteric adipose tissue, also known as creeping fat, is closely correlated with intestinal stricture and fibrosis. Recent findings have revealed that bacterial translocation to creeping fat might exacerbate colitis and promote intestinal fibrosis. However, there is still a gap in determining whether gut microbiota links the formation of creeping fat to intestinal fibrosis. Hence, this review aims to summarize the known microbial influences on intestinal fibrosis, describes the microbial characteristics of creeping fat in Crohn's disease, and discusses the crosstalk between creeping fat-associated dysbiosis and the development of intestinal fibrosis.
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Affiliation(s)
- Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Rongchang Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jing Nie
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinshen He
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zihao Lin
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zishan Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Longyuan Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaozhi Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shixian Hu
- Department of Precision Medicine, Sun Yat-Sen University First Affiliated Hospital, Guangzhou, China
| | - Yijun Zhu
- Department of Precision Medicine, Sun Yat-Sen University First Affiliated Hospital, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Qi Z, Zhou L, Dai S, Zhang P, Zhong H, Zhou W, Zhao X, Xu H, Zhao G, Wu H, Ge J. Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate. LIFE METABOLISM 2025; 4:loaf002. [PMID: 40078933 PMCID: PMC11897983 DOI: 10.1093/lifemeta/loaf002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/09/2025] [Accepted: 01/21/2025] [Indexed: 03/14/2025]
Abstract
Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting (IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E (ApoE) knockout (ApoE -/- ) mice, by enhancing intestinal flora production of indole-3-propionic acid (IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor (PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in ApoE -/- mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.
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Affiliation(s)
- Zhiyong Qi
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Luning Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Shimo Dai
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Peng Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Haoxuan Zhong
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Wenxuan Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Xin Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Huajie Xu
- Department of Infectious Disease, Zhongshan Hospital, Fudan University, 180 Fenglin Road , Shanghai 200032, China
| | - Gang Zhao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Hongyi Wu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Shanghai 200032, China
- Institutes of Biomedical Sciences, Fudan University, 131 Dong’an Road, Shanghai 200032, China
- Key Laboratory of Viral Heart Diseases, National Health Commission, 180 Fenglin Road, Shanghai 200032, China
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Han Z, Fu J, Gong A, Ren W. Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1118-1131. [PMID: 39825207 DOI: 10.1007/s11427-024-2789-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/20/2024] [Indexed: 01/20/2025]
Abstract
The gut microbiota plays key roles in host health by shaping the host immune responses through their metabolites, like indole derivatives from tryptophan. However, the direct role of these indole derivatives in macrophage fate decision and the underlying mechanism remains unknown. Here, we found that bacterial indole-3-propionic acid (IPA) downregulates interleukin-1beta (IL-1β) production in M1 macrophages through inhibition of nuclear factor-kappa B (NF-κB) signaling. Mechanistically, IPA binds specifically with methionine adenosyl-transferase 2A (MAT2A) to promote S-adenosylmethionine (SAM) synthesis, which facilitates the DNA methylation of ubiquitin-specific peptidase 16 (USP16, a deubiquitinase), and in turn promotes Toll-like receptor 4 (TLR4) ubiquitination and NF-κB inhibition. Furthermore, IPA administration attenuates sepsis in mouse models induced by lipopolysaccharides (LPS), showcasing its potential as a microbial-derived adjunct in alleviating inflammation. Collectively, our findings reveal a newly found microbial metabolite-immune system regulatory pathway mediated by IPA.
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Affiliation(s)
- Ziyi Han
- State Key Laboratory of Livestock and Poultry Breeding, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
- Animal Disease-resistant Nutrition, Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 625014, China
| | - Jian Fu
- State Key Laboratory of Livestock and Poultry Breeding, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Aiyan Gong
- China Institute of Veterinary Drug Control, Beijing, 100081, China
| | - Wenkai Ren
- State Key Laboratory of Livestock and Poultry Breeding, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
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Kaden T, Alonso‐Román R, Stallhofer J, Gresnigt MS, Hube B, Mosig AS. Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease. Adv Healthc Mater 2025; 14:e2402756. [PMID: 39491534 PMCID: PMC12004439 DOI: 10.1002/adhm.202402756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/29/2024] [Indexed: 11/05/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.
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Affiliation(s)
- Tim Kaden
- Dynamic42 GmbH07745JenaGermany
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
| | - Raquel Alonso‐Román
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | | | - Mark S. Gresnigt
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | - Bernhard Hube
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Institute of MicrobiologyFaculty of Biological SciencesFriedrich Schiller University07743JenaGermany
| | - Alexander S. Mosig
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
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10
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Huang R, Shen ZY, Huang D, Zhao SH, Dan LX, Wu P, Tang QZ, Ma ZG. Microbiota-indole-3-propionic acid-heart axis mediates the protection of leflunomide against αPD1-induced cardiotoxicity in mice. Nat Commun 2025; 16:2651. [PMID: 40108157 PMCID: PMC11923180 DOI: 10.1038/s41467-025-58107-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 03/12/2025] [Indexed: 03/22/2025] Open
Abstract
Anti-programmed death 1 (αPD1) immune checkpoint blockade is used in combination for cancer treatment but associated with cardiovascular toxicity. Leflunomide (Lef) can suppress the growth of several tumor and mitigate cardiac remodeling in mice. However, the role of Lef in αPD1-induced cardiotoxicity remains unclear. Here, we report that Lef treatment inhibits αPD1-related cardiotoxicity without compromising the efficacy of αPD1-mediated immunotherapy. Lef changes community structure of gut microbiota in αPD1-treated melanoma-bearing mice. Moreover, mice receiving microbiota transplants from Lef+αPD1-treated melanoma-bearing mice have better cardiac function compared to mice receiving transplants from αPD1-treated mice. Mechanistically, we analyze metabolomics and identify indole-3-propionic acid (IPA), which protects cardiac dysfunction in αPD1-treated mice. IPA can directly bind to the aryl hydrocarbon receptor and promote phosphoinositide 3-kinase expression, thus curtailing the cardiomyocyte response to immune injury. Our findings reveal that Lef mitigates αPD1-induced cardiac toxicity in melanoma-bearing mice through modulation of the microbiota-IPA-heart axis.
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Affiliation(s)
- Rong Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Zhuo-Yu Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Dan Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Shu-Hong Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Ling-Xuan Dan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Pan Wu
- Department of Adult Internal Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China.
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11
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Fiorucci S, Marchianò S, Distrutti E, Biagioli M. Bile acids and their receptors in hepatic immunity. LIVER RESEARCH (BEIJING, CHINA) 2025; 9:1-16. [PMID: 40206435 PMCID: PMC11977286 DOI: 10.1016/j.livres.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/05/2024] [Accepted: 01/23/2025] [Indexed: 04/11/2025]
Abstract
Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.
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Affiliation(s)
- Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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12
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Xing Y, Zhong W, Wu X, Ni Z, Lv W, Fan Y, Chen L, Lin H, Xie Y, Lin J, Niu Y. AFB1 consolidates HBV harm to induce liver injury and carcinogenic risk by inactivating FTCD-AS1-PXR-MASP1 axis. Toxicology 2025; 511:154057. [PMID: 39824452 DOI: 10.1016/j.tox.2025.154057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/20/2025]
Abstract
Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4-6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed in vivo and in vitro. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury.
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Affiliation(s)
- Yaqi Xing
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Wusheng Zhong
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Xuejun Wu
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Zhengzhong Ni
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Wenya Lv
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Ying Fan
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Ling Chen
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Haorui Lin
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Yangmin Xie
- Department of Experimental Animal Center, Medical College of Shantou University, Shantou 515041, China
| | - Jianwei Lin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
| | - Yongdong Niu
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China.
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13
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Basaly V, Bhattacharya A, Guo GL. Insights of direct and indirect regulation of PXR through phosphorylation in fatty liver disease. Mol Pharmacol 2025; 107:100014. [PMID: 40023513 DOI: 10.1016/j.molpha.2024.100014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/13/2024] [Indexed: 03/04/2025] Open
Abstract
The pregnane X receptor (PXR), a ligand-activated nuclear receptor, regulates the transcription of several genes that encode many enzymes and transporters related to drug metabolism. PXR also performs an important role as a physiological sensor in the modulation of endobiotic metabolism for hormones, bile acids, cholesterol, fatty acids, and glucose. Dysregulation of these PXR-mediated pathways is implicated in the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributing to the complex interplay of factors involved in chronic liver disease development and exacerbation affecting millions worldwide. This review highlights the current knowledge of PXR expression and its role in endobiotic metabolism related to MASH development, which is associated with diverse causes and dire outcomes. This review focuses on elucidating the molecular pathways associated with PXR activation directly or indirectly and PXR interaction with other regulatory factors. Although there is still much to comprehend about the intricate details of these pathways, the conclusion is drawn that PXR exerts a crucial role in the pathological and physiological pathways of hepatic cellular processes, which holds promise as a potential pharmacological target for exploring novel therapeutic approaches for MASH treatment and/or prevention. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR) plays a fundamental role in regulating gene expression involved in xenobiotic and endobiotic metabolism. Dysregulation of PXR-mediated pathways is related to the development of metabolic dysfunction-associated steatohepatitis. The ligand-independent pathways regulating PXR hepatic functions through phosphorylation shed light on possible indirect molecular mechanisms and pathways that regulate PXR activity and function. Understanding these pathways may provide insight into new pharmaceutical interventions for metabolic dysfunction-associated steatohepatitis development.
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Affiliation(s)
- Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey.
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14
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Xu H, Luo Y, An Y, Wu X. The mechanism of action of indole-3-propionic acid on bone metabolism. Food Funct 2025; 16:406-421. [PMID: 39764708 DOI: 10.1039/d4fo03783a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.
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Affiliation(s)
- Huimin Xu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Yingzhe Luo
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yi An
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Xi Wu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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15
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Shen Z, Wang J, Chen Y, Fang P, Yuan A, Chen AF, Yan X, Lyu Y, Pu J. Activation of nuclear receptor pregnane-X-receptor protects against abdominal aortic aneurysm by inhibiting oxidative stress. Redox Biol 2024; 77:103397. [PMID: 39427444 PMCID: PMC11534186 DOI: 10.1016/j.redox.2024.103397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/05/2024] [Accepted: 10/13/2024] [Indexed: 10/22/2024] Open
Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate [Ca3(PO4)2]. The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA.
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MESH Headings
- Pregnane X Receptor/metabolism
- Pregnane X Receptor/genetics
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/prevention & control
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/genetics
- Oxidative Stress/drug effects
- Animals
- Humans
- Mice
- Disease Models, Animal
- Male
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
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Affiliation(s)
- Zhi Shen
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Jinxi Wang
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yifei Chen
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Peiliang Fang
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Ancai Yuan
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Alex F Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Xiaoxiang Yan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuyan Lyu
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Jun Pu
- Department of Cardiology, Renji Hospital, School of Medicine, State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
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16
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Lin J, Yang J, Cui L, Nagpal R, Singh P, Salazar G, Rao Q, Peng Y, Sun Q. Sturgeon-derived peptide LLLE alleviates colitis via regulating gut microbiota and its metabolites. Curr Res Food Sci 2024; 9:100898. [PMID: 39569007 PMCID: PMC11577126 DOI: 10.1016/j.crfs.2024.100898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/28/2024] [Accepted: 10/25/2024] [Indexed: 11/22/2024] Open
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease, entails chronic inflammation of the gastrointestinal tract. The pathogenesis of IBD implicates genetic factors, gut microbiome alterations, and immune dysregulation, contributing to its increasing global prevalence. The sturgeon-derived peptide, which exhibits promising anti-inflammatory effects, provides potential therapeutic insights for managing IBD symptoms. This study aims to elucidate the therapeutic mechanisms of novel sturgeon-derived peptide (LLLE, Leu-Leu-Leu-Glu) by investigating their effects on intestinal inflammation, gut microbiota composition, and fecal metabolites in a mouse model of IBD. LLLE administration alleviated weight loss and disease activity index (DAI) scores in dextran sulfate sodium salt (DSS)-induced colitis in mice. Histopathological examination showed LLLE pretreatment improved colon morphology and histopathological condition and decreased serum interleukin-6 (IL-6) levels. 16S rRNA sequencing indicated LLLE-modulation of gut microbiota, especially alleviated DSS-elevated Bacteroidetes. Fecal metabolomic analysis unveiled that LLLE restores critical metabolites such as indole-3-propionic acid, which is pivotal in anti-inflammatory responses. Altogether, sturgeon peptide exhibits considerable promise as a therapeutic agent for colitis, owing to its anti-inflammatory effects, modulation of gut microbiota, and restoration of essential fecal metabolites.
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Affiliation(s)
- Jie Lin
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Jiani Yang
- School of Food and Biological Engineering, Jiangsu University, 212013, Zhenjiang, Jiangsu Province, China
| | - Leqi Cui
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Ravinder Nagpal
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Prashant Singh
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Gloria Salazar
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Qinchun Rao
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Ye Peng
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
| | - Quancai Sun
- Department of Health, Nutrition and Food Sciences, Florida State University, Tallahassee, FL, United States
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17
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Xue H, Wang Y, Mei C, Han L, Lu M, Li X, Chen T, Wang F, Tang X. Gut microbiome and serum metabolome alterations associated with lactose intolerance (LI): a case‒control study and paired-sample study based on the American Gut Project (AGP). mSystems 2024; 9:e0083924. [PMID: 39320101 PMCID: PMC11494873 DOI: 10.1128/msystems.00839-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 07/04/2024] [Indexed: 09/26/2024] Open
Abstract
Lactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms that arise following lactose consumption. Recent evidence suggests that the gut microbiome may influence lactose levels in the gut. However, there is limited understanding regarding the alterations in microbiota and metabolism between individuals with LI and non-LI. This study conducted a paired-sample investigation utilizing data from the American Gut Project (AGP) and performed metagenomic and untargeted metabolomic analyses in a Chinese cohort to explore the interaction between the gut microbiome and serum metabolites. In addition, fecal microbiota transplantation (FMT) experiments were conducted to further examine the impact of the LI-associated gut microbiome on inflammatory outcomes. We identified 14 microbial genera that significantly differed between LI and controls from AGP data. Using a machine learning approach, group separation was predicted based on seven species and nine metabolites in the Chinese cohort. Notably, increased levels of Escherichia coli in the LI group were negatively correlated with several metabolites, including PC (22:6/0:0), indole, and Lyso PC, while reduced levels of Faecalibacterium prausnitzii and Eubacterium rectale were positively correlated with indole and furazolidone. FMT-LI rats displayed visceral hypersensitivity and an altered gut microbiota composition compared to FMT-HC rats. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI, which was confirmed by FMT-LI rats showing higher expression of ERK and RAS, along with increased concentrations of proinflammatory cytokines. This study provides valuable insights into the disrupted microbial and metabolic traits associated with LI, emphasizing potential microbiome-based approaches for its prevention and treatment. IMPORTANCE Lactose intolerance (LI) is a prevalent condition characterized by gastrointestinal symptoms after lactose consumption due to a deficiency of lactase. There is limited understanding regarding the microbiota and metabolic alterations between individuals with LI and non-LI. This study represents the first exploration to investigate metagenomic and metabolomic signatures among subjects with lactose intolerance as far as our knowledge. We identified 14 microbial genera in the Western cohort and 7 microbial species, along with 9 circulating metabolites in the Chinese cohort, which significantly differed in LI patients. Metagenomic and metabolomic analyses revealed an enrichment of MAPK signaling in LI patients. This finding was confirmed by FMT-LI rats, exhibiting increased expression of ERK and RAS, along with higher concentrations of pro-inflammatory cytokines. Our study provides insights into the disrupted functional and metabolic traits of the gut microbiome in LI, highlighting potential microbiome-based approaches for preventing and treating LI.
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Affiliation(s)
- Hong Xue
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yitian Wang
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chunfeng Mei
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lili Han
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mengxiong Lu
- Department of Integrated Traditional Chinese and Western Medicine, Peking University Health Science Center, Beijing, China
- Department of Gastrointestinal Medicine, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
| | - Xuan Li
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ting Chen
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- Digestive Laboratory of Traditional Chinese Medicine, Research Institute of Spleen and Stomach Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Integrated Traditional Chinese and Western Medicine, Peking University Health Science Center, Beijing, China
- Department of Gastrointestinal Medicine, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
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18
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Li X, Hu S, Shen X, Zhang R, Liu C, Xiao L, Lin J, Huang L, He W, Wang X, Huang L, Zheng Q, Wu L, Sun C, Peng Z, Chen M, Li Z, Feng R, Zhu Y, Wang Y, Li Z, Mao R, Feng ST. Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease. EMBO Mol Med 2024; 16:2427-2449. [PMID: 39271960 PMCID: PMC11473649 DOI: 10.1038/s44321-024-00129-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 09/15/2024] Open
Abstract
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.
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Affiliation(s)
- Xuehua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Shixian Hu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2nd, 510080, Guangzhou, Guangdong, People's Republic of China
| | - Xiaodi Shen
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Ruonan Zhang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Lin Xiao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Jinjiang Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Weitao He
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Xinyue Wang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Lili Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Qingzhu Zheng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Luyao Wu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Canhui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Zhenpeng Peng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Ziping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Rui Feng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
| | - Yijun Zhu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road 2nd, 510080, Guangzhou, Guangdong, People's Republic of China
| | - Yangdi Wang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China.
| | - Zhoulei Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China.
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China.
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, 510080, Guangzhou, People's Republic of China.
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Drygiannakis I, Kolios G, Filidou E, Bamias G, Valatas V. Intestinal Stromal Cells in the Turmoil of Inflammation and Defective Connective Tissue Remodeling in Inflammatory Bowel Disease. Inflamm Bowel Dis 2024; 30:1604-1618. [PMID: 38581412 DOI: 10.1093/ibd/izae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Indexed: 04/08/2024]
Abstract
In steady state, intestinal subepithelial myofibroblasts form a thin layer below the basement membrane. Unlike the rest of the stromal cells in the lamina propria, they express tensile proteins, guide epithelial regeneration, and sense luminal microbiota. Upon inflammation in inflammatory bowel disease (IBD), they express activation markers, accept trophic signaling by infiltrating neutrophils and macrophages, and are activated by cytokines from helper T cells to produce a narrow spectrum of cytokines and a wider spectrum of chemokines, attract cells of innate and adaptive immunity, orchestrate inflammatory responses, and qualitatively and quantitatively modify the extracellular matrix. Thus, beyond being structural tissue components, they assume active roles in the pathogenesis of complicated IBD. Discrimination between myofibroblasts and fibroblasts may be an oversimplification in light of single-cell sequencing data unveiling the complexity of multiple phenotypes of stromal cells with distinct roles and plasticity. Spatial transcriptomics revealed distinct phenotypes by histologic localization and, more intriguingly, the assembly of mucosal neighborhoods that support spatially distinct functions. Current IBD treatments target inflammation but fail in fibrostenotic or fistulizing disease. Baseline and recent findings on stromal cells, molecules, and pathways involved in disrupted extracellular matrix homeostasis are reviewed to provide relevant pharmacologic targets.
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Affiliation(s)
- Ioannis Drygiannakis
- Gastroenterology Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece
- Gastroenterology Clinic, University Hospital of Heraklion, Heraklion, Greece
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Giorgos Bamias
- Gastrointestinal Unit, Third Academic Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vassilis Valatas
- Gastroenterology Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece
- Gastroenterology Clinic, University Hospital of Heraklion, Heraklion, Greece
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20
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Zhang B, Ren D, Yang C, Zhao Y, Zhang X, Tian X, Yang X. Intracellular Polysaccharides of Eurotium cristatum Exhibited Anticolitis Effects in Association with Gut Tryptophan Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:16347-16358. [PMID: 38982686 DOI: 10.1021/acs.jafc.4c04024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
This study is to investigate the protective effects of Eurotium cristatum intracellular polysaccharides (ECIP) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC). The oral administration of ECIP could downregulate the disease activity index (DAI) and ameliorate the colonic shortening, immune stress, and damage caused by DSS. In addition, ECIP treatment increased the colonic contents of SCFAs including acetic, propionic, and butyric acids in UC mice. Targeted and untargeted metabolic analysis suggested that ECIP dramatically altered the tryptophan metabolism in the feces of UC mice and promoted the conversion of tryptophan into indole metabolites including indolepyruvate and indole-3-acetic acid (IAA) and indolealdehyde (IAId). Moreover, ECIP observably increased the content of colonic IL-22 and stimulated the relative concentration and relative expression of tight junction molecules in mRNA and proteins levels. Conclusively, consumption of ECIP can improve colon damage and its related effects of UC by promoting the production of IAA and IAId to reinforce intestinal barriers.
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Affiliation(s)
- Bo Zhang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Daoyuan Ren
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Chengcheng Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Yan Zhao
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- Key Laboratory of Ministry of Education for Medicinal Resource and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China
| | - Xiangnan Zhang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Xinwei Tian
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Xingbin Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, Shaanxi Normal University, Xi'an 710119, China
- Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, Shaanxi Normal University, Xi'an 710119, China
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
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21
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Liu Z, Huang Z, Wang Y, Xiong S, Lin S, He J, Tan J, Liu C, Wu X, Nie J, Huang W, Zhang Y, Zhou L, Mao R. Intestinal strictures in Crohn's disease: An update from 2023. United European Gastroenterol J 2024; 12:802-813. [PMID: 38546434 PMCID: PMC11250166 DOI: 10.1002/ueg2.12568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/12/2024] [Indexed: 07/17/2024] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory disease that leads to intestinal stricture in nearly 35% of cases within 10 years of initial diagnosis. The unknown pathogenesis, lack of universally accepted criteria, and absence of an effective management approach remain unconquered challenges in structuring CD. The pathogenesis of stricturing CD involves intricate interactions between factors such as immune cell dysbiosis, fibroblast activation, and microecology imbalance. New techniques such as single-cell sequencing provide a fresh perspective. Non-invasive diagnostic tools such as serum biomarkers and novel cross-sectional imaging techniques offer a precise understanding of intestinal fibrostenosis. Here, we provide a timely and comprehensive review of the worthy advancements in intestinal strictures in 2023, aiming to dispense cutting-edge information regarding fibrosis and to build a cornerstone for researchers and clinicians to make greater progress in the field of intestinal strictures.
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Affiliation(s)
- Zishan Liu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Zhuoyan Huang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Yu Wang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Shanshan Xiong
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Sinan Lin
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Jinshen He
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Jinyu Tan
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Caiguang Liu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Xiaomin Wu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Jing Nie
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Weidong Huang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Yao Zhang
- Department of GastroenterologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Longyuan Zhou
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Ren Mao
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
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22
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Huang Z, Wells JM, Fogliano V, Capuano E. Microbial tryptophan catabolism as an actionable target via diet-microbiome interactions. Crit Rev Food Sci Nutr 2024:1-15. [PMID: 38950607 DOI: 10.1080/10408398.2024.2369947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
In recent years, the role of microbial tryptophan (Trp) catabolism in host-microbiota crosstalk has become a major area of scientific interest. Microbiota-derived Trp catabolites positively contribute to intestinal and systemic homeostasis by acting as ligands of aryl hydrocarbon receptor and pregnane X receptor, and as signaling molecules in microbial communities. Accumulating evidence suggests that microbial Trp catabolism could be therapeutic targets in treating human diseases. A number of bacteria and metabolic pathways have been identified to be responsible for the conversion of Trp in the intestine. Interestingly, many Trp-degrading bacteria can benefit from the supplementation of specific dietary fibers and polyphenols, which in turn increase the microbial production of beneficial Trp catabolites. Thus, this review aims to highlight the emerging role of diets and food components, i.e., food matrix, fiber, and polyphenol, in modulating the microbial catabolism of Trp and discuss the opportunities for potential therapeutic interventions via specifically designed diets targeting the Trp-microbiome axis.
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Affiliation(s)
- Zhan Huang
- Food Quality and Design Group, Department of Agrotechnology and Food Sciences, Wageningen University, Wageningen, the Netherlands
- Host-Microbe Interactomics Group, Department of Animal Sciences, Wageningen University, Wageningen, the Netherlands
| | - Jerry M Wells
- Host-Microbe Interactomics Group, Department of Animal Sciences, Wageningen University, Wageningen, the Netherlands
| | - Vincenzo Fogliano
- Food Quality and Design Group, Department of Agrotechnology and Food Sciences, Wageningen University, Wageningen, the Netherlands
| | - Edoardo Capuano
- Food Quality and Design Group, Department of Agrotechnology and Food Sciences, Wageningen University, Wageningen, the Netherlands
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23
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Wang J, Yang B, Chandra J, Ivanov A, Brown JM, Florian R. Preventing fibrosis in IBD: update on immune pathways and clinical strategies. Expert Rev Clin Immunol 2024; 20:727-734. [PMID: 38475672 PMCID: PMC11180587 DOI: 10.1080/1744666x.2024.2330604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 03/11/2024] [Indexed: 03/14/2024]
Abstract
INTRODUCTION Intestinal fibrosis is a common and serious complication of inflammatory bowel diseases (IBD) driving stricture formation in Crohn's disease patients and leading to submucosal damage in ulcerative colitis. Recent studies provided novel insights into the role of immune and nonimmune components in the pathogenesis of intestinal fibrosis. Those new findings may accelerate the development of anti-fibrotic treatment in IBD patients. AREAS COVERED This review is designed to cover the recent progress in mechanistic research and therapeutic developments on intestinal fibrosis in IBD patients, including new cell clusters, cytokines, proteins, microbiota, creeping fat, and anti-fibrotic therapies. EXPERT OPINION Due to the previously existing major obstacle of missing consensus on stricture definitions and the absence of clinical trial endpoints, testing of drugs with an anti-fibrotic mechanism is just starting in stricturing Crohn's disease (CD). A biomarker to stratify CD patients at diagnosis without any complications into at-risk populations for future strictures would be highly desirable. Further investigations are needed to identify novel mechanisms of fibrogenesis in the intestine that are targetable and ideally gut specific.
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Affiliation(s)
- Jie Wang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Bo Yang
- Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Jyotsna Chandra
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Andrei Ivanov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - J. Mark Brown
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Rieder Florian
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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24
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Zhao X, Pang J, Zhang W, Peng X, Yang Z, Bai G, Xia Y. Tryptophan metabolism and piglet diarrhea: Where we stand and the challenges ahead. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 17:123-133. [PMID: 38766516 PMCID: PMC11101943 DOI: 10.1016/j.aninu.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/13/2024] [Accepted: 03/20/2024] [Indexed: 05/22/2024]
Abstract
The intestinal architecture of piglets is vulnerable to disruption during weaning transition and leads to diarrhea, frequently accompanied by inflammation and metabolic disturbances (including amino acid metabolism). Tryptophan (Trp) plays an essential role in orchestrating intestinal immune tolerance through its metabolism via the kynurenine, 5-hydroxytryptamine, or indole pathways, which could be dictated by the gut microbiota either directly or indirectly. Emerging evidence suggests a strong association between piglet diarrhea and Trp metabolism. Here we aim to summarize the intricate balance of microbiota-host crosstalk by analyzing alterations in both the host and microbial pathways of Trp and discuss how Trp metabolism may affect piglet diarrhea. Overall, this review could provide valuable insights to explore effective strategies for managing piglet diarrhea and the related challenges.
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Affiliation(s)
- Xuan Zhao
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Jiaman Pang
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Wanghong Zhang
- Yunnan Vocational College of Agriculture, Kunming 650211, China
| | - Xie Peng
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Zhenguo Yang
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Guangdong Bai
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Yaoyao Xia
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
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25
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Lu C, Zhang J, Zhang Y, Bao X. NR1I2 as a core biological target in chronic venous ulcer tissues treated with ultrasound therapy. Medicine (Baltimore) 2024; 103:e38092. [PMID: 38728468 PMCID: PMC11081579 DOI: 10.1097/md.0000000000038092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 04/11/2024] [Indexed: 05/12/2024] Open
Abstract
Ultrasound therapy is a method of applying ultrasonic energy to the stimulation produced by human body to change the function and tissue state of the body in order to achieve the purpose of treating diseases. Chronic venous ulcer is a common chronic skin ulcer. GSE222503 for ultrasound therapy of chronic venous ulcers was downloaded from gene expression omnibus database, which were used to identify differentially expressed genes. Weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, immune infiltration analysis and construction and analysis of protein-protein interaction network were performed. Draw gene expression heatmaps. Comparative toxicogenomics database analysis was performed. Two hundred thirty-five differentially expressed genes were obtained. According to gene ontology analysis, in biological process analysis, they were mainly enriched in positive regulation of cellular biosynthetic process, reproductive cell development, vasculogenesis, vascular morphogenesis, and inflammatory response. In cellular component analysis, they were mainly enriched in leading edge of growing cell, extracellular matrix binding organelle, F-actin capping protein complex. In molecular function analysis, they were mainly concentrated in receptor ligand activity, cytokine receptor binding. In Kyoto encyclopedia of genes and genomes analysis, they were mainly enriched in cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, HIF-1 signaling pathway, heme biosynthesis. In weighted gene co-expression network analysis, the soft threshold power was set to 9. Thirty modules were generated. PF4, NR1I2, TTC16, H3C12, KLRB1, CYP21A2 identified by 4 algorithms (MCC, EPC, closeness, stress). Heatmap of core gene expression showed that H3C12, KLRB1, PF4, NR1I2 were all underexpressed in samples of ultrasound-treated chronic venous ulcers and overexpressed in samples of untreated chronic venous ulcers. Comparative toxicogenomics database analysis showed that H3C12, KLRB1, PF4, NR1I2 are associated with thrombophlebitis, phlebitis, vascular malformations, metabolic syndrome, ulcers, and inflammation. In samples of chronic venous ulcer tissue treated with ultrasound, NR1I2 shows low expression, while in samples of chronic venous ulcer tissue without ultrasound treatment, it shows high expression. This finding suggests a potential role of NR1I2 in the process of ultrasound therapy for chronic venous ulcers, which may be related to the therapeutic effect of ultrasound therapy on chronic venous ulcers.
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Affiliation(s)
- Chuanyingzi Lu
- Rehabilitation Ultrasonics Department, Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
| | - Jingli Zhang
- Rehabilitation Ultrasonics Department, Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yajing Zhang
- Rehabilitation Ultrasonics Department, Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
| | - Xiaoshi Bao
- Rehabilitation Ultrasonics Department, Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
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26
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Staudinger JL, Mahroke A, Patel G, Dattel C, Reddy S. Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health. Cells 2024; 13:681. [PMID: 38667296 PMCID: PMC11049418 DOI: 10.3390/cells13080681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
This review explores the likely clinical impact of Pregnane X Receptor (PXR) activation by vitamin K on human health. PXR, initially recognized as a master regulator of xenobiotic metabolism in liver, emerges as a key regulator influencing intestinal homeostasis, inflammation, oxidative stress, and autophagy. The activation of PXR by vitamin K highlights its role as a potent endogenous and local agonist with diverse clinical implications. Recent research suggests that the vitamin K-mediated activation of PXR highlights this vitamin's potential in addressing pathophysiological conditions by promoting hepatic detoxification, fortifying gut barrier integrity, and controlling pro-inflammatory and apoptotic pathways. PXR activation by vitamin K provides an intricate association with cancer cell survival, particularly in colorectal and liver cancers, to provide new insights into potential novel therapeutic strategies. Understanding the clinical implications of PXR activation by vitamin K bridges molecular mechanisms with health outcomes, further offering personalized therapeutic approaches for complex diseases.
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Affiliation(s)
- Jeff L. Staudinger
- Division of Basic Sciences, Farber-McIntire Campus, College of Osteopathic Medicine, Kansas City University, Joplin Campus, 2901 St Johns Blvd, Joplin, MO 64804, USA (C.D.); (S.R.)
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27
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Cicchinelli S, Gemma S, Pignataro G, Piccioni A, Ojetti V, Gasbarrini A, Franceschi F, Candelli M. Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators. Pharmaceuticals (Basel) 2024; 17:490. [PMID: 38675450 PMCID: PMC11053610 DOI: 10.3390/ph17040490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Fibrosis, sustained by the transformation of intestinal epithelial cells into fibroblasts (epithelial-to-mesenchymal transition, EMT), has been extensively studied in recent decades, with the molecular basis well-documented in various diseases, including inflammatory bowel diseases (IBDs). However, the factors influencing these pathways remain unclear. In recent years, the role of the gut microbiota in health and disease has garnered significant attention. Evidence suggests that an imbalanced or dysregulated microbiota, along with environmental and genetic factors, may contribute to the development of IBDs. Notably, microbes produce various metabolites that interact with host receptors and associated signaling pathways, influencing physiological and pathological changes. This review aims to present recent evidence highlighting the emerging role of the most studied metabolites as potential modulators of molecular pathways implicated in intestinal fibrosis and EMT in IBDs. These studies provide a deeper understanding of intestinal inflammation and fibrosis, elucidating the molecular basis of the microbiota role in IBDs, paving the way for future treatments.
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Affiliation(s)
- Sara Cicchinelli
- Department of Emergency, S.S. Filippo e Nicola Hospital, 67051 Avezzano, Italy;
| | - Stefania Gemma
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giulia Pignataro
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Andrea Piccioni
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Veronica Ojetti
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Marcello Candelli
- Department of Emergency, Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
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28
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Caffrey EB, Sonnenburg JL, Devkota S. Our extended microbiome: The human-relevant metabolites and biology of fermented foods. Cell Metab 2024; 36:684-701. [PMID: 38569469 DOI: 10.1016/j.cmet.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/06/2024] [Accepted: 03/11/2024] [Indexed: 04/05/2024]
Abstract
One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.
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Affiliation(s)
- Elisa B Caffrey
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
| | - Justin L Sonnenburg
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Center for Human Microbiome Studies, Stanford University School of Medicine, Stanford, CA, USA.
| | - Suzanne Devkota
- F. Widjaja Foundation Inflammatory Bowel Diseases Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Human Microbiome Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Bai J, Wang Y, Li F, Wu Y, Chen J, Li M, Wang X, Lv B. Research advancements and perspectives of inflammatory bowel disease: A comprehensive review. Sci Prog 2024; 107:368504241253709. [PMID: 38778725 PMCID: PMC11113063 DOI: 10.1177/00368504241253709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence, such as Crohn's disease and ulcerative colitis. The accurate etiology and pathogenesis of IBD remain unclear, and it is generally believed that it is related to genetic susceptibility, gut microbiota, environmental factors, immunological abnormalities, and potentially other factors. Currently, the mainstream therapeutic drugs are amino salicylic acid agents, corticosteroids, immunomodulators, and biological agents, but the remission rates do not surpass 30-60% of patients in a real-life setting. As a consequence, there are many studies focusing on emerging drugs and bioactive ingredients that have higher efficacy and long-term safety for achieving complete deep healing. This article begins with a review of the latest, systematic, and credible summaries of the pathogenesis of IBD. In addition, we provide a summary of the current treatments and drugs for IBD. Finally, we focus on the therapeutic effects of emerging drugs such as microRNAs and lncRNAs, nanoparticles-mediated drugs and natural products on IBD and their mechanisms of action.
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Affiliation(s)
- Junyi Bai
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Ying Wang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Fuhao Li
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yueyao Wu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jun Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Meng Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xi Wang
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Bin Lv
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
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Williams LM, Cao S. Harnessing and delivering microbial metabolites as therapeutics via advanced pharmaceutical approaches. Pharmacol Ther 2024; 256:108605. [PMID: 38367866 PMCID: PMC10985132 DOI: 10.1016/j.pharmthera.2024.108605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/05/2024] [Accepted: 02/08/2024] [Indexed: 02/19/2024]
Abstract
Microbial metabolites have emerged as key players in the interplay between diet, the gut microbiome, and host health. Two major classes, short-chain fatty acids (SCFAs) and tryptophan (Trp) metabolites, are recognized to regulate inflammatory, immune, and metabolic responses within the host. Given that many human diseases are associated with dysbiosis of the gut microbiome and consequent reductions in microbial metabolite production, the administration of these metabolites represents a direct, multi-targeted treatment. While a multitude of preclinical studies showcase the therapeutic potential of both SCFAs and Trp metabolites, they often rely on high doses and frequent dosing regimens to achieve systemic effects, thereby constraining their clinical applicability. To address these limitations, a variety of pharmaceutical formulations approaches that enable targeted, delayed, and/or sustained microbial metabolite delivery have been developed. These approaches, including enteric encapsulations, esterification to dietary fiber, prodrugs, and nanoformulations, pave the way for the next generation of microbial metabolite-based therapeutics. In this review, we first provide an overview of the roles of microbial metabolites in maintaining host homeostasis and outline how compromised metabolite production contributes to the pathogenesis of inflammatory, metabolic, autoimmune, allergic, infectious, and cancerous diseases. Additionally, we explore the therapeutic potential of metabolites in these disease contexts. Then, we provide a comprehensive and up-to-date review of the pharmaceutical strategies that have been employed to enhance the therapeutic efficacy of microbial metabolites, with a focus on SCFAs and Trp metabolites.
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Affiliation(s)
- Lindsey M Williams
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, United States
| | - Shijie Cao
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, United States.
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31
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Wu HX, Long CR, Zhang ZH, Chen YL, Wang YY, Xiang SJ, Zhou BJ. Tryptophan metabolism and liver fibrosis. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:192-198. [DOI: 10.11569/wcjd.v32.i3.192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2024]
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32
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Yang W, Yu T, Cong Y. Stromal Cell Regulation of Intestinal Inflammatory Fibrosis. Cell Mol Gastroenterol Hepatol 2024; 17:703-711. [PMID: 38246590 PMCID: PMC10958116 DOI: 10.1016/j.jcmgh.2024.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024]
Abstract
Intestinal inflammatory fibrosis is a severe consequence of inflammatory bowel diseases (IBDs). There is currently no cure for the treatment of intestinal fibrosis in IBD. Although inflammation is necessary for triggering fibrosis, the anti-inflammatory agents used to treat IBD are ineffective in preventing the progression of intestinal fibrosis and stricture formation once initiated, suggesting that inflammatory signals are not the sole drivers of fibrosis progression once it is established. Among multiple mechanisms involved in the initiation and progression of intestinal fibrosis in IBD, stromal cells play critical roles in mediating the process. In this review, we summarize recent progress on how stromal cells regulate intestinal fibrosis in IBD and how they are regulated by focusing on immune regulation and gut microbiota. We also outline the challenges moving forward in the field.
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Affiliation(s)
- Wenjing Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Center for Human Immunobiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Tianming Yu
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Center for Human Immunobiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Yingzi Cong
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Center for Human Immunobiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Reens AL, Cosetta CM, Saur R, Trofimuk O, Brooker SL, Lee ML, Sun AK, McKenzie GJ, Button JE. Tunable control of B. infantis abundance and gut metabolites by co-administration of human milk oligosaccharides. Gut Microbes 2024; 16:2304160. [PMID: 38235736 PMCID: PMC10798361 DOI: 10.1080/19490976.2024.2304160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 01/08/2024] [Indexed: 01/19/2024] Open
Abstract
Precision engineering of the gut microbiome holds promise as an effective therapeutic approach for diseases associated with a disruption in this microbial community. Engrafting a live biotherapeutic product (LBP) in a predictable, controllable manner is key to the consistent success of this approach and has remained a challenge for most LBPs under development. We recently demonstrated high-level engraftment of Bifidobacterium longum subsp. infantis (B. infantis) in adults when co-dosed with a specific prebiotic, human milk oligosaccharides (HMO). Here, we present a cellular kinetic-pharmacodynamic approach, analogous to pharmacokinetic-pharmacodynamic-based analyses of small molecule- and biologic-based drugs, to establish how HMO controls expansion, abundance, and metabolic output of B. infantis in a human microbiota-based model in gnotobiotic mice. Our data demonstrate that the HMO dose controls steady-state abundance of B. infantis in the microbiome, and that B. infantis together with HMO impacts gut metabolite levels in a targeted, HMO-dependent manner. We also found that HMO creates a privileged niche for B. infantis expansion across a 5-log range of bacterial inocula. These results demonstrate remarkable control of both B. infantis levels and the microbiome community metabolic outputs using this synbiotic approach, and pave the way for precision engineering of desirable microbes and metabolites to treat a range of diseases.
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Affiliation(s)
| | | | | | | | | | - Martin L. Lee
- Prolacta Bioscience, Duarte, CA, USA
- Department of Biostatistics, University of California Los Angeles Fielding School of Public Health, Los AngelesCA, USA
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Song Y, Lau HCH, Zhang X, Yu J. Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma. Cancer Biol Med 2023; 21:j.issn.2095-3941.2023.0394. [PMID: 38148326 PMCID: PMC10884537 DOI: 10.20892/j.issn.2095-3941.2023.0394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.
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Affiliation(s)
- Yang Song
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
- Department of Gastroenterology, Zhongshan Hospital Xiamen University, Xiamen 361004, China
| | - Harry CH Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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Li N, Ma P, Li Y, Shang X, Nan X, Shi L, Han X, Liu J, Hong Y, Li Q, Cui J, Li J, Peng G. Gut microbiota-derived 12-ketolithocholic acid suppresses the IL-17A secretion from colonic group 3 innate lymphoid cells to prevent the acute exacerbation of ulcerative colitis. Gut Microbes 2023; 15:2290315. [PMID: 38062857 PMCID: PMC10730201 DOI: 10.1080/19490976.2023.2290315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Intestinal microbiota dysbiosis and metabolic disruption are well-known as the primary triggers of ulcerative colitis (UC). However, their role in regulating the group 3 innate lymphoid cells (ILC3s), which are essential for intestinal health, remains unexplored during the development of disease severity. Here, our results showed that the microbiota structure of patients with severe UC (SUCs) differed from those with mild UC (MiUCs), moderate UC (MoUCs), and healthy controls (HCs). Microbes producing secondary bile acids (SBAs) and SBAs decreased with the aggravation of UC, and a strong positive correlation existed between them. Next, fecal microbiota transfer was used to reproduce the human-derived microbiota in mice and decipher the microbiota-mediated inflammatory modulation during an increase in disease severity. Mice receiving SUC-derived microbiota exhibited enhancive inflammation, a lowered percentage of ILC3s, and the down-regulated expressions of bile acid receptors, including vitamin D receptor (VDR) and pregnane X receptor (PXR), in the colon. Similar to clinical results, SBA-producing microbes, deoxycholic acids (DCA), and 12-ketolithocholic acids (12-KLCA) were diminished in the intestine of these recipients. Finally, we compared the therapeutic potential of DCA and 12-KLCA in preventing colitis and the regulatory mechanisms mediated by ILC3s. 12-KLCA but not DCA represented a strong anti-inflammatory effect associated with the higher expression of VDR and the lower secretion of IL-17A from colonic ILC3s. Collectively, these findings provide new signatures for monitoring the acute deterioration of UC by targeting gut microbiota and bile acid metabolism and demonstrate the therapeutic and preventive potential of a novel microbiota-derived metabolite, 12-KLCA.
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Affiliation(s)
- Na Li
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Peiguang Ma
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Yalan Li
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Xuekai Shang
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Xinmei Nan
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Lei Shi
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Xiao Han
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jiajing Liu
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Yanfei Hong
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Qiuyi Li
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Jiaqi Cui
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Junxiang Li
- Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Guiying Peng
- Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
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Krishnamurthy HK, Pereira M, Bosco J, George J, Jayaraman V, Krishna K, Wang T, Bei K, Rajasekaran JJ. Gut commensals and their metabolites in health and disease. Front Microbiol 2023; 14:1244293. [PMID: 38029089 PMCID: PMC10666787 DOI: 10.3389/fmicb.2023.1244293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose of review This review comprehensively discusses the role of the gut microbiome and its metabolites in health and disease and sheds light on the importance of a holistic approach in assessing the gut. Recent findings The gut microbiome consisting of the bacteriome, mycobiome, archaeome, and virome has a profound effect on human health. Gut dysbiosis which is characterized by perturbations in the microbial population not only results in gastrointestinal (GI) symptoms or conditions but can also give rise to extra-GI manifestations. Gut microorganisms also produce metabolites (short-chain fatty acids, trimethylamine, hydrogen sulfide, methane, and so on) that are important for several interkingdom microbial interactions and functions. They also participate in various host metabolic processes. An alteration in the microbial species can affect their respective metabolite concentrations which can have serious health implications. Effective assessment of the gut microbiome and its metabolites is crucial as it can provide insights into one's overall health. Summary Emerging evidence highlights the role of the gut microbiome and its metabolites in health and disease. As it is implicated in GI as well as extra-GI symptoms, the gut microbiome plays a crucial role in the overall well-being of the host. Effective assessment of the gut microbiome may provide insights into one's health status leading to more holistic care.
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Affiliation(s)
| | | | - Jophi Bosco
- Vibrant America LLC., San Carlos, CA, United States
| | | | | | | | - Tianhao Wang
- Vibrant Sciences LLC., San Carlos, CA, United States
| | - Kang Bei
- Vibrant Sciences LLC., San Carlos, CA, United States
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Zou C, Zan X, Jia Z, Zheng L, Gu Y, Liu F, Han Y, Xu C, Wu A, Zhi Q. Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives. Clin Transl Med 2023; 13:e1479. [PMID: 37983927 PMCID: PMC10659771 DOI: 10.1002/ctm2.1479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/07/2023] [Accepted: 11/03/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Alternative splicing (AS) is an omnipresent regulatory mechanism of gene expression that enables the generation of diverse splice isoforms from a single gene. Recently, AS events have gained considerable momentum in the pathogenesis of inflammatory bowel disease (IBD). METHODS Our review has summarized the complex process of RNA splicing, and firstly highlighted the potential involved molecules that target aberrant splicing events in IBD. The quantitative transcriptome analyses such as microarrays, next-generation sequencing (NGS) for AS events in IBD have been also discussed. RESULTS Available evidence suggests that some abnormal splicing RNAs can lead to multiple intestinal disorders during the onset of IBD as well as the progression to colitis-associated cancer (CAC), including gut microbiota perturbations, intestinal barrier dysfunctions, innate/adaptive immune dysregulations, pro-fibrosis activation and some other risk factors. Moreover, current data show that the advanced technologies, including microarrays and NGS, have been pioneeringly employed to screen the AS candidates and elucidate the potential regulatory mechanisms of IBD. Besides, other biotechnological progresses such as the applications of third-generation sequencing (TGS), single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), will be desired with great expectations. CONCLUSIONS To our knowledge, the current review is the first one to evaluate the potential regulatory mechanisms of AS events in IBD. The expanding list of aberrantly spliced genes in IBD along with the developed technologies provide us new clues to how IBD develops, and how these important AS events can be explored for future treatment.
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Affiliation(s)
- Chentao Zou
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xinquan Zan
- Department of General SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Zhenyu Jia
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Lu Zheng
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Yijie Gu
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Fei Liu
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Ye Han
- Department of General SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Chunfang Xu
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Airong Wu
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Qiaoming Zhi
- Department of General SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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38
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Button JE, Cosetta CM, Reens AL, Brooker SL, Rowan-Nash AD, Lavin RC, Saur R, Zheng S, Autran CA, Lee ML, Sun AK, Alousi AM, Peterson CB, Koh AY, Rechtman DJ, Jenq RR, McKenzie GJ. Precision modulation of dysbiotic adult microbiomes with a human-milk-derived synbiotic reshapes gut microbial composition and metabolites. Cell Host Microbe 2023; 31:1523-1538.e10. [PMID: 37657443 DOI: 10.1016/j.chom.2023.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/13/2023] [Accepted: 08/07/2023] [Indexed: 09/03/2023]
Abstract
Manipulation of the gut microbiome using live biotherapeutic products shows promise for clinical applications but remains challenging to achieve. Here, we induced dysbiosis in 56 healthy volunteers using antibiotics to test a synbiotic comprising the infant gut microbe, Bifidobacterium longum subspecies infantis (B. infantis), and human milk oligosaccharides (HMOs). B. infantis engrafted in 76% of subjects in an HMO-dependent manner, reaching a relative abundance of up to 81%. Changes in microbiome composition and gut metabolites reflect altered recovery of engrafted subjects compared with controls. Engraftment associates with increases in lactate-consuming Veillonella, faster acetate recovery, and changes in indolelactate and p-cresol sulfate, metabolites that impact host inflammatory status. Furthermore, Veillonella co-cultured in vitro and in vivo with B. infantis and HMO converts lactate produced by B. infantis to propionate, an important mediator of host physiology. These results suggest that the synbiotic reproducibly and predictably modulates recovery of a dysbiotic microbiome.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Martin L Lee
- Prolacta Bioscience, Duarte, CA 91010, USA; Department of Biostatistics, University of California Los Angeles, Fielding School of Public Health, Los Angeles, CA 90095, USA
| | - Adam K Sun
- Prolacta Bioscience, Duarte, CA 91010, USA
| | - Amin M Alousi
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Christine B Peterson
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Andrew Y Koh
- Department of Pediatrics, Division of Hematology/Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | | | - Robert R Jenq
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Amini SE, Bresson SE, Ruzzin J. Mice lacking intestinal Nr1i2 have normal intestinal homeostasis under steady-state conditions and are not hypersensitive to inflammation under lipopolysaccharide treatment. FASEB J 2023; 37:e23117. [PMID: 37490003 DOI: 10.1096/fj.202301126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/14/2023] [Indexed: 07/26/2023]
Abstract
Nr1i2, a nuclear receptor known for its key function in xenobiotic detoxification, has emerged as a potential regulator of intestinal homeostasis and inflammation. However, the role of Nr1i2 in different intestinal segments remains poorly known. Moreover, in vivo investigations on intestinal Nr1i2 have essentially been performed in whole-body Nr1i2 knockout (Nr1i2-/- ) mice where the deletion of Nr1i2 in all tissues may affect the intestinal phenotype. To better understand the role of Nr1i2 in the intestine, we generated intestinal epithelial-specific Nr1i2 knockout (iNr1i2-/- ) mice and studied the duodenum, jejunum, ileum, and colon of these animals during steady-state conditions and lipopolysaccharide (LPS)-induced inflammation. As compared to control (iNr1i2+/+ ) mice, iNr1i2-/- mice showed normal intestinal permeability as assessed by in vivo FITC-dextran test. The expression of genes involved in inflammation, tight- and adherens-junction, proliferation, glucose, and lipid metabolism was comparable in the duodenum, jejunum, ileum, and colon of iNr1i2-/- and iNr1i2+/+ mice. In line with these findings, histological analyses of the jejunum revealed no difference between iNr1i2-/- and iNr1i2+/+ mice. When treated with LPS, the intestine of iNr1i2-/- mice had no increased inflammatory response as compared to iNr1i2+/+ mice. Moreover, the health monitoring of LPS-treated iNr1i2-/- and iNr1i2+/+ mice was similar. Taken together, our results demonstrate that the specific deletion of Nr1i2 in the intestinal epithelium does not cause major intestinal damages in mice during both steady-state and inflammatory conditions.
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Affiliation(s)
- Salah Edden Amini
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sophie Emilie Bresson
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jérôme Ruzzin
- Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
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Kim S, Li H, Jin Y, Armad J, Gu H, Mani S, Cui JY. Maternal PBDE exposure disrupts gut microbiome and promotes hepatic proinflammatory signaling in humanized PXR-transgenic mouse offspring over time. Toxicol Sci 2023; 194:209-225. [PMID: 37267213 PMCID: PMC10375318 DOI: 10.1093/toxsci/kfad056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023] Open
Abstract
Developmental exposure to the persistent environmental pollutant, polybrominated diphenyl ethers (PBDEs), is associated with increased diabetes prevalence. The microbial tryptophan metabolite, indole-3-propionic acid (IPA), is associated with reduced risk of type 2 diabetes and lower-grade inflammation and is a pregnane X receptor (PXR) activator. To explore the role of IPA in modifying the PBDE developmental toxicity, we orally exposed humanized PXR-transgenic (hPXR-TG) mouse dams to vehicle, 0.1 mg/kg/day DE-71 (an industrial PBDE mixture), DE-71+IPA (20 mg/kg/day), or IPA, from 4 weeks preconception to the end of lactation. Pups were weaned at 21 days of age and IPA supplementation continued in the corresponding treatment groups. Tissues were collected at various ages until 6 months of age (n = 5 per group). In general, the effect of maternal DE-71 exposure on the gut microbiome of pups was amplified over time. The regulation of hepatic cytokines and prototypical xenobiotic-sensing transcription factor target genes by DE-71 and IPA was age- and sex-dependent, where DE-71-mediated mRNA increased selected cytokines (Il10, Il12p40, Il1β [both sexes], and [males]). The hepatic mRNA of the aryl hydrocarbon receptor (AhR) target gene Cyp1a2 was increased by maternal DE-71 and DE-71+IPA exposure at postnatal day 21 but intestinal Cyp1a1 was not altered by any of the exposures and ages. Maternal DE-71 exposure persistently increased serum indole, a known AhR ligand, in age- and sex-dependent manner. In conclusion, maternal DE-71 exposure produced a proinflammatory signature along the gut-liver axis, including gut dysbiosis, dysregulated tryptophan microbial metabolism, attenuated PXR signaling, and elevated AhR signaling in postweaned hPXR-TG pups over time, which was partially corrected by IPA supplementation.
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Affiliation(s)
- Sarah Kim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
| | - Hao Li
- Departments of Medicine, Molecular Pharmacology, and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
| | - Yan Jin
- Center for Translational Science, Florida International University, Port St. Lucie, Florida 34987-2352, USA
| | - Jasmine Armad
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
| | - Haiwei Gu
- Center for Translational Science, Florida International University, Port St. Lucie, Florida 34987-2352, USA
| | - Sridhar Mani
- Departments of Medicine, Molecular Pharmacology, and Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
| | - Julia Y Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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Li S. Modulation of immunity by tryptophan microbial metabolites. Front Nutr 2023; 10:1209613. [PMID: 37521424 PMCID: PMC10382180 DOI: 10.3389/fnut.2023.1209613] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/30/2023] [Indexed: 08/01/2023] Open
Abstract
Tryptophan (Trp) is an essential amino acid that can be metabolized via endogenous and exogenous pathways, including the Kynurenine Pathway, the 5-Hydroxyindole Pathway (also the Serotonin pathway), and the Microbial pathway. Of these, the Microbial Trp metabolic pathways in the gut have recently been extensively studied for their production of bioactive molecules. The gut microbiota plays an important role in host metabolism and immunity, and microbial Trp metabolites can influence the development and progression of various diseases, including inflammatory, cardiovascular diseases, neurological diseases, metabolic diseases, and cancer, by mediating the body's immunity. This review briefly outlines the crosstalk between gut microorganisms and Trp metabolism in the body, starting from the three metabolic pathways of Trp. The mechanisms by which microbial Trp metabolites act on organism immunity are summarized, and the potential implications for disease prevention and treatment are highlighted.
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Wang S, Xiong L, Ruan Z, Gong X, Luo Y, Wu C, Wang Y, Shang H, Chen J. Indole-3-propionic acid alleviates sepsis-associated acute liver injury by activating pregnane X receptor. Mol Med 2023; 29:65. [PMID: 37208586 DOI: 10.1186/s10020-023-00658-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/24/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND The morbidity and mortality of sepsis are extremely high, which is a major problem plaguing human health. However, current drugs and measures for the prevention and treatment of sepsis have little effect. Sepsis-associated acute liver injury (SALI) is an independent risk factor for sepsis, which seriously affects the prognosis of sepsis. Studies have found that gut microbiota is closely related to SALI, and indole-3-propionic Acid (IPA) can activate Pregnane X receptor (PXR). However, the role of IPA and PXR in SALI has not been reported. METHODS This study aimed to explore the association between IPA and SALI. The clinical data of SALI patients were collected and IPA level in feces was detected. The sepsis model was established in wild-type mice and PXR knockout mice to investigate the role of IPA and PXR signaling in SALI. RESULTS We showed that the level of IPA in patients' feces is closely related to SALI, and the level of IPA in feces has a good ability to identify and diagnose SALI. IPA pretreatment significantly attenuated septic injury and SALI in wild-type mice, but not found in knockout PXR gene mice. CONCLUSIONS IPA alleviates SALI by activating PXR, which reveals a new mechanism of SALI, and provides potentially effective drugs and targets for the prevention of SALI.
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Affiliation(s)
- Shuang Wang
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Liangzhi Xiong
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Zhihua Ruan
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Xiaofang Gong
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Yanrong Luo
- Physical examination center, Shiyan Hospital of Integrated Traditional and Western Medicine, Shiyan, 442000, Hubei, China
| | - Chengyi Wu
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Yu Wang
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
| | - Hui Shang
- Department of Orthopaedic, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
| | - Jingyi Chen
- Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
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Pan T, Pei Z, Fang Z, Wang H, Zhu J, Zhang H, Zhao J, Chen W, Lu W. Uncovering the specificity and predictability of tryptophan metabolism in lactic acid bacteria with genomics and metabolomics. Front Cell Infect Microbiol 2023; 13:1154346. [PMID: 36992687 PMCID: PMC10040830 DOI: 10.3389/fcimb.2023.1154346] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/01/2023] [Indexed: 03/16/2023] Open
Abstract
Tryptophan is metabolized by microorganisms into various indole derivatives that have been proven to alleviate diseases and promote human health. Lactic acid bacteria (LAB) are a broad microbial concept, some of which have been developed as probiotics. However, the capacity of most LAB to metabolize tryptophan is unknown. In this study, the aim is to reveal the rule of tryptophan metabolism in LAB by multi-omics. The findings showed that LAB were rich in genes for tryptophan catabolism and that multiple genes were shared among LAB species. Although the number of their homologous sequences was different, they could still form the same metabolic enzyme system. The metabolomic analysis revealed that LAB were capable of producing a variety of metabolites. Strains belonging to the same species can produce the same metabolites and have similar yields. A few strains showed strain-specificity in the production of indole-3-lactic acid (ILA), indole-3-acetic acid, and 3-indolealdehyde (IAld). In the genotype-phenotype association analysis, the metabolites of LAB were found to be highly consistent with the outcomes of gene prediction, particularly ILA, indole-3-propionic acid, and indole-3-pyruvic acid. The overall prediction accuracy was more than 87% on average, which indicated the predictability of tryptophan metabolites of LAB. Additionally, genes influenced the concentration of metabolites. The levels of ILA and IAld were significantly correlated with the numbers of aromatic amino acid aminotransferase and amidase, respectively. The unique indolelactate dehydrogenase in Ligilactobacillus salivarius was the primary factor contributing to its large production of ILA. In summary, we demonstrated the gene distribution and production level of tryptophan metabolism in LAB and explored the correlation between genes and phenotypes. The predictability and specificity of the tryptophan metabolites in LAB were proven. These results provide a novel genomic method for the discovery of LAB with tryptophan metabolism potential and offer experimental data for probiotics that produce specific tryptophan metabolites.
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Affiliation(s)
- Tong Pan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Zhangming Pei
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Zhifeng Fang
- School of Food Science and Technology, Shihezi University, Shihezi, China
| | - Hongchao Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jinlin Zhu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
| | - Wenwei Lu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou, China
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi, China
- *Correspondence: Wenwei Lu,
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