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Antonini Cencicchio M, Montini F, Palmieri V, Massimino L, Lo Conte M, Finardi A, Mandelli A, Asnicar F, Pavlovic R, Drago D, Ungaro F, Andolfo A, Segata N, Martinelli V, Furlan R, Falcone M. Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity. Cell Rep Med 2025:102028. [PMID: 40101713 DOI: 10.1016/j.xcrm.2025.102028] [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: 02/21/2024] [Revised: 09/25/2024] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3+ regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.
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Affiliation(s)
| | - Federico Montini
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy; Clinical Neurology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Vittoria Palmieri
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy
| | - Luca Massimino
- Experimental Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Marta Lo Conte
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy
| | - Annamaria Finardi
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Alessandra Mandelli
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Radmila Pavlovic
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Denise Drago
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Federica Ungaro
- Experimental Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Gastroenterology and Digestive Endoscopy Department, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Nicola Segata
- Department CIBIO, University of Trento, 38123 Trento, Italy
| | | | - Roberto Furlan
- Clinical Neuroimmunology Unit, INSPE, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marika Falcone
- Autoimmune Pathogenesis Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan Italy.
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Liu Y, Li F, Wang J, Yang R. Exploring effects of gut microbiota on tertiary lymphoid structure formation for tumor immunotherapy. Front Immunol 2025; 15:1518779. [PMID: 40124706 PMCID: PMC11925796 DOI: 10.3389/fimmu.2024.1518779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/20/2024] [Indexed: 03/25/2025] Open
Abstract
Anti-tumor immunity, including innate and adaptive immunity is critical in inhibiting tumorigenesis and development of tumor. The adaptive immunity needs specific lymph organs such as tertiary lymphoid structures (TLSs), which are highly correlated with improved survival outcomes in many cancers. In recent years, with increasing attention on the TLS in tumor microenvironment, TLSs have emerged as a novel target for anti-tumor therapy. Excitingly, studies have shown the contribution of TLSs to the adaptive immune responses. However, it is unclear how TLSs to form and how to more effectively defense against tumor through TLS formation. Recent studies have shown that the inflammation plays a critical role in TLS formation. Interestingly, studies have also found that gut microbiota can regulate the occurrence and development of inflammation. Therefore, we here summarize the potential effects of gut microbiota- mediated inflammation or immunosuppression on the TLS formation in tumor environments. Meanwhile, this review also explores how to manipulate mature TLS formation through regulating gut microbiota/metabolites or gut microbiota associated signal pathways for anti-tumor immunity, which potentially lead to a next-generation cancer immunotherapy.
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Affiliation(s)
- Yuqing Liu
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Fan Li
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Juanjuan Wang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Rongcun Yang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
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3
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Lu X, Xv Y, Hu W, Sun B, Hu H. Targeting CD4+ T cells through gut microbiota: therapeutic potential of traditional Chinese medicine in inflammatory bowel disease. Front Cell Infect Microbiol 2025; 15:1557331. [PMID: 40099014 PMCID: PMC11911530 DOI: 10.3389/fcimb.2025.1557331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/18/2025] [Indexed: 03/19/2025] Open
Abstract
Inflammatory Bowel Disease (IBD) is an autoimmune disease characterized by chronic relapsing inflammation of the intestinal tract. Gut microbiota (GM) and CD4+T cells are important in the development of IBD. A lot of studies have shown that GM and their metabolites like short-chain fatty acids, bile acids and tryptophan can be involved in the differentiation of CD4+T cells through various mechanisms, which in turn regulate the immune homeostasis of the IBD patients. Therefore, regulating CD4+T cells through GM may be a potential therapeutic direction for the treatment of IBD. Many studies have shown that Traditional Chinese Medicine (TCM) formulas and some herbal extracts can affect CD4+T cell differentiation by regulating GM and its metabolites. In this review, we mainly focus on the role of GM and their metabolites in regulating the differentiation of CD4+T cells and their correlation with IBD. We also summarize the current research progress on the regulation of this process by TCM.
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Affiliation(s)
- Xingyao Lu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yichuan Xv
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiye Hu
- Department of Liver Disease, Shanghai Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Boyun Sun
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongyi Hu
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Li Z, Deng L, Cheng M, Ye X, Yang N, Fan Z, Sun L. Emerging role of bile acids in colorectal liver metastasis: From molecular mechanism to clinical significance (Review). Int J Oncol 2025; 66:24. [PMID: 39981904 PMCID: PMC11844338 DOI: 10.3892/ijo.2025.5730] [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: 10/25/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.
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Affiliation(s)
- Zhaoyu Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Lingjun Deng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Mengting Cheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Xiandong Ye
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Nanyan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
| | - Li Sun
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
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Peterson D, Weidenmaier C, Timberlake S, Gura Sadovsky R. Depletion of key gut bacteria predicts disrupted bile acid metabolism in inflammatory bowel disease. Microbiol Spectr 2025; 13:e0199924. [PMID: 39670752 PMCID: PMC11792471 DOI: 10.1128/spectrum.01999-24] [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: 08/10/2024] [Accepted: 11/15/2024] [Indexed: 12/14/2024] Open
Abstract
The gut microbiome plays a key role in bile acid (BA) metabolism, where a diversity of metabolic products contribute to human health and disease. In particular, Inflammatory Bowel Disease (IBD) is characterized by a low concentration of secondary bile acids (SBAs), whose transformation from primary bile acids (PBAs) is an essential function performed solely by gut bacteria. BA-transformation activity mediated by the bile acid inducible (bai) operon has been functionally characterized in the genus Clostridium, and homologous bai gene sequences have been found in metagenome-assembled genomes (MAGs) belonging to other taxa in the human gut, but it is unclear which species of bai-carrying bacteria perform physiologically significant amounts of bile acid transformation in healthy and sick individuals. Here, we analyzed hundreds of stool samples with paired metagenomic and metabolomic data from IBD patients and controls and found that the abundance of the bai operon in metagenomic samples was highly predictive of that sample's high- or low-SBA metabolic state. We further found that bai genes from the Clostridium species best characterized as BA transformers were more prevalent in IBD patients than in non-IBD controls, while bai genes from uncharacterized taxa known only from MAGs were much more physiologically relevant in non-IBD samples. These un-isolated clades of BA-transforming bacteria merit further research; as beyond their prevalence in the human population, we found some cases in which they engrafted in IBD patients who had undergone fecal microbiota transplantation and experienced a clinical response.IMPORTANCEIn this paper, we identify specific bacteria that perform an important metabolic function in the human gut and demonstrate that in the guts of a large subset of patients with IBD, these bacteria are missing and the function is defective. This is a rare example where the correlation between the absence of specific bacteria and the dysfunction of metabolism is directly observed, not in mice nor in the lab, but in physiologic microbial communities in the human gut. Our results point to a path for studying how a small but important set of bacteria is affected by conditions in the IBD gut and perhaps to the development of interventions to mitigate the loss of these bacteria in IBD.
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Mir R, Albarqi SA, Albalawi W, Alatwi HE, Alatawy M, Bedaiwi RI, Almotairi R, Husain E, Zubair M, Alanazi G, Alsubaie SS, Alghabban RI, Alfifi KA, Bashir S. Emerging Role of Gut Microbiota in Breast Cancer Development and Its Implications in Treatment. Metabolites 2024; 14:683. [PMID: 39728464 DOI: 10.3390/metabo14120683] [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: 10/15/2024] [Revised: 11/14/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Background: The human digestive system contains approximately 100 trillion bacteria. The gut microbiota is an emerging field of research that is associated with specific biological processes in many diseases, including cardiovascular disease, obesity, diabetes, brain disease, rheumatoid arthritis, and cancer. Emerging evidence indicates that the gut microbiota affects the response to anticancer therapies by modulating the host immune system. Recent studies have explained a high correlation between the gut microbiota and breast cancer: dysbiosis in breast cancer may regulate the systemic inflammatory response, hormone metabolism, immune response, and the tumor microenvironment. Some of the gut bacteria are related to estrogen metabolism, which may increase or decrease the risk of breast cancer by changing the number of hormones. Further, the gut microbiota has been seen to modulate the immune system in respect of its ability to protect against and treat cancers, with a specific focus on hormone receptor-positive breast cancer. Probiotics and other therapies claiming to control the gut microbiome by bacterial means might be useful in the prevention, or even in the treatment, of breast cancer. Conclusions: The present review underlines the various aspects of gut microbiota in breast cancer risk and its clinical application, warranting research on individualized microbiome-modulated therapeutic approaches to breast cancer treatment.
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Affiliation(s)
- Rashid Mir
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, Prince Fahd Bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Shrooq A Albarqi
- Molecular Medicine, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Wed Albalawi
- Molecular Medicine, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Hanan E Alatwi
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Marfat Alatawy
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Ruqaiah I Bedaiwi
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, Prince Fahd Bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Reema Almotairi
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, Prince Fahd Bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Eram Husain
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, Prince Fahd Bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Mohammad Zubair
- Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Ghaida Alanazi
- Molecular Medicine, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Shouq S Alsubaie
- Molecular Medicine, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Razan I Alghabban
- Molecular Medicine, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Khalid A Alfifi
- Department of Laboratory and Blood Bank, King Fahd Special Hospital, Tabuk 47717, Saudi Arabia
| | - Shabnam Bashir
- Mubarak Hospital, Srinagar 190002, Jammu and Kashmir, India
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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8
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Liu R, Wang J, Liu Y, Gao Y, Yang R. Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor. Cancer Lett 2024; 598:217115. [PMID: 39025428 DOI: 10.1016/j.canlet.2024.217115] [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: 02/21/2024] [Revised: 06/26/2024] [Accepted: 07/09/2024] [Indexed: 07/20/2024]
Abstract
Gut microbiota contributes to the homeostasis of immune system and is related to various diseases such as tumorigenesis. Ferroptosis, a new type of cell death, is also involved in the disease pathogenesis. Recent studies have found the correlations of gut microbiota mediated ferroptosis and immune cell death. Gut microbiota derived immunosuppressive metabolites, which can promote differentiation and function of immune cells, tend to inhibit ferroptosis through their receptors, whereas inflammatory metabolites from gut microbiota also affect the differentiation and function of immune cells and their ferroptosis. Thus, it is possible for gut microbiota to regulate immune cell ferroptosis. Indeed, gut microbiota metabolite receptor aryl hydrocarbon receptor (AhR) can affect ferroptosis of intestinal intraepithelial lymphocytes, leading to disease pathogenesis. Since immune cell ferroptosis in tumor microenvironment (TME) affects the occurrence and development of tumor, the modulation of gut microbiota in these cell ferroptosis might influence on the tumorigenesis, and also immunotherapy against tumors. Here we will summarize the recent advance of ferroptosis mediated by gut microbiota metabolites, which potentially acts as regulator(s) on immune cells in TME for therapy against tumor.
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Affiliation(s)
- Ruobing Liu
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Juanjuan Wang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Yuqing Liu
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Yunhuan Gao
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Rongcun Yang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China.
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Cheng W, Zhu N, Wang J, Yang R. A role of gut microbiota metabolites in HLA-E and NKG2 blockage immunotherapy against tumors: new insights for clinical application. Front Immunol 2024; 15:1331518. [PMID: 39229258 PMCID: PMC11368731 DOI: 10.3389/fimmu.2024.1331518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 07/16/2024] [Indexed: 09/05/2024] Open
Abstract
One of major breakthroughs in immunotherapy against tumor is from blocking immune checkpoint molecules on tumor and reactive T cells. The development of CTLA-4 and PD-1 blockage antibodies has triggered to search for additional effective therapeutic strategies. This causes recent findings that blocking the interaction of checkpoint molecule NKG2A in NK and CD8 T cells with HLA-E in tumors is effective in defensing tumors. Interestingly, gut microbiota also affects this immune checkpoint immunotherapy against tumor. Gut microbiota such as bacteria can contribute to the regulation of host immune response and homeostasis. They not only promote the differentiation and function of immunosuppressive cells but also the inflammatory cells through the metabolites such as tryptophan (Trp) and bile acid (BA) metabolites as well as short chain fatty acids (SCFAs). These gut microbiota metabolites (GMMs) educated immune cells can affect the differentiation and function of effective CD8 and NK cells. Notably, these metabolites also directly affect the activity of CD8 and NK cells. Furthermore, the expression of CD94/NKG2A in the immune cells and/or their ligand HLA-E in the tumor cells is also regulated by gut microbiota associated immune factors. These findings offer new insights for the clinical application of gut microbiota in precise and/or personalized treatments of tumors. In this review, we will discuss the impacts of GMMs and GMM educated immune cells on the activity of effective CD8 and NK cells and the expression of CD94/NKG2A in immune cells and/or their ligand HLA-E in tumor cells.
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Affiliation(s)
- Wenyue Cheng
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Ningning Zhu
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Juanjuan Wang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Rongcun Yang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [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: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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11
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Cheng W, Li F, Yang R. The Roles of Gut Microbiota Metabolites in the Occurrence and Development of Colorectal Cancer: Multiple Insights for Potential Clinical Applications. GASTRO HEP ADVANCES 2024; 3:855-870. [PMID: 39280926 PMCID: PMC11401567 DOI: 10.1016/j.gastha.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 05/21/2024] [Indexed: 09/18/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. The occurrence and development of CRC are related to multiple risk factors such as gut microbiota. Indeed, gut microbiota plays an important role in the different phases of colorectal cancers (CRCs) from oncogenesis to metastasis. Some specific bacteria such as Fusobacterium nucleatum (F. nucleatum) associated with CRCs have been found. However, recently identified bile acid and tryptophan metabolites as well as short chain fatty acids (SCFAs), which are derived from gut microbiota, can also exert effects on the CRCs such as that SCFAs directly inhibit CRC growth. Importantly these metabolites also modulate immune responses to affect CRCs. They not only act as tumor inhibiting factor(s) but also promotor(s) in the occurrence, development, and metastasis of CRCs. While gut microbiota metabolites (GMMs) inhibit immunity against CRCs, some of them also improve immune responses to CRCs. Notably, GMMs also potentially affect the shaping of immune-privileged metastatic niches through direct roles or immune cells such as macrophages and myeloid-derived suppressive cells. These findings offer new insights for clinical application of gut microbiota in precise and personalized treatments of CRCs. Here, we will mainly discuss direct and indirect (via immune cells) effects of GMMs, especially SCFAs, bile acid and tryptophan metabolites on the occurrence, development and metastasis of CRCs.
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Affiliation(s)
- Wenyue Cheng
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Fan Li
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Rongcun Yang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
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12
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Crouch LI, Rodrigues CS, Bakshani CR, Tavares-Gomes L, Gaifem J, Pinho SS. The role of glycans in health and disease: Regulators of the interaction between gut microbiota and host immune system. Semin Immunol 2024; 73:101891. [PMID: 39388764 DOI: 10.1016/j.smim.2024.101891] [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: 08/02/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
The human gut microbiota is home to a diverse collection of microorganisms that has co-evolved with the host immune system in which host-microbiota interactions are essential to preserve health and homeostasis. Evidence suggests that the perturbation of this symbiotic host-microbiome relationship contributes to the onset of major diseases such as chronic inflammatory diseases including Inflammatory Bowel Disease. The host glycocalyx (repertoire of glycans/sugar-chains at the surface of gut mucosa) constitutes a major biological and physical interface between the intestinal mucosa and microorganisms, as well as with the host immune system. Glycans are an essential niche for microbiota colonization and thus an important modulator of host-microorganism interactions both in homeostasis and in disease. In this review, we discuss the role of gut mucosa glycome as an instrumental pathway that regulates host-microbiome interactions in homeostasis but also in health to inflammation transition. We also discuss the power of mucosa glycosylation remodelling as an attractive preventive and therapeutic strategy to preserve gut homeostasis.
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Affiliation(s)
- Lucy I Crouch
- Department of Microbes, Infection and Microbiomes, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK.
| | - Cláudia S Rodrigues
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
| | - Cassie R Bakshani
- Department of Microbes, Infection and Microbiomes, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
| | - Leticia Tavares-Gomes
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Joana Gaifem
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Salomé S Pinho
- i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal.
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13
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Li Y, Zhu C, Yao J, Zhu C, Li Z, Liu HY, Zhu M, Li K, Ahmed AA, Li S, Hu P, Cai D. Lithocholic Acid Alleviates Deoxynivalenol-Induced Inflammation and Oxidative Stress via PPARγ-Mediated Epigenetically Transcriptional Reprogramming in Porcine Intestinal Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:5452-5462. [PMID: 38428036 DOI: 10.1021/acs.jafc.3c08044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Deoxynivalenol (DON) is a common mycotoxin that induces intestinal inflammation and oxidative damage in humans and animals. Given that lithocholic acid (LCA) has been suggested to inhibit intestinal inflammation, we aimed to investigate the protective effects of LCA on DON-exposed porcine intestinal epithelial IPI-2I cells and the underlying mechanisms. Indeed, LCA rescued DON-induced cell death in IPI-2I cells and reduced DON-stimulated inflammatory cytokine levels and oxidative stress. Importantly, the nuclear receptor PPARγ was identified as a key transcriptional factor involved in the DON-induced inflammation and oxidative stress processes in IPI-2I cells. The PPARγ function was found compromised, likely due to the hyperphosphorylation of the p38 and ERK signaling pathways. In contrast, the DON-induced inflammatory responses and oxidative stress were restrained by LCA via PPARγ-mediated reprogramming of the core inflammatory and antioxidant genes. Notably, the PPARγ-modulated transcriptional regulations could be attributed to the altered recruitments of coactivator SRC-1/3 and corepressor NCOR1/2, along with the modified histone marks H3K27ac and H3K18la. This study emphasizes the protective actions of LCA on DON-induced inflammatory damage and oxidative stress in intestinal epithelial cells via PPARγ-mediated epigenetically transcriptional reprogramming, including histone acetylation and lactylation.
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Affiliation(s)
- Yanwei Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Chuyang Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Jiacheng Yao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Cuipeng Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Zhaojian Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Hao-Yu Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Miaonan Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Kaiqi Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Abdelkareem A Ahmed
- Department of Veterinary Biomedical Sciences, Botswana University of Agriculture and Natural Resources, Gaborone 0027, Botswana
| | - Shicheng Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
| | - Ping Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
| | - Demin Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
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14
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Wang J, Zhu N, Su X, Yang R. Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors. Cancer Lett 2024; 582:216582. [PMID: 38065401 DOI: 10.1016/j.canlet.2023.216582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/17/2023] [Accepted: 11/30/2023] [Indexed: 01/16/2024]
Abstract
Tumor cells can evade immune surveillance by expressing immune checkpoint molecule ligands, resulting in effective immune cell inactivation. Immune checkpoint blockades (ICBs) have dramatically improved survival of patients with multiple types of cancers. However, responses to ICB immunotherapy are heterogeneous with lower patient response rates. The advances have established that the gut microbiota can be as a promising target to overcome resistance to ICB immunotherapy. Furthermore, some bacterial species have shown to promote improved responses to ICBs. However, gut microbiota is critical in maintaining gut and systemic immune homeostasis. It not only promotes differentiation and function of immunosuppressive immune cells but also inhibits inflammatory cells via gut microbiota derived products such as short chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, which play an important role in tumor immunity. Since the gut microbiota can either inhibit or enhance immune against tumor, it should be a double-edged sword in ICBs against tumor. In this review, we discuss the effects of gut microbiota on immune cells and also tumor cells, especially enhances of gut microbiota on ICB immunotherapy. These discussions can hopefully promote the development of ICB immunotherapy.
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Affiliation(s)
- Juanjuan Wang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
| | - Ningning Zhu
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
| | - Xiaomin Su
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
| | - Rongcun Yang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, 300071, China; Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
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15
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Pan Y, Zhang H, Li M, He T, Guo S, Zhu L, Tan J, Wang B. Novel approaches in IBD therapy: targeting the gut microbiota-bile acid axis. Gut Microbes 2024; 16:2356284. [PMID: 38769683 PMCID: PMC11110704 DOI: 10.1080/19490976.2024.2356284] [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: 01/10/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.
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Affiliation(s)
- Yinping Pan
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Haojie Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Minghui Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Tingjing He
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Sihao Guo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical engineering, Chongqing University of Education, Chongqing, PR China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, PR China
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16
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Thiele Orberg E, Meedt E, Hiergeist A, Xue J, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen KP, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, van den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E, Poeck H. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. NATURE CANCER 2024; 5:187-208. [PMID: 38172339 DOI: 10.1038/s43018-023-00669-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 10/13/2023] [Indexed: 01/05/2024]
Abstract
The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies.
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Affiliation(s)
- Erik Thiele Orberg
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
- German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, Munich, Germany.
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
| | - Elisabeth Meedt
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Andreas Hiergeist
- Institute of Clinical Microbiology and Hygiene, University Medical Center, Regensburg, Germany
| | - Jinling Xue
- Institute of Virology, Helmholtz Zentrum Munich, Munich, Germany
- Chair of Prevention for Microbial Infectious Disease, Central Institute of Disease Prevention and School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Paul Heinrich
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Jinlong Ru
- Institute of Virology, Helmholtz Zentrum Munich, Munich, Germany
- Chair of Prevention for Microbial Infectious Disease, Central Institute of Disease Prevention and School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Sakhila Ghimire
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Oriana Miltiadous
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sarah Lindner
- Department of Immunology, Sloan Kettering Institute, New York, NY, USA
| | - Melanie Tiefgraber
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Sophia Göldel
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Tina Eismann
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Alix Schwarz
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Sascha Göttert
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Sebastian Jarosch
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, Munich, Germany
- Comparative Experimental Pathology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christian Schulz
- Department of Internal Medicine II, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Michael Gigl
- Bavarian Center for Biomolecular Mass Spectrometry, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Julius C Fischer
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar TUM, Munich, Germany
| | - Klaus-Peter Janssen
- Department of Surgery, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar TUM, Munich, Germany
| | - Michael Quante
- Department of Internal Medicine II, University Medical Center, Freiburg, Germany
| | - Simon Heidegger
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Peter Herhaus
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Mareike Verbeek
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Jürgen Ruland
- German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany
| | - Marcel R M van den Brink
- Department of Immunology, Sloan Kettering Institute, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Daniela Weber
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Matthias Edinger
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Daniel Wolff
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Dirk H Busch
- Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass Spectrometry, School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Florian Bassermann
- Department of Internal Medicine III, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
- German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Munich, Germany
| | - André Gessner
- Institute of Clinical Microbiology and Hygiene, University Medical Center, Regensburg, Germany
| | - Li Deng
- Institute of Virology, Helmholtz Zentrum Munich, Munich, Germany
- Chair of Prevention for Microbial Infectious Disease, Central Institute of Disease Prevention and School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Ernst Holler
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany
| | - Hendrik Poeck
- Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany.
- Leibniz Institute for Immunotherapy, Regensburg, Germany.
- Bavarian Cancer Research Center (BZKF), Regensburg, Germany.
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17
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Nenkov M, Shi Y, Ma Y, Gaßler N, Chen Y. Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy. Int J Mol Sci 2023; 25:6. [PMID: 38203175 PMCID: PMC10778939 DOI: 10.3390/ijms25010006] [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: 11/08/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.
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Affiliation(s)
- Miljana Nenkov
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yihui Shi
- California Pacific Medical Center Research Institute, Sutter Bay Hospitals, San Francisco, CA 94107, USA;
| | - Yunxia Ma
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Nikolaus Gaßler
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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18
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Kiriyama Y, Nochi H. The Role of Gut Microbiota-Derived Lithocholic Acid, Deoxycholic Acid and Their Derivatives on the Function and Differentiation of Immune Cells. Microorganisms 2023; 11:2730. [PMID: 38004742 PMCID: PMC10672800 DOI: 10.3390/microorganisms11112730] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
A wide variety and large number of bacterial species live in the gut, forming the gut microbiota. Gut microbiota not only coexist harmoniously with their hosts, but they also induce significant effects on each other. The composition of the gut microbiota can be changed due to environmental factors such as diet and antibiotic intake. In contrast, alterations in the composition of the gut microbiota have been reported in a variety of diseases, including intestinal, allergic, and autoimmune diseases and cancer. The gut microbiota metabolize exogenous dietary components ingested from outside the body to produce short-chain fatty acids (SCFAs) and amino acid metabolites. Unlike SCFAs and amino acid metabolites, the source of bile acids (BAs) produced by the gut microbiota is endogenous BAs from the liver. The gut microbiota metabolize BAs to generate secondary bile acids, such as lithocholic acid (LCA), deoxycholic acid (DCA), and their derivatives, which have recently been shown to play important roles in immune cells. This review focuses on current knowledge of the role of LCA, DCA, and their derivatives on immune cells.
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Affiliation(s)
- Yoshimitsu Kiriyama
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan;
- Institute of Neuroscience, Tokushima Bunri University, Sanuki 769-2193, Japan
| | - Hiromi Nochi
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Japan;
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19
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Pichichero ME. Variability of vaccine responsiveness in early life. Cell Immunol 2023; 393-394:104777. [PMID: 37866234 DOI: 10.1016/j.cellimm.2023.104777] [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: 06/15/2023] [Revised: 09/18/2023] [Accepted: 10/14/2023] [Indexed: 10/24/2023]
Abstract
Vaccinations in early life elicit variable antibody and cellular immune responses, sometimes leaving fully vaccinated children unprotected against life-threatening infectious diseases. Specific immune cell populations and immune networks may have a critical period of development and calibration in a window of opportunity occurring during the first 100 days of early life. Among the early life determinants of vaccine responses, this review will focus on modifiable factors involving development of the infant microbiota and metabolome: antibiotic exposure, breast versus formula feeding, and Caesarian section versus vaginal delivery of newborns. How microbiota may serve as natural adjuvants for vaccine responses and how microbiota-derived metabolites influence vaccine responses are also reviewed. Early life poor vaccine responsiveness can be linked to increased infection susceptibility because both phenotypes share similar immunity dysregulation profiles. An early life pre-vaccination endotype, when interventions have the highest potential for success, should be sought that predicts vaccine response trajectories.
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Affiliation(s)
- Michael E Pichichero
- Center for Infectious Diseases and Immunology, Research Institute, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621, USA.
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20
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Zhou M, Liu X, He J, Xu X, Ju C, Luo S, Lu X, Du P, Chen Y. High-fructose corn syrup aggravates colitis via microbiota dysbiosis-mediated Th17/Treg imbalance. Clin Sci (Lond) 2023; 137:1619-1635. [PMID: 37818653 DOI: 10.1042/cs20230788] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 10/12/2023]
Abstract
Dietary fructose is widely used in beverages, processed foods, and Western diets as food additives, and is closely related to the increased prevalence of multiple diseases, including inflammatory bowel disease (IBD). However, the detailed mechanism by which high fructose disrupts intestinal homeostasis remains elusive. The present study showed that high-fructose corn syrup (HFCS) administration exacerbated intestinal inflammation and deteriorated barrier integrity. Several in vivo experimental models were utilized to verify the importance of gut microbiota and immune cells in HFCS-mediated dextran sulfate sodium (DSS)-induced colitis. In addition, untargeted metabolomics analysis revealed the imbalance between primary bile acids (PBAs) and secondary bile acids (SBAs) in feces. Hence, high fructose was speculated to modulate gut microbiota community and reduced the relative abundance of Clostridium and Clostridium scindens at genus and species level respectively, followed by a decrease in SBAs, especially isoalloLCA, thereby affecting Th17/Treg cells equilibrium and promoting intestinal inflammation. These findings provide novel insights into the crosstalk between gut flora, bile acids, and mucosal immunity, and highlight potential strategies for precise treatment of IBD.
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Affiliation(s)
- Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xiaoman Liu
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jing He
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyu Xu
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenxi Ju
- Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shangjian Luo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xiajuan Lu
- Department of Gastroenterology, Kongjiang Hospital of Yangpu District, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
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21
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Wang C, Ma Q, Yu X. Bile Acid Network and Vascular Calcification-Associated Diseases: Unraveling the Intricate Connections and Therapeutic Potential. Clin Interv Aging 2023; 18:1749-1767. [PMID: 37885621 PMCID: PMC10599251 DOI: 10.2147/cia.s431220] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Bile acids play a crucial role in promoting intestinal nutrient absorption and biliary cholesterol excretion, thereby protecting the liver from cholesterol accumulation and bile acid toxicity. Additionally, bile acids can bind to specific nuclear and membrane receptors to regulate energy expenditure and specific functions of particular tissues. Vascular calcification refers to the pathological process of calcium-phosphate deposition in blood vessel walls, which serves as an independent predictor for cardiovascular adverse events. In addition to aging, this pathological change is associated with aging-related diseases such as atherosclerosis, hypertension, chronic kidney disease, diabetes mellitus, and osteoporosis. Emerging evidence suggests a close association between the bile acid network and these aforementioned vascular calcification-associated conditions. Several bile acids have been proven to participate in calcium-phosphate metabolism, affecting the transdifferentiation of vascular smooth muscle cells and thus influencing vascular calcification. Targeting the bile acid network shows potential for ameliorating these diseases and their concomitant vascular calcification by regulating pathways such as energy metabolism, inflammatory response, oxidative stress, and cell differentiation. Here, we present a summary of the metabolism and functions of the bile acid network and aim to provide insights into the current research on the profound connections between the bile acid network and these vascular calcification-associated diseases, as well as the therapeutic potential.
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Affiliation(s)
- Cui Wang
- Laboratory of Endocrinology & Metabolism/Department of Endocrinology & Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
| | - Qing Ma
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
| | - Xijie Yu
- Laboratory of Endocrinology & Metabolism/Department of Endocrinology & Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
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22
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Enriquez AB, Ten Caten F, Ghneim K, Sekaly RP, Sharma AA. Regulation of Immune Homeostasis, Inflammation, and HIV Persistence by the Microbiome, Short-Chain Fatty Acids, and Bile Acids. Annu Rev Virol 2023; 10:397-422. [PMID: 37774124 DOI: 10.1146/annurev-virology-040323-082822] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2023]
Abstract
Despite antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) (PLWH) continue to experience chronic inflammation and immune dysfunction, which drives the persistence of latent HIV and prevalence of clinical comorbidities. Elucidating the mechanisms that lead to suboptimal immunity is necessary for developing therapeutics that improve the quality of life of PLWH. Although previous studies have found associations between gut dysbiosis and immune dysfunction, the cellular/molecular cascades implicated in the manifestation of aberrant immune responses downstream of microbial perturbations in PLWH are incompletely understood. Recent literature has highlighted that two abundant metabolite families, short-chain fatty acids (SCFAs) and bile acids (BAs), play a crucial role in shaping immunity. These metabolites can be produced and/or modified by bacterial species that make up the gut microbiota and may serve as the causal link between changes to the gut microbiome, chronic inflammation, and immune dysfunction in PLWH. In this review, we discuss our current understanding of the role of the microbiome on HIV acquisition and latent HIV persistence despite ART. Further, we describe cellular/molecular cascades downstream of SCFAs and BAs that drive innate or adaptive immune responses responsible for promoting latent HIV persistence in PLWH. This knowledge can be used to advance HIV cure efforts.
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Affiliation(s)
- Ana Beatriz Enriquez
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Felipe Ten Caten
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Khader Ghneim
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Rafick-Pierre Sekaly
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
| | - Ashish Arunkumar Sharma
- Pathology Advanced Translational Research Unit, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA;
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23
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Lai Y, Wu X, Chao E, Bloomstein JD, Wei G, Hwang ST, Shi Z. Impact of Gut Bacterial Metabolites on Psoriasis and Psoriatic Arthritis: Current Status and Future Perspectives. J Invest Dermatol 2023; 143:1657-1666. [PMID: 37422760 DOI: 10.1016/j.jid.2023.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/04/2023] [Accepted: 05/17/2023] [Indexed: 07/10/2023]
Abstract
There is growing evidence that supports a role of gut dysbiosis in the pathogenesis of psoriasis (Pso). Thus, probiotic supplementation and fecal microbiota transplantation may serve as promising preventive and therapeutic strategies for patients with Pso. One of the basic mechanisms through which the gut microbiota interacts with the host is through bacteria-derived metabolites, usually intermediate or end products produced by microbial metabolism. In this study, we provide an up-to-date review of the most recent literature on microbial-derived metabolites and highlight their roles in the immune system, with a special focus on Pso and one of its most common comorbidities, psoriatic arthritis.
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Affiliation(s)
- Yuhsien Lai
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuesong Wu
- Department of Dermatology, University of California, Davis, Sacramento, California, USA
| | - Ellen Chao
- Department of Dermatology, University of California, Davis, Sacramento, California, USA
| | | | - Grace Wei
- Department of Dermatology, University of California, Davis, Sacramento, California, USA
| | - Sam T Hwang
- Department of Dermatology, University of California, Davis, Sacramento, California, USA
| | - Zhenrui Shi
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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24
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Tveter KM, Mezhibovsky E, Wu Y, Roopchand DE. Bile acid metabolism and signaling: Emerging pharmacological targets of dietary polyphenols. Pharmacol Ther 2023; 248:108457. [PMID: 37268113 PMCID: PMC10528343 DOI: 10.1016/j.pharmthera.2023.108457] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/03/2023] [Accepted: 05/22/2023] [Indexed: 06/04/2023]
Abstract
Beyond their role as emulsifiers of lipophilic compounds, bile acids (BAs) are signaling endocrine molecules that show differential affinity and specificity for a variety of canonical and non-canonical BA receptors. Primary BAs (PBAs) are synthesized in the liver while secondary BAs (SBAs) are gut microbial metabolites of PBA species. PBAs and SBAs signal to BA receptors that regulate downstream pathways of inflammation and energy metabolism. Dysregulation of BA metabolism or signaling has emerged as a feature of chronic disease. Dietary polyphenols are non-nutritive plant-derived compounds associated with decreased risk of metabolic syndrome, type-2 diabetes, hepatobiliary and cardiovascular disease. Evidence suggests that the health promoting effects of dietary polyphenols are linked to their ability to alter the gut microbial community, the BA pool, and BA signaling. In this review we provide an overview of BA metabolism and summarize studies that link the cardiometabolic improvements of dietary polyphenols to their modulation of BA metabolism and signaling pathways, and the gut microbiota. Finally, we discuss approaches and challenges in deciphering cause-effect relationships between dietary polyphenols, BAs, and gut microbes.
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Affiliation(s)
- Kevin M Tveter
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Esther Mezhibovsky
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA.
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25
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Ghaseminejad-Raeini A, Ghaderi A, Sharafi A, Nematollahi-Sani B, Moossavi M, Derakhshani A, Sarab GA. Immunomodulatory actions of vitamin D in various immune-related disorders: a comprehensive review. Front Immunol 2023; 14:950465. [PMID: 37520529 PMCID: PMC10379649 DOI: 10.3389/fimmu.2023.950465] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
For many years, vitamin D has been acknowledged for its role in maintaining calcium and phosphate balance. However, in recent years, research has assessed its immunomodulatory role and come up with conflicting conclusions. Because the vitamin D receptor is expressed in a variety of immune cell types, study into the precise role of this molecule in diseases, notably autoimmune disorders, has been made possible. The physiologically activated version of vitamin D also promotes a tolerogenic immunological condition in addition to modulating innate and acquired immune cell responses. According to a number of recent studies, this important micronutrient plays a complex role in numerous biochemical pathways in the immune system and disorders that are associated with them. Research in this field is still relatively new, and some studies claim that patients with severe autoimmune illnesses frequently have vitamin D deficiencies or insufficiencies. This review seeks to clarify the most recent research on vitamin D's immune system-related roles, including the pathophysiology of major disorders.
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Affiliation(s)
| | - Ali Ghaderi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Sharafi
- Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Moossavi
- Nanobiology and Nanomedicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afshin Derakhshani
- Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Gholamreza Anani Sarab
- Cellular and Molecular Research Committee, Birjand University of Medical Sciences, Birjand, Iran
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26
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Wei G, Shi Z, Wu X, Hwang ST. The Emerging Potential of Bile Acids as a Modulator of Psoriatic Inflammation. JOURNAL OF PSORIASIS AND PSORIATIC ARTHRITIS 2023; 8:118-123. [PMID: 39296312 PMCID: PMC11361517 DOI: 10.1177/24755303231177965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
Background Bile acids (BAs) are cholesterol-based amphipathic surfactants that are most widely known for their contributions to lipid metabolism, but more recently have been increasingly recognized as a key signaling molecule in inflammatory diseases as well as, potentially, psoriatic disease. Objective This brief review reviews relevant literature in order to briefly describe the synthesis of bile acids and their subsequent metabolism and to analyze recent animal and human data that supports anti-inflammatory activity of some BAs in psoriasiform dermatitis. Methods Pubmed and other public sources were used to survey the literature relevant to the topic of bile acids and their potential use in psoriasis. Conclusion There is clinical and preclinical evidence to support a potential role for BA Supplementation (or modulation BA metabolism and signaling) in the treatment of psoriasis.
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Affiliation(s)
- Grace Wei
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
- Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Zhenrui Shi
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuesong Wu
- Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Samuel T Hwang
- Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, USA
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27
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Mohammed AD, Ball RAW, Kubinak JL. The interplay between bile acids and mucosal adaptive immunity. PLoS Pathog 2023; 19:e1011356. [PMID: 37347728 PMCID: PMC10286976 DOI: 10.1371/journal.ppat.1011356] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2023] Open
Affiliation(s)
- Ahmed Dawood Mohammed
- Department of Pathology, Microbiology, Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
| | - Ryan A. W. Ball
- Department of Pathology, Microbiology, Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
| | - Jason L. Kubinak
- Department of Pathology, Microbiology, Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
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28
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Su X, Gao Y, Yang R. Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity. Front Immunol 2023; 14:1127743. [PMID: 37256134 PMCID: PMC10225537 DOI: 10.3389/fimmu.2023.1127743] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/07/2023] [Indexed: 06/01/2023] Open
Abstract
Bile acids (BAs) as cholesterol-derived molecules play an essential role in some physiological processes such as nutrient absorption, glucose homeostasis and regulation of energy expenditure. They are synthesized in the liver as primary BAs such as cholic acid (CA), chenodeoxycholic acid (CDCA) and conjugated forms. A variety of secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA) and their derivatives is synthesized in the intestine through the involvement of various microorganisms. In addition to essential physiological functions, BAs and their metabolites are also involved in the differentiation and functions of innate and adaptive immune cells such as macrophages (Macs), dendritic cells (DCs), myeloid derived suppressive cells (MDSCs), regulatory T cells (Treg), Breg cells, T helper (Th)17 cells, CD4 Th1 and Th2 cells, CD8 cells, B cells and NKT cells. Dysregulation of the BAs and their metabolites also affects development of some diseases such as inflammatory bowel diseases. We here summarize recent advances in how BAs and their metabolites maintain gut and systemic homeostasis, including the metabolism of the BAs and their derivatives, the role of BAs and their metabolites in the differentiation and function of immune cells, and the effects of BAs and their metabolites on immune-associated disorders.
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Affiliation(s)
- Xiaomin Su
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yunhuan Gao
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Rongcun Yang
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
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29
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Zhang Y, Chen R, Zhang D, Qi S, Liu Y. Metabolite interactions between host and microbiota during health and disease: Which feeds the other? Biomed Pharmacother 2023; 160:114295. [PMID: 36709600 DOI: 10.1016/j.biopha.2023.114295] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/20/2023] [Accepted: 01/20/2023] [Indexed: 01/30/2023] Open
Abstract
Metabolites produced by the host and microbiota play a crucial role in how human bodies develop and remain healthy. Most of these metabolites are produced by microbiota and hosts in the digestive tract. Metabolites in the gut have important roles in energy metabolism, cellular communication, and host immunity, among other physiological activities. Although numerous host metabolites, such as free fatty acids, amino acids, and vitamins, are found in the intestine, metabolites generated by gut microbiota are equally vital for intestinal homeostasis. Furthermore, microbiota in the gut is the sole source of some metabolites, including short-chain fatty acids (SCFAs). Metabolites produced by microbiota, such as neurotransmitters and hormones, may modulate and significantly affect host metabolism. The gut microbiota is becoming recognized as a second endocrine system. A variety of chronic inflammatory disorders have been linked to aberrant host-microbiota interplays, but the precise mechanisms underpinning these disturbances and how they might lead to diseases remain to be fully elucidated. Microbiome-modulated metabolites are promising targets for new drug discovery due to their endocrine function in various complex disorders. In humans, metabolotherapy for the prevention or treatment of various disorders will be possible if we better understand the metabolic preferences of bacteria and the host in specific tissues and organs. Better disease treatments may be possible with the help of novel complementary therapies that target host or bacterial metabolism. The metabolites, their physiological consequences, and functional mechanisms of the host-microbiota interplays will be highlighted, summarized, and discussed in this overview.
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Affiliation(s)
- Yan Zhang
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Rui Chen
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - DuoDuo Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.
| | - Shuang Qi
- Department of Anethesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
| | - Yan Liu
- Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
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30
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Wang J, Zhu N, Su X, Gao Y, Yang R. Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis. Cells 2023; 12:cells12050793. [PMID: 36899929 PMCID: PMC10000530 DOI: 10.3390/cells12050793] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
The gut microbiota, including bacteria, archaea, fungi, viruses and phages, inhabits the gastrointestinal tract. This commensal microbiota can contribute to the regulation of host immune response and homeostasis. Alterations of the gut microbiota have been found in many immune-related diseases. The metabolites generated by specific microorganisms in the gut microbiota, such as short-chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, not only affect genetic and epigenetic regulation but also impact metabolism in the immune cells, including immunosuppressive and inflammatory cells. The immunosuppressive cells (such as tolerogenic macrophages (tMacs), tolerogenic dendritic cells (tDCs), myeloid-derived suppressive cells (MDSCs), regulatory T cells (Tregs), regulatory B cells (Breg) and innate lymphocytes (ILCs)) and inflammatory cells (such as inflammatory Macs (iMacs), DCs, CD4 T helper (Th)1, CD4Th2, Th17, natural killer (NK) T cells, NK cells and neutrophils) can express different receptors for SCFAs, Trp and BA metabolites from different microorganisms. Activation of these receptors not only promotes the differentiation and function of immunosuppressive cells but also inhibits inflammatory cells, causing the reprogramming of the local and systemic immune system to maintain the homeostasis of the individuals. We here will summarize the recent advances in understanding the metabolism of SCFAs, Trp and BA in the gut microbiota and the effects of SCFAs, Trp and BA metabolites on gut and systemic immune homeostasis, especially on the differentiation and functions of the immune cells.
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Affiliation(s)
- Juanjuan Wang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Ningning Zhu
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Xiaomin Su
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Yunhuan Gao
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Rongcun Yang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin 300071, China
- Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Nankai University, Tianjin 300071, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
- Correspondence:
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31
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Aggeletopoulou I, Marangos M, Assimakopoulos SF, Mouzaki A, Thomopoulos K, Triantos C. Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2023:S0002-9440(23)00055-X. [PMID: 36868465 DOI: 10.1016/j.ajpath.2023.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 03/05/2023]
Abstract
Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. In this review, we examine the role of the gut microbiome in IBD and discuss how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece; Division of Hematology, Department of Internal Medicine, Laboratory of Immunohematology, Medical School, University Hospital of Patras, Patras, Greece.
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Laboratory of Immunohematology, Medical School, University Hospital of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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32
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Yoon JH, Do JS, Velankanni P, Lee CG, Kwon HK. Gut Microbial Metabolites on Host Immune Responses in Health and Disease. Immune Netw 2023; 23:e6. [PMID: 36911800 PMCID: PMC9995988 DOI: 10.4110/in.2023.23.e6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 03/07/2023] Open
Abstract
Intestinal microorganisms interact with various immune cells and are involved in gut homeostasis and immune regulation. Although many studies have discussed the roles of the microorganisms themselves, interest in the effector function of their metabolites is increasing. The metabolic processes of these molecules provide important clues to the existence and function of gut microbes. The interrelationship between metabolites and T lymphocytes in particular plays a significant role in adaptive immune functions. Our current review focuses on 3 groups of metabolites: short-chain fatty acids, bile acids metabolites, and polyamines. We collated the findings of several studies on the transformation and production of these metabolites by gut microbes and explained their immunological roles. Specifically, we summarized the reports on changes in mucosal immune homeostasis represented by the Tregs and Th17 cells balance. The relationship between specific metabolites and diseases was also analyzed through latest studies. Thus, this review highlights microbial metabolites as the hidden treasure having potential diagnostic markers and therapeutic targets through a comprehensive understanding of the gut-immune interaction.
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Affiliation(s)
- Jong-Hwi Yoon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jun-Soo Do
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Priyanka Velankanni
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
| | - Choong-Gu Lee
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
- Division of Bio-Medical Science and Technology, Korea Institute of Science and Technology (KIST) School, University of Science and Technology, Seoul 02792, Korea
| | - Ho-Keun Kwon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 03722, Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Korea
- Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
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33
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Campbell C, Kandalgaonkar MR, Golonka RM, Yeoh BS, Vijay-Kumar M, Saha P. Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy. Biomedicines 2023; 11:294. [PMID: 36830830 PMCID: PMC9953403 DOI: 10.3390/biomedicines11020294] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota-immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota-immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions.
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Affiliation(s)
- Connor Campbell
- Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Mrunmayee R. Kandalgaonkar
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Rachel M. Golonka
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Beng San Yeoh
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Matam Vijay-Kumar
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | - Piu Saha
- Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
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34
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Larabi AB, Masson HLP, Bäumler AJ. Bile acids as modulators of gut microbiota composition and function. Gut Microbes 2023; 15:2172671. [PMID: 36740850 PMCID: PMC9904317 DOI: 10.1080/19490976.2023.2172671] [Citation(s) in RCA: 108] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/16/2023] [Indexed: 02/07/2023] Open
Abstract
Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but the factors driving dysbiosis remain incompletely understood. One factor governing the microbiota composition in the gut is bile. Bile acids shape the microbiota composition through their antimicrobial activity and by activating host signaling pathways that maintain gut homeostasis. Although bile acids are host-derived, their functions are integrally linked to bacterial metabolism, which shapes the composition of the intestinal bile acid pool. Conditions that change the size or composition of the bile acid pool can trigger alterations in the microbiota composition that exacerbate inflammation or favor infection with opportunistic pathogens. Therefore, manipulating the composition or size of the bile acid pool might be a promising strategy to remediate dysbiosis.
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Affiliation(s)
- Anaïs B. Larabi
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
| | - Hugo L. P. Masson
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
| | - Andreas J. Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA, USA
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35
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Forde B, Yao L, Shaha R, Murphy S, Lunjani N, O'Mahony L. Immunomodulation by foods and microbes: Unravelling the molecular tango. Allergy 2022; 77:3513-3526. [PMID: 35892227 PMCID: PMC10087875 DOI: 10.1111/all.15455] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/15/2022] [Accepted: 07/23/2022] [Indexed: 01/28/2023]
Abstract
Metabolic health and immune function are intimately connected via diet and the microbiota. Nearly 90% of all immune cells in the body are associated with the gastrointestinal tract and these immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important systemic ramifications. Microbial dysbiosis has consistently been observed in patients with atopic dermatitis, food allergy and asthma and the molecular mechanisms linking changes in microbial populations with disease risk and disease endotypes are being intensively investigated. The discovery of novel bacterial metabolites that impact immune function is at the forefront of host-microbe research. Co-evolution of microbial communities within their hosts has resulted in intertwined metabolic pathways that affect physiological and pathological processes. However, recent dietary and lifestyle changes are thought to negatively influence interactions between microbes and their host. This review provides an overview of some of the critical metabolite-receptor interactions that have been recently described, which may underpin the immunomodulatory effects of the microbiota, and are of relevance for allergy, asthma and infectious diseases.
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Affiliation(s)
- Brian Forde
- APC Microbiome Ireland, UCC, Cork, Ireland.,School of Microbiology, UCC, Cork, Ireland
| | - Lu Yao
- APC Microbiome Ireland, UCC, Cork, Ireland.,School of Microbiology, UCC, Cork, Ireland
| | - Rupin Shaha
- APC Microbiome Ireland, UCC, Cork, Ireland.,School of Microbiology, UCC, Cork, Ireland
| | | | - Nonhlanhla Lunjani
- APC Microbiome Ireland, UCC, Cork, Ireland.,University of Cape Town, Cape Town, South Africa
| | - Liam O'Mahony
- APC Microbiome Ireland, UCC, Cork, Ireland.,School of Microbiology, UCC, Cork, Ireland.,Department of Medicine, UCC, Cork, Ireland
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36
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Lê A, Mantel M, Marchix J, Bodinier M, Jan G, Rolli-Derkinderen M. Inflammatory bowel disease therapeutic strategies by modulation of the microbiota: how and when to introduce pre-, pro-, syn-, or postbiotics? Am J Physiol Gastrointest Liver Physiol 2022; 323:G523-G553. [PMID: 36165557 DOI: 10.1152/ajpgi.00002.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel diseases (IBD), a heterogeneous group of inflammatory conditions that encompass both ulcerative colitis and Crohn's disease, represent a major public health concern. The etiology of IBD is not yet fully understood and no cure is available, with current treatments only showing long-term effectiveness in a minority of patients. A need to increase our knowledge on IBD pathophysiology is growing, to define preventive measures, to improve disease outcome, and to develop new effective and lasting treatments. IBD pathogenesis is sustained by aberrant immune responses, associated with alterations of the intestinal epithelial barrier (IEB), modifications of the enteric nervous system, and changes in microbiota composition. Currently, most of the treatments target the inflammation and the immune system, but holistic approaches targeting lifestyle and diet improvements are emerging. As dysbiosis is involved in IBD pathogenesis, pre-, pro-, syn-, and postbiotics are used/tested to reduce the inflammation or strengthen the IEB. The present review will resume these works, pointing out the stage of life, the duration, and the environmental conditions that should go along with microbiota or microbiota-derived treatments.
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Affiliation(s)
- Amélie Lê
- The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes Université, Institut National pour la Santé et la Recherche Médicale, Nantes, France
| | - Marine Mantel
- The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes Université, Institut National pour la Santé et la Recherche Médicale, Nantes, France
- Unité Mixte de Recherche Science et Technologie du Lait et de l'Oeuf, Agrocampus Ouest, Institut Agro, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Rennes, France
| | - Justine Marchix
- The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes Université, Institut National pour la Santé et la Recherche Médicale, Nantes, France
| | - Marie Bodinier
- Unité de Recherche 1268 Biopolymères Interactions Assemblages, I Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Pays de la Loire, Nantes, France
| | - Gwénaël Jan
- Unité Mixte de Recherche Science et Technologie du Lait et de l'Oeuf, Agrocampus Ouest, Institut Agro, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Rennes, France
| | - Malvyne Rolli-Derkinderen
- The Enteric Nervous System in Gut and Brain Disorders, Institut des Maladies de l'Appareil Digestif, Nantes Université, Institut National pour la Santé et la Recherche Médicale, Nantes, France
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37
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Bai Y, Zhao T, Gao M, Zou Y, Lei X. A Novel Gene Alignment in Dorea sp. AM58-8 Produces 7-Dehydroxy-3β Bile Acids from Primary Bile Acids. Biochemistry 2022; 61:2870-2878. [PMID: 36130198 DOI: 10.1021/acs.biochem.2c00264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Bile acids are essential metabolites and signaling molecules in mammals. Primary bile acids are synthesized from cholesterol in the liver. At the same time, the microbiota in the mammalian gut has many interactions with bile acid, including various biotransformation processes such as 7-dehydroxylation and 3-epimerization. 7-Dehydroxylation is mediated by a bile acid-inducible (bai) operon, while 7-dehydroxylation and 3-epimerization are independently observed in only a few strains. Herein, we describe a novel microbe, Dorea sp. AM58-8, that can accomplish a two-step transformation and turn primary bile acids into both 3α secondary bile acids like deoxycholic acid and lithocholic acid, and 3β secondary bile acids like isodeoxycholic acid and isolithocholic acid. We subsequently characterized BaiA, BaiB, BaiE, and their substrate profiles biochemically. The potential bai gene clusters in the metagenomes were further mined. Their evolution, potential functions, and possible regulatory pathways were predicted using bioinformatics based on our understanding of the 7-dehydroxylation pathway in Dorea sp. AM58-8. This study of Dorea sp. AM58-8 also helps us distinguish the inactive bacteria that seem to have the 7-dehydroxylation pathway proteins and discover the 7-dehydroxylation pathway in other mammalian gut microbes.
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Affiliation(s)
- Yingjie Bai
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.,Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China
| | - Tianhu Zhao
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.,Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China
| | - Mengyu Gao
- BGI-Beijing, Beijing 100101, China.,BGI-Shenzhen, Shenzhen 518116, China
| | - Yuanqiang Zou
- BGI-Shenzhen, Shenzhen 518116, China.,Shenzhen Engineering Laboratory of Detection and Intervention of the Human Intestinal Microbiome, BGI-Shenzhen, Shenzhen, 518116, China.,Qingdao-Europe Advanced Institute for Life Sciences, BGI-Shenzhen, Qingdao 266555, China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.,Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China.,Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518107, China
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38
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Godlewska U, Bulanda E, Wypych TP. Bile acids in immunity: Bidirectional mediators between the host and the microbiota. Front Immunol 2022; 13:949033. [PMID: 36052074 PMCID: PMC9425027 DOI: 10.3389/fimmu.2022.949033] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/26/2022] [Indexed: 01/03/2023] Open
Abstract
Host-microbiota interactions are bidirectional. On one hand, ecological pressures exerted by the host shape the composition and function of the microbiota. On the other, resident microbes trigger multiple pathways that influence the immunity of the host. Bile acids participate in both parts of this interplay. As host-derived compounds, they display bacteriostatic properties and affect the survival and growth of the members of the microbial community. As microbiota-modified metabolites, they further influence the microbiota composition and, in parallel, modulate the immunity of the host. Here, we provide a comprehensive overview of the mechanisms behind this unique dialogue and discuss how we can harness bile acids to treat intestinal inflammation.
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39
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Crohn’s Disease, Host–Microbiota Interactions, and Immunonutrition: Dietary Strategies Targeting Gut Microbiome as Novel Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms23158361. [PMID: 35955491 PMCID: PMC9369148 DOI: 10.3390/ijms23158361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Crohn’s disease (CD) is a complex, disabling, idiopathic, progressive, and destructive disorder with an unknown etiology. The pathogenesis of CD is multifactorial and involves the interplay between host genetics, and environmental factors, resulting in an aberrant immune response leading to intestinal inflammation. Due to the high morbidity and long-term management of CD, the development of non-pharmacological approaches to mitigate the severity of CD has recently attracted great attention. The gut microbiota has been recognized as an important player in the development of CD, and general alterations in the gut microbiome have been established in these patients. Thus, the gut microbiome has emerged as a pre-eminent target for potential new treatments in CD. Epidemiological and interventional studies have demonstrated that diet could impact the gut microbiome in terms of composition and functionality. However, how specific dietary strategies could modulate the gut microbiota composition and how this would impact host–microbe interactions in CD are still unclear. In this review, we discuss the most recent knowledge on host–microbe interactions and their involvement in CD pathogenesis and severity, and we highlight the most up-to-date information on gut microbiota modulation through nutritional strategies, focusing on the role of the microbiota in gut inflammation and immunity.
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40
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Caliceti C, Punzo A, Silla A, Simoni P, Roda G, Hrelia S. New Insights into Bile Acids Related Signaling Pathways in the Onset of Colorectal Cancer. Nutrients 2022; 14:nu14142964. [PMID: 35889921 PMCID: PMC9317521 DOI: 10.3390/nu14142964] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/12/2022] [Accepted: 07/19/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer (CRC) ranks as the second among the causes of tumor death worldwide, with an estimation of 1.9 million new cases in 2020 and more than 900,000 deaths. This rate might increase by 60% over the next 10 years. These data are unacceptable considering that CRC could be successfully treated if diagnosed in the early stages. A high-fat diet promotes the hepatic synthesis of bile acids (BAs) increasing their delivery to the colonic lumen and numerous scientific reports correlate BAs, especially secondary BAs, with CRC incidence. We reviewed the physicochemical and biological characteristics of BAs, focusing on the major pathways involved in CRC risk and progression. We specifically pointed out the role of BAs as signaling molecules and the tangled relationships among their nuclear and membrane receptors with the big bang of molecular and cellular events that trigger CRC occurrence.
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Affiliation(s)
- Cristiana Caliceti
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
- Interdepartmental Centre for Renewable Sources, Environment, Sea and Energy (CIRI FRAME), Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy;
- Correspondence:
| | - Angela Punzo
- Department of Chemistry “Giacomo Ciamician” Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy;
| | - Alessia Silla
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (A.S.); (S.H.)
| | - Patrizia Simoni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Giulia Roda
- Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy;
| | - Silvana Hrelia
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (A.S.); (S.H.)
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41
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Di Modica M, Arlotta V, Sfondrini L, Tagliabue E, Triulzi T. The Link Between the Microbiota and HER2+ Breast Cancer: The New Challenge of Precision Medicine. Front Oncol 2022; 12:947188. [PMID: 35912227 PMCID: PMC9326166 DOI: 10.3389/fonc.2022.947188] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
The microbiota is emerging as a key player in cancer due to its involvement in several host physiological functions, including digestion, development of the immune system, and modulation of endocrine function. Moreover, its participation in the efficacy of anticancer treatments has been well described. For instance, the involvement of the breast microbiota in breast cancer (BC) development and progression has gained ground in the past several years. In this review, we report and discuss new findings on the impact of the gut and breast microbiota on BC, focusing on the HER2+ BC subtype, and the possibility of defining microbial signatures that are associated with disease aggressiveness, treatment response, and therapy toxicity. We also discuss novel insights into the mechanisms through which microorganism-host interactions occur and the possibility of microbiota editing in the prevention and treatment optimization of BC.
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Affiliation(s)
- Martina Di Modica
- Molecular Targeting Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Valeria Arlotta
- Molecular Targeting Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
| | - Lucia Sfondrini
- Molecular Targeting Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
| | - Elda Tagliabue
- Molecular Targeting Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
- *Correspondence: Elda Tagliabue,
| | - Tiziana Triulzi
- Molecular Targeting Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy
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42
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Sheng W, Ji G, Zhang L. The Effect of Lithocholic Acid on the Gut-Liver Axis. Front Pharmacol 2022; 13:910493. [PMID: 35873546 PMCID: PMC9301130 DOI: 10.3389/fphar.2022.910493] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/16/2022] [Indexed: 11/14/2022] Open
Abstract
Lithocholic acid (LCA) is a monohydroxy bile acid produced by intestinal flora, which has been found to be associated with a variety of hepatic and intestinal diseases. LCA is previously considered to be toxic, however, recent studies revealed that LCA and its derivatives may exert anti-inflammatory and anti-tumor effects under certain conditions. LCA goes through enterohepatic circulation along with other bile acids, here, we mainly discuss the effects of LCA on the gut-liver axis, including the regulation of gut microbiota, intestinal barrier, and relevant nuclear receptors (VDR, PXR) and G protein-coupled receptor five in related diseases. In addition, we also find that some natural ingredients are involved in regulating the detoxification and excretion of LCA, and the interaction with LCA also mediates its own biological activity.
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43
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Hitch TCA, Hall LJ, Walsh SK, Leventhal GE, Slack E, de Wouters T, Walter J, Clavel T. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunol 2022; 15:1095-1113. [PMID: 36180583 PMCID: PMC9705255 DOI: 10.1038/s41385-022-00564-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/12/2022] [Accepted: 08/22/2022] [Indexed: 02/04/2023]
Abstract
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
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Affiliation(s)
- Thomas C A Hitch
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
| | - Lindsay J Hall
- Gut Microbes & Health, Quadram Institute Biosciences, Norwich, UK
- Intestinal Microbiome, School of Life Sciences, ZIEL-Institute for Food & Health, Technical University of Munich, Freising, Germany
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Sarah Kate Walsh
- School of Food and Nutritional Sciences, University College Cork, Cork, Ireland
- APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland
| | | | - Emma Slack
- Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
| | | | - Jens Walter
- APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany.
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44
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Guan B, Tong J, Hao H, Yang Z, Chen K, Xu H, Wang A. Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases. Acta Pharm Sin B 2022; 12:2129-2149. [PMID: 35646540 PMCID: PMC9136572 DOI: 10.1016/j.apsb.2021.12.011] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 02/08/2023] Open
Abstract
Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.
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Key Words
- AS, atherosclerosis
- ASBT, apical sodium-dependent bile salt transporter
- BAs, bile acids
- BSEP, bile salt export pump
- BSH, bile salt hydrolases
- Bile acid
- CA, cholic acid
- CAR, constitutive androstane receptor
- CCs, cholesterol crystals
- CDCA, chenodeoxycholic acid
- CMD, cardiometabolic disease
- CVDs, cardiovascular diseases
- CYP7A1, cholesterol 7 alpha-hydroxylase
- CYP8B1, sterol 12α-hydroxylase
- Cardiometabolic diseases
- DAMPs, danger-associated molecular patterns
- DCA, deoxycholic acid
- DCs, dendritic cells
- ERK, extracellular signal-regulated kinase
- FA, fatty acids
- FFAs, free fatty acids
- FGF, fibroblast growth factor
- FMO3, flavin-containing monooxygenase 3
- FXR, farnesoid X receptor
- GLP-1, glucagon-like peptide 1
- HCA, hyocholic acid
- HDL, high-density lipoprotein
- HFD, high fat diet
- HNF, hepatocyte nuclear receptor
- IL, interleukin
- IR, insulin resistance
- JNK, c-Jun N-terminal protein kinase
- LCA, lithocholic acid
- LDL, low-density lipoprotein
- LDLR, low-density lipoprotein receptor
- LPS, lipopolysaccharide
- NAFLD, non-alcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-κB
- NLRP3, NLR family pyrin domain containing 3
- Nuclear receptors
- OCA, obeticholic acid
- PKA, protein kinase A
- PPARα, peroxisome proliferator-activated receptor alpha
- PXR, pregnane X receptor
- RCT, reverses cholesterol transportation
- ROR, retinoid-related orphan receptor
- S1PR2, sphingosine-1-phosphate receptor 2
- SCFAs, short-chain fatty acids
- SHP, small heterodimer partner
- Systemic immunometabolism
- TG, triglyceride
- TGR5, takeda G-protein receptor 5
- TLR, toll-like receptor
- TMAO, trimethylamine N-oxide
- Therapeutic opportunities
- UDCA, ursodeoxycholic acid
- VDR, vitamin D receptor
- cAMP, cyclic adenosine monophosphate
- mTOR, mammalian target of rapamycin
- ox-LDL, oxidated low-density lipoprotein
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Affiliation(s)
- Baoyi Guan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Jinlin Tong
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhixu Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Keji Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Hao Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Anlu Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
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45
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Field MA, Yadav S, Dudchenko O, Esvaran M, Rosen BD, Skvortsova K, Edwards RJ, Keilwagen J, Cochran BJ, Manandhar B, Bustamante S, Rasmussen JA, Melvin RG, Chernoff B, Omer A, Colaric Z, Chan EKF, Minoche AE, Smith TPL, Gilbert MTP, Bogdanovic O, Zammit RA, Thomas T, Aiden EL, Ballard JWO. The Australian dingo is an early offshoot of modern breed dogs. SCIENCE ADVANCES 2022; 8:eabm5944. [PMID: 35452284 PMCID: PMC9032958 DOI: 10.1126/sciadv.abm5944] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 03/09/2022] [Indexed: 06/11/2023]
Abstract
Dogs are uniquely associated with human dispersal and bring transformational insight into the domestication process. Dingoes represent an intriguing case within canine evolution being geographically isolated for thousands of years. Here, we present a high-quality de novo assembly of a pure dingo (CanFam_DDS). We identified large chromosomal differences relative to the current dog reference (CanFam3.1) and confirmed no expanded pancreatic amylase gene as found in breed dogs. Phylogenetic analyses using variant pairwise matrices show that the dingo is distinct from five breed dogs with 100% bootstrap support when using Greenland wolf as the outgroup. Functionally, we observe differences in methylation patterns between the dingo and German shepherd dog genomes and differences in serum biochemistry and microbiome makeup. Our results suggest that distinct demographic and environmental conditions have shaped the dingo genome. In contrast, artificial human selection has likely shaped the genomes of domestic breed dogs after divergence from the dingo.
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Affiliation(s)
- Matt A. Field
- Centre for Tropical Bioinformatics and Molecular Biology, College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, QLD 4878, Australia
- Garvan Institute of Medical Research, Victoria Street, Darlinghurst, NSW 2010, Australia
| | - Sonu Yadav
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, High St, Kensington, NSW 2052, Australia
| | - Olga Dudchenko
- The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
| | - Meera Esvaran
- School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Benjamin D. Rosen
- Animal Genomics and Improvement Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA
| | - Ksenia Skvortsova
- Garvan Institute of Medical Research, Victoria Street, Darlinghurst, NSW 2010, Australia
| | - Richard J. Edwards
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, High St, Kensington, NSW 2052, Australia
| | - Jens Keilwagen
- Julius Kühn-Institut, Erwin-Baur-Str. 27, 06484 Quedlinburg, Germany
| | - Blake J. Cochran
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Bikash Manandhar
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Sonia Bustamante
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW 2052, Australia
| | - Jacob Agerbo Rasmussen
- Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark
- Center for Evolutionary Hologenomics, Faculty of Health and Medical Sciences, The GLOBE Institute University of Copenhagen, Copenhagen, Denmark
| | - Richard G. Melvin
- Department of Biomedical Sciences, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA
| | - Barry Chernoff
- College of the Environment, Departments of Biology, and Earth and Environmental Sciences, Wesleyan University, Middletown, CT 06459, USA
| | - Arina Omer
- The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zane Colaric
- The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
| | - Eva K. F. Chan
- Garvan Institute of Medical Research, Victoria Street, Darlinghurst, NSW 2010, Australia
- Statewide Genomics, New South Wales Health Pathology, 45 Watt St, Newcastle, NSW 2300, Australia
| | - Andre E. Minoche
- Garvan Institute of Medical Research, Victoria Street, Darlinghurst, NSW 2010, Australia
| | - Timothy P. L. Smith
- U.S. Meat Animal Research Center, Agricultural Research Service, USDA, Rd 313, Clay Center, NE 68933, USA
| | - M. Thomas P. Gilbert
- Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark
- University Museum, NTNU, Trondheim, Norway
| | - Ozren Bogdanovic
- Garvan Institute of Medical Research, Victoria Street, Darlinghurst, NSW 2010, Australia
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, High St, Kensington, NSW 2052, Australia
| | - Robert A. Zammit
- Vineyard Veterinary Hospital, 703 Windsor Rd, Vineyard, NSW 2765, Australia
| | - Torsten Thomas
- School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Erez L. Aiden
- The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
- UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Pudong 201210, China
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - J. William O. Ballard
- Department of Environment and Genetics, SABE, La Trobe University, Melbourne, VIC 3086, Australia
- School of Biosciences, University of Melbourne, Royal Parade, Parkville, VIC 3052, Australia
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46
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Thomas JP, Modos D, Rushbrook SM, Powell N, Korcsmaros T. The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease. Front Immunol 2022; 13:829525. [PMID: 35185922 PMCID: PMC8850271 DOI: 10.3389/fimmu.2022.829525] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.
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Affiliation(s)
- John P Thomas
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom.,Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
| | - Dezso Modos
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom
| | - Simon M Rushbrook
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom.,Department of Hepatology, University of East Anglia Medical School, Norwich, United Kingdom
| | - Nick Powell
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Tamas Korcsmaros
- Gut Microbes and Health Programme, Quadram Bioscience, Norwich, United Kingdom.,Organisms and Ecosystem, Earlham Institute, Norwich, United Kingdom.,Division of Digestive Diseases, Imperial College London, London, United Kingdom
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47
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Kriaa A, Mariaule V, Jablaoui A, Rhimi S, Mkaouar H, Hernandez J, Korkmaz B, Lesner A, Maguin E, Aghdassi A, Rhimi M. Bile Acids: Key Players in Inflammatory Bowel Diseases? Cells 2022; 11:cells11050901. [PMID: 35269523 PMCID: PMC8909766 DOI: 10.3390/cells11050901] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) have emerged as a public health problem worldwide with a limited number of efficient therapeutic options despite advances in medical therapy. Although changes in the gut microbiota composition are recognized as key drivers of dysregulated intestinal immunity, alterations in bile acids (BAs) have been shown to influence gut homeostasis and contribute to the pathogenesis of the disease. In this review, we explore the interactions involving BAs and gut microbiota in IBDs, and discuss how the gut microbiota–BA–host axis may influence digestive inflammation.
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Affiliation(s)
- Aicha Kriaa
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Vincent Mariaule
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Amin Jablaoui
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Soufien Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Hela Mkaouar
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Juan Hernandez
- Oniris, Department of Clinical Sciences, Nantes-Atlantic College of Veterinary Medicine and Food Sciences, University of Nantes, 101 Route de Gachet, 44300 Nantes, France;
| | - Brice Korkmaz
- INSERM UMR-1100, “Research Center for Respiratory Diseases”, University of Tours, 37032 Tours, France;
| | - Adam Lesner
- Faculty of Chemistry, University of Gdansk, Uniwersytet Gdanski, Chemistry, Wita Stwosza 63, PL80-308 Gdansk, Poland;
| | - Emmanuelle Maguin
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
| | - Ali Aghdassi
- Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany;
| | - Moez Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France; (A.K.); (V.M.); (A.J.); (S.R.); (H.M.); (E.M.)
- Correspondence:
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48
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Balazs I, Horvath A, Leber B, Feldbacher N, Sattler W, Rainer F, Fauler G, Vermeren S, Stadlbauer V. Serum bile acids in liver cirrhosis promote neutrophil dysfunction. Clin Transl Med 2022; 12:e735. [PMID: 35220689 PMCID: PMC8882235 DOI: 10.1002/ctm2.735] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/26/2022] [Accepted: 01/29/2022] [Indexed: 01/05/2023] Open
Affiliation(s)
- Irina Balazs
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Angela Horvath
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Bettina Leber
- Department of SurgeryDivision of Transplantation SurgeryMedical University of GrazGrazAustria
| | - Nicole Feldbacher
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Wolfgang Sattler
- Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging)Division of Molecular Biology and BiochemistryMedical University of GrazGrazAustria
- Center for Explorative LipidomicsBioTechMed GrazGrazAustria
| | - Florian Rainer
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
| | - Sonja Vermeren
- Centre for Inflammation Research, Institute for Regeneration and RepairUniversity of EdinburghEdinburghUK
| | - Vanessa Stadlbauer
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
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49
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Vernia F, Valvano M, Longo S, Cesaro N, Viscido A, Latella G. Vitamin D in Inflammatory Bowel Diseases. Mechanisms of Action and Therapeutic Implications. Nutrients 2022; 14:269. [PMID: 35057450 PMCID: PMC8779654 DOI: 10.3390/nu14020269] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/04/2022] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
(1) Background: Vitamin D is an immunoregulatory factor influencing intestinal homeostasis. Recent evidence supports a central role of this micronutrient in the course of Inflammatory Bowel Diseases (IBD). This narrative review aims to provide a general overview of the possible biological mechanisms of action of vitamin D and its therapeutic implications in IBD. (2) Methods: A systematic electronic search of the English literature up to October 2021 was performed using Medline and the Cochrane Library. Only papers written in English that analyzed the role of vitamin D in IBD were included. (3) Results: In vitro and animal studies reported that vitamin D signaling improves epithelial barrier integrity regulating the expression of several junctional proteins, defensins, and mucins, modulates the inflammatory response, and affects gut microbiome composition. Recent studies also suggest that vitamin D deficiency is highly prevalent among IBD patients and that low serum levels correlate with disease activity and, less clearly, with disease course. (4) Conclusions: An increasing body of evidence suggests some role of vitamin D in the pathophysiology of IBD, nonetheless the underlying mechanisms have been so far only partially elucidated. A strong correlation with disease activity has been reported but its implication in the treatment is still undefined. Thus, studies focused on this issue, the definition of vitamin D levels responsible for clinical effects, and the potential role of vitamin D as a therapeutic agent are strongly encouraged.
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Affiliation(s)
| | | | | | | | | | - Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazza S. Tommasi, Coppito, 67100 L’Aquila, Italy; (F.V.); (M.V.); (S.L.); (N.C.); (A.V.)
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50
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Thibaut MM, Bindels LB. Crosstalk between bile acid-activated receptors and microbiome in entero-hepatic inflammation. Trends Mol Med 2022; 28:223-236. [DOI: 10.1016/j.molmed.2021.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
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