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Xu Y, Gao Z, Liu J, Yang Q, Xu S. Role of gut microbiome in suppression of cancers. Gut Microbes 2025; 17:2495183. [PMID: 40254597 PMCID: PMC12013426 DOI: 10.1080/19490976.2025.2495183] [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: 12/14/2024] [Revised: 03/23/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025] Open
Abstract
The pathogenesis of cancer is closely related to the disruption of homeostasis in the human body. The gut microbiome plays crucial roles in maintaining the homeostasis of its host throughout lifespan. In recent years, a large number of studies have shown that dysbiosis of the gut microbiome is involved in the entire process of cancer initiation, development, and prognosis by influencing the host immune system and metabolism. Some specific intestinal bacteria promote the occurrence and development of cancers under certain conditions. Conversely, some other specific intestinal bacteria suppress the oncogenesis and progression of cancers, including inhibiting the occurrence of cancers, delaying the progression of cancers and boosting the therapeutic effect on cancers. The promoting effects of the gut microbiome on cancers have been comprehensively discussed in the previous review. This article will review the latest advances in the roles and mechanisms of gut microbiome in cancer suppression, providing a new perspective for developing strategies of cancer prevention and treatment.
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Affiliation(s)
- Yao Xu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P. R. China
| | - Zhaoyu Gao
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Jiaying Liu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
| | - Qianqian Yang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
| | - Shunjiang Xu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
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2
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Cebi M, Yilmaz Y. Epithelial barrier hypothesis in the context of nutrition, microbial dysbiosis, and immune dysregulation in metabolic dysfunction-associated steatotic liver. Front Immunol 2025; 16:1575770. [PMID: 40438102 PMCID: PMC12116361 DOI: 10.3389/fimmu.2025.1575770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/25/2025] [Indexed: 06/01/2025] Open
Abstract
In recent years, the prevalence of chronic liver diseases, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), has increased significantly. This upward trend is largely associated with lifestyle-related factors such as unhealthy dietary habits, physical inactivity, and various environmental influences. Among the key elements contributing to the pathogenesis of MASLD, the integrity of the intestinal epithelial barrier emerges as a critical determinant, given its central role in maintaining immune homeostasis along the gut-liver axis. Disruption of this barrier, often driven by excessive consumption of saturated fats and refined carbohydrates in combination with low dietary fiber intake, can lead to microbial dysbiosis. This imbalance in the gut microbiota triggers immune dysregulation and promotes systemic inflammation, thereby exacerbating hepatic injury. This review discusses the contribution of epithelial barrier dysfunction to the development and progression of MASLD, with a particular focus on how increased intestinal permeability may initiate and sustain chronic liver inflammation. Additionally, the influence of dietary and environmental factors on epithelial integrity, immune responses, and the inflammatory cascade is addressed. A better understanding of the complex interplay between gut barrier impairment, immune modulation, and liver pathology may offer valuable insights into MASLD pathophysiology and contribute to the development of more targeted therapeutic strategies.
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Affiliation(s)
- Merve Cebi
- Department of Medical Biology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
- The Global NASH Council, Washington, DC, United States
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3
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Silla A, Punzo A, Caliceti C, Barbalace MC, Hrelia S, Malaguti M. The Role of Antioxidant Compounds from Citrus Waste in Modulating Neuroinflammation: A Sustainable Solution. Antioxidants (Basel) 2025; 14:581. [PMID: 40427463 PMCID: PMC12108332 DOI: 10.3390/antiox14050581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
In normal conditions, neuroinflammation induces microglia and astrocyte activation to maintain brain homeostasis. However, excessive or prolonged neuroinflammation can inflict harmful damage on brain tissue. Numerous factors can trigger chronic neuroinflammation, ultimately leading to neurodegeneration. In this context, considering the pressing need for novel, natural approaches to mitigate neuroinflammatory damage, attention has turned to unconventional sources such as agricultural by-products. Citrus fruits are widely consumed globally, producing substantial waste, including peels, seeds, and pulp. Traditionally regarded as agricultural waste, these by-products are now recognized as valuable reservoirs of bioactive compounds, including flavonoids, carotenoids, terpenoids, and limonoids. Among these, citrus polyphenols-particularly flavanones like hesperidin, naringenin, and eriocitrin-have emerged as potent modulators of neuroinflammatory pathways through their multifaceted interactions with cellular antioxidant systems, pro-inflammatory signaling cascades, neurovascular integrity, and gut-brain axis dynamics. This review aims to characterize the key molecules present in citrus waste and synthesizes preclinical and clinical evidence to elucidate the biochemical mechanisms underlying neuroinflammation in neurodegenerative disorders.
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Affiliation(s)
- Alessia Silla
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (A.S.); (A.P.); (C.C.)
| | - Angela Punzo
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (A.S.); (A.P.); (C.C.)
| | - Cristiana Caliceti
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (A.S.); (A.P.); (C.C.)
| | - Maria Cristina Barbalace
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47921 Rimini, Italy; (M.C.B.); (M.M.)
| | - Silvana Hrelia
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47921 Rimini, Italy; (M.C.B.); (M.M.)
| | - Marco Malaguti
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47921 Rimini, Italy; (M.C.B.); (M.M.)
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4
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Savarese G, Schiattarella GG, Lindberg F, Anker MS, Bayes-Genis A, Bäck M, Braunschweig F, Bucciarelli-Ducci C, Butler J, Cannata A, Capone F, Chioncel O, D'Elia E, González A, Filippatos G, Girerd N, Hulot JS, Lam CSP, Lund LH, Maack C, Moura B, Petrie MC, Piepoli M, Shehab A, Yilmaz MB, Seferovic P, Tocchetti CG, Rosano GMC, Metra M. Heart failure and obesity: Translational approaches and therapeutic perspectives. A scientific statement of the Heart Failure Association of the ESC. Eur J Heart Fail 2025. [PMID: 40328668 DOI: 10.1002/ejhf.3676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 04/02/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Obesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few years, new evidence on the mechanisms linking obesity with HF has been reported, particularly in relation to HF with preserved ejection fraction. Novel therapies inducing weight loss appear to have favourable effects on health status and cardiovascular risk. Against the backdrop of this rapidly evolving evidence landscape, HF clinicians are increasingly required to tailor their preventive, diagnostic, and therapeutic approaches to HF in the presence of obesity. This scientific statement by the Heart Failure Association of the European Society of Cardiology provides an up-to-date summary on obesity in HF, covering key areas such as epidemiology, translational aspects, diagnostic challenges, therapeutic approaches, and trial design.
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Affiliation(s)
- Gianluigi Savarese
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Gabriele G Schiattarella
- Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charité (DHZC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Felix Lindberg
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Markus S Anker
- Department of Cardiology CBF German Heart Center Charité, DZHK, BCRT, University Medicine Berlin FU and HU, Berlin, Germany
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germasn Trias I Pujol, CIBERCV, Badalona, Spain
| | - Magnus Bäck
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | | | - Chiara Bucciarelli-Ducci
- Royal Brompton and Harefield Hospitals, Guys' and St Thomas NHS Trust, London, UK
- School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College University, London, UK
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- University of Mississippi, Jackson, MS, USA
| | - Antonio Cannata
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine, Faculty of Life Science, King's College London, London, UK
- Cardiology Department, King's College Hospital NHS Foundation Trust, London, UK
| | - Federico Capone
- Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Deutsches Herzzentrum der Charité (DHZC), Charité - Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Unit of Internal Medicine III, Department of Medicine (DIMED), Padua University Hospital, University of Padua, Padova, Italy
- Department of Biomedical Sciences, University of Padua, Padova, Italy
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', University of Medicine Carol Davila, Bucharest, Romania
| | - Emilia D'Elia
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy
- School of Medicine and Surgery, University Milano-Bicocca, Milan, Italy
| | - Arantxa González
- Program of Cardiovascular Diseases, CIMA Universidad de Navarra, Department of Cardiology and Cardiac Surgery, Clínica Universidad de Navarra and IdiSNA, Pamplona, Spain
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | - Gerasimos Filippatos
- Department of Cardiology, University Hospital Attikon, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nicolas Girerd
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France
| | - Jean-Sébastien Hulot
- Université Paris Cité, INSERM, PARCC, Paris, France
- CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France
| | - Carolyn S P Lam
- National Heart Centre Singapore & Duke-National University of Singapore, Singapore
| | - Lars H Lund
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christoph Maack
- Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
- Medical Clinic 1, University Clinic Würzburg, Würzburg, Germany
| | - Brenda Moura
- Department of Cardiology, Armed Forces Hospital, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Mark C Petrie
- School of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Massimo Piepoli
- Clinical Cardiology, IRCCS Policlinico San Donato, Milan, Italy
- Department of Preventive Cardiology, University of Wroclaw, Wroclaw, Poland
| | - Abdullah Shehab
- Department of Cardiology, Royal Burjeel Hospital, UAE University, Al Ain, UAE
| | - Mehmet B Yilmaz
- Department of Cardiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Peter Seferovic
- Faculty of Medicine, University of Belgrade, and Serbian Academy of Sciences and Arts, Belgrade, Serbia
- University of Belgrade, Belgrade, Serbia
| | - Carlo G Tocchetti
- Cardio-Oncology Unit, Department of Translational Medical Sciences (DISMET), Center for Basic and Clinical Immunology Research (CISI), Interdepartmental Center of Clinical and Translational Sciences (CIRCET), Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Giuseppe M C Rosano
- Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy
- Cardiology, San Raffaele Cassino Hospital, Cassino, Italy
| | - Marco Metra
- Cardiology and Cardiac Catheterization Laboratory, Cardio-Thoracic Department, Civil Hospitals, Brescia, Italy
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
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5
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Zheng Y, Yang G, Li P, Tian B. Bioelectric and physicochemical foundations of bioelectronics in tissue regeneration. Biomaterials 2025; 322:123385. [PMID: 40367812 DOI: 10.1016/j.biomaterials.2025.123385] [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: 12/21/2024] [Revised: 04/15/2025] [Accepted: 05/01/2025] [Indexed: 05/16/2025]
Abstract
Understanding and exploiting bioelectric signaling pathways and physicochemical properties of materials that interface with living tissues is central to advancing tissue regeneration. In particular, the emerging field of bioelectronics leverages these principles to develop personalized, minimally invasive therapeutic strategies tailored to the dynamic demands of individual patients. By integrating sensing and actuation modules into flexible, biocompatible devices, clinicians can continuously monitor and modulate local electrical microenvironments, thereby guiding regenerative processes without extensive surgical interventions. This review provides a critical examination of how fundamental bioelectric cues and physicochemical considerations drive the design and engineering of next-generation bioelectronic platforms. These platforms not only promote the formation and maturation of new tissues across neural, cardiac, musculoskeletal, skin, and gastrointestinal systems but also precisely align therapies with the unique structural, functional, and electrophysiological characteristics of each tissue type. Collectively, these insights and innovations represent a convergence of biology, electronics, and materials science that holds tremendous promise for enhancing the efficacy, specificity, and long-term stability of regenerative treatments, ushering in a new era of advanced tissue engineering and patient-centered regenerative medicine.
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Affiliation(s)
- Yuze Zheng
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Guangqing Yang
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Pengju Li
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, 60637, USA
| | - Bozhi Tian
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA; The James Franck Institute, The University of Chicago, Chicago, IL, 60637, USA; The Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.
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6
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Vella VR, Ainsworth-Cruickshank G, Luft C, Wong KE, Parfrey LW, Vogl AW, Holman PJ, Bodnar TS, Raineki C. Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: A developmental perspective. Neurochem Int 2025; 185:105952. [PMID: 39988283 DOI: 10.1016/j.neuint.2025.105952] [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: 11/04/2024] [Revised: 01/25/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE-induced alterations to brain and serum cytokine levels and both the composition and metabolic output of the gut microbiota. Using a well-established rat model of PAE, cytokine levels in the serum, prefrontal cortex, amygdala, and hypothalamus as well as gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed at three postnatal (P) timepoints: P8 (infancy), P22 (weaning), and P38 (adolescence). Male PAE rats had increased cytokine levels in the amygdala and hypothalamus, but not prefrontal cortex, at P8. This altered neuroimmune function was not seen in the PAE females. The effect of PAE on central cytokine levels was reduced at P22/38, the same age at which PAE-induced alterations in serum cytokine levels emerge in both sexes. PAE reduced bacterial diversity in both sexes at P8, but only in females at P38, where a PAE-induced unique community composition emerged. Both sexes had alterations to specific bacterial taxa (e.g., Firmicutes), some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results demonstrate that PAE leads to sex- and age-specific alterations in immune function, gut microbiota and SCFA production, highlighting the need to consider both age and sex in future work.
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Affiliation(s)
- Victoria R Vella
- Department of Psychology, Brock University, St. Catharines, Ontario, Canada
| | | | - Carolina Luft
- Department of Psychology, Brock University, St. Catharines, Ontario, Canada
| | - Kingston E Wong
- Department of Psychology, Brock University, St. Catharines, Ontario, Canada
| | - Laura W Parfrey
- Department of Botany, University of British Columbia, British Columbia, Canada
| | - A Wayne Vogl
- Life Sciences Centre, Department of Cellular and Physiological Sciences, University of British Columbia, British Columbia, Canada
| | - Parker J Holman
- Department of Psychology, Brock University, St. Catharines, Ontario, Canada
| | - Tamara S Bodnar
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Charlis Raineki
- Department of Psychology, Brock University, St. Catharines, Ontario, Canada.
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7
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Zhang R, Zhang X, Lau HCH, Yu J. Gut microbiota in cancer initiation, development and therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1283-1308. [PMID: 39821827 DOI: 10.1007/s11427-024-2831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.
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Affiliation(s)
- Ruyi Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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8
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Zhao X, Zhu M, Wang Z, Gao M, Long Y, Zhou S, Wang W. The Alleviative Effect of Sodium Butyrate on Dexamethasone-Induced Skeletal Muscle Atrophy. Cell Biol Int 2025; 49:508-521. [PMID: 39936899 DOI: 10.1002/cbin.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/18/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Skeletal muscle mass is significantly negatively regulated by glucocorticoids. Following glucocorticoid administration, the balance between protein synthesis and breakdown in skeletal muscle is disrupted, shifting towards a predominance of catabolic metabolism. Short-chain fatty acids like sodium butyrate have been found to regulate inflammatory reactions and successively activate signaling pathways. The preventive benefits of sodium butyrate against dexamethasone-induced skeletal muscle atrophy and myotube atrophy models were examined in this work, and the underlying mechanism was clarified. A total of 32 6-week-old C57BL/6 inbred male mice were randomly assigned to one of four groups and treated with dexamethasone to induce muscle atrophy and sodium butyrate. We found that sodium succinate alleviated dexamethasone-induced myotube atrophy in the myotube atrophy model by lowering the gene expression of two E3 ubiquitin ligases, Atrogin-1 and MURF1, and activating the AKT/mTOR signaling pathway. Pertussis toxin reversed this effect, indicating that G protein-coupled receptors were involved in sodium butyrate's action as a mediator. Additionally, pre-treatment with sodium butyrate lowered weight and muscle mass loss in a mouse model of skeletal muscle atrophy, dramatically decreased the MURF1 gene expression and decreased the nuclear translocation of the glucocorticoid receptor. In conclusion, this study shows that sodium butyrate inhibits the expression of atrophy genes, thus preventing the breakdown of proteins and the loss of muscle mass, while also inhibiting weight loss, in animal models.
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Affiliation(s)
- Xingchen Zhao
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
| | - Mingqiang Zhu
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
| | - Zifan Wang
- College of Animal Science and Veterinary, Shenyang Agricultural University, Shenyang, Liaoning, China
| | - Ming Gao
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
| | - Yifei Long
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
| | - Shuo Zhou
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
| | - Wei Wang
- Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong, China
- College of Animal Science and Veterinary, Shenyang Agricultural University, Shenyang, Liaoning, China
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9
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Liao M, Zhu Y, Cui Q, Yue M, Li J, Gao L, He Y, Guo Y, Zhang W, Wei Z, Xia Y, Dai Y. Intestinal Butyrate Ameliorates Rheumatoid Arthritis Through Promoting the Expression of Cortistatin in Ileum via HDAC3-Vitamin D Receptor Pathway. Immunology 2025. [PMID: 40304573 DOI: 10.1111/imm.13939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 04/17/2025] [Accepted: 04/20/2025] [Indexed: 05/02/2025] Open
Abstract
Butyrate, administered orally or via drinking water, can effectively ameliorate experimental rheumatoid arthritis (RA) in mice despite its limited bioavailability. The discrepancy urges us to explore the involvement and role of intestinal anti-RA factors in the action of butyrate. In this study, we found that substituting drinking water with butyrate (75 mM) could promote the expression of cortistatin (CST) in the ileal epithelium of mice with collagen-induced arthritis (CIA), but butyrate did not alter the expression of other anti-RA neuropeptides in the intestine and the expression of CST in the spleen and brain. The anti-RA efficacy of butyrate was remarkably reduced following adeno-associated virus (AAV)-mediated knockdown of CST. Transcription factor screening revealed that butyrate upregulated CST expression via the vitamin D receptor (VDR). Notably, butyrate-induced VDR and CST expression in intestinal epithelial cells was diminished by α-cyano-4-hydroxycinnamic acid (CHC) rather than siRNA targeting G protein-coupled receptors (GPCRs), suggesting that butyrate functions through an intracellular pathway. Furthermore, butyrate significantly reduced HDAC activity in intestinal epithelial cells and HDAC3 plasmid transfection attenuated the upregulation of butyrate against VDR and CST expression. Chromatin immunoprecipitation assay showed that butyrate selectively enhanced histone acetylation in the P3 and P4 regions of the VDR promoter. In summary, intestinal butyrate exerts an anti-RA effect through selectively promoting the expression of CST in ileal epithelial cells via the HDAC3-VDR pathway.
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Affiliation(s)
- Minghui Liao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanrong Zhu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qi Cui
- The Second Affiliated Hospital of Inner Mongolia University for the Nationalities, Inner Mongolia General Forestry Hospital, Inner Mongolia Autonomous Region, China
| | - Mengfan Yue
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jialin Li
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Gao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue He
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yilei Guo
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenjie Zhang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yufeng Xia
- Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Hazime H, Ducasa GM, Santander AM, Brito N, Gonzalez-Horta EE, Quintero MA, Barnes S, Wilson L, Zhang Y, Yu F, Gharaibeh RZ, Jobin C, Faust KM, Damas OM, Deshpande A, Kerman DH, Proksell S, Pignac-Kobinger J, Fernández I, Burgueño JF, Abreu MT. DUOX2 activation drives bacterial translocation and subclinical inflammation in IBD-associated dysbiosis. Gut 2025:gutjnl-2024-334346. [PMID: 40301115 DOI: 10.1136/gutjnl-2024-334346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 04/09/2025] [Indexed: 05/01/2025]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear. OBJECTIVE We interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome. DESIGN DUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. We assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host-microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples. RESULTS DUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects. CONCLUSIONS Elevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.
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Affiliation(s)
- Hajar Hazime
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Gloria Michelle Ducasa
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ana M Santander
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nivis Brito
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Maria A Quintero
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Stephen Barnes
- Department of Pharmacology and Toxicology, The University of Alabama Heersink School of Medicine, Birmingham, Alabama, USA
| | - Landon Wilson
- Department of Pharmacology and Toxicology, The University of Alabama Heersink School of Medicine, Birmingham, Alabama, USA
| | | | - Fahong Yu
- University of Florida, Gainesville, Florida, USA
| | - Raad Z Gharaibeh
- Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Christian Jobin
- Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, USA
| | - Katerina M Faust
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Oriana M Damas
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Amar Deshpande
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - David H Kerman
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Siobhan Proksell
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Judith Pignac-Kobinger
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Irina Fernández
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Juan F Burgueño
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Maria T Abreu
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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11
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Nazir A, Hussain FHN, Nadeem Hussain TH, Al Dweik R, Raza A. Therapeutic targeting of the host-microbiota-immune axis: implications for precision health. Front Immunol 2025; 16:1570233. [PMID: 40364844 PMCID: PMC12069365 DOI: 10.3389/fimmu.2025.1570233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/24/2025] [Indexed: 05/15/2025] Open
Abstract
The human body functions as a complex ecosystem, hosting trillions of microbes that collectively form the microbiome, pivotal in immune system regulation. The host-microbe immunological axis maintains homeostasis and influences key physiological processes, including metabolism, epithelial integrity, and neural function. Recent advancements in microbiome-based therapeutics, including probiotics, prebiotics and fecal microbiota transplantation, offer promising strategies for immune modulation. Microbial therapies leveraging microbial metabolites and engineered bacterial consortia are emerging as novel therapeutic strategies. However, significant challenges remain, including individual microbiome variability, the complexity of host-microbe interactions, and the need for precise mechanistic insights. This review comprehensively examines the host microbiota immunological interactions, elucidating its mechanisms, therapeutic potential, and the future directions of microbiome-based immunomodulation in human health. It will also critically evaluate challenges, limitations, and future directions for microbiome-based precision medicine.
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Affiliation(s)
- Asiya Nazir
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | | | | | - Rania Al Dweik
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Afsheen Raza
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
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12
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Roa-Cordero MV, Arenas-Sepúlveda CA, Herrera-Plata MC, Leal-Pinto SM, Villota-Salazar NA, González-Prieto JM. Switching off the yeast-to-hyphae transition in Yarrowia lipolytica through histone deacetylase inhibitors. Res Microbiol 2025:104299. [PMID: 40306381 DOI: 10.1016/j.resmic.2025.104299] [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: 07/23/2024] [Revised: 03/23/2025] [Accepted: 04/08/2025] [Indexed: 05/02/2025]
Abstract
Fungi can develop a variety of morphotypes to survive, colonize, adapt and prevail under different environmental conditions. In general, two morphological shapes encompass the others: yeast (unicellular) and hyphae (multicellular). Under specific conditions, some fungi can adopt these two cellular morphologies, and for this reason, they are called dimorphic. Histone acetylation and deacetylation are well-known important mechanisms of chromatin remodelling that control cell differentiation processes as dimorphism. The reactions involved are catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the present work, we used Yarrowia lipolytica as a dimorphic fungal model to investigate the effect of HDAC chemical inhibition on the growth and yeast-to-hyphae switch of fungi. For this purpose, we tested the compounds sodium butyrate (SB) and valproic acid (VPA) as epigenetic modulators. Our results indicated that Y. lipolytica tolerates high doses of these inhibitors due to its lipolytic nature. However, once the metabolic capability of the fungus is overcome, SB and VPA strongly suppress hyphal growth, suggesting that histone acetylation plays a pivotal role in the regulation of this process.
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Affiliation(s)
- Martha Viviana Roa-Cordero
- Universidad de Santander, Facultad de Ciencias Médicas y de la Salud, Instituto de Investigación Masira, 680006, Bucaramanga, Colombia.
| | | | - María Cristina Herrera-Plata
- Universidad de Santander, Facultad de Ciencias Exactas, Naturales y Agropecuarias, 680006, Bucaramanga, Colombia.
| | - Sandra Milena Leal-Pinto
- Universidad de Santander, Facultad de Ciencias Médicas y de la Salud, Instituto de Investigación Masira, 680006, Bucaramanga, Colombia.
| | - Nubia Andrea Villota-Salazar
- Biotecnología Vegetal, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Blvd. del Maestro. S/N esq. Elías Piña. Col. Narciso Mendoza, 88710, Reynosa, Tamaulipas, Mexico.
| | - Juan Manuel González-Prieto
- Biotecnología Vegetal, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Blvd. del Maestro. S/N esq. Elías Piña. Col. Narciso Mendoza, 88710, Reynosa, Tamaulipas, Mexico.
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13
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Kachoueiyan F, Kalkhoran NY, Kalkhoran AY, Kyada A, Rekha MM, Chaudhary K, Barwal A, Sead FF, Joshi KK. Butyrate: a key mediator of gut-brain communication in Alzheimer's disease. Metab Brain Dis 2025; 40:189. [PMID: 40266405 DOI: 10.1007/s11011-025-01617-7] [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: 01/11/2025] [Accepted: 04/16/2025] [Indexed: 04/24/2025]
Abstract
Alzheimer's disease (AD), a prevalent neurodegenerative disorder, represents a significant global health challenge, characterized by cognitive decline and neuroinflammation. Recent investigations have highlighted the critical role of the gut-brain axis in the pathogenesis of AD, particularly focusing on the influence of short-chain fatty acids (SCFAs), metabolites produced by the gut microbiota through the fermentation of dietary fiber. Among SCFAs, butyrate has emerged as a crucial mediator, positively impacting various pathological processes associated with AD, including epigenetic regulation, neuroinflammation modulation, maintenance of the blood-brain barrier (BBB), enhanced intestinal integrity, regulation of brain metabolism, and interference with amyloid protein formation as well as tau protein hyperphosphorylation. Furthermore, distinctions in butyrate profile and microbial communities have been observed between AD patients and healthy individuals, underscoring the importance of gut microbiota in AD progression. This review summarizes the current understanding of the many functions of butyrate in reducing the consequences of AD and emphasizes the possibility of addressing the gut microbiota as a therapeutic approach to managing AD.
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Affiliation(s)
- Faeze Kachoueiyan
- Department of Biology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Niosha Yahyavi Kalkhoran
- Department of Biology, Biological Sciences College, Varamin-Pishva Branch, Islamic Azad University, Varamin, Iran
| | - Anousha Yahyavi Kalkhoran
- Department of Biology, Biological Sciences College, Varamin-Pishva Branch, Islamic Azad University, Varamin, Iran
| | - Ashishkumar Kyada
- Department of Pharmacy, Faculty of Health Sciences, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India.
| | - M M Rekha
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Amit Barwal
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjheri, Mohali, 140307, Punjab, India
| | - Fadhil Faez Sead
- Department of Dentistry, College of Dentistry, The Islamic University, Najaf, Iraq
- Department of medical analysis, Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India
- Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
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14
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Li S, Wang L, Han M, Fan H, Tang H, Gao H, Li G, Xu Z, Zhou Z, Du J, Peng C, Peng F. Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites. Front Immunol 2025; 16:1532528. [PMID: 40297576 PMCID: PMC12035444 DOI: 10.3389/fimmu.2025.1532528] [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: 11/22/2024] [Accepted: 03/20/2025] [Indexed: 04/30/2025] Open
Abstract
Background Recent studies have highlighted the importance of cross-talk along the gut-brain axis in regulating inflammatory nociception, inflammatory responses, and immune homeostasis. The gut microbiota, particularly its bacterial composition, plays a crucial role in the development and function of the immune system. Moreover, metabolites produced by the gut microbiota can significantly impact both systemic immune responses and central nervous system (CNS) immunity. Sodium butyrate is a key metabolite produced by the gut microbiota and, as a histone deacetylase inhibitor, can enhance the anti-tumor immunity of cytotoxic CD8+ T cells. However, it remains unclear whether sodium butyrate treatment can enhance the efficacy of PD-1 blockade in glioma therapy. In this research, the effect and underlying mechanism of combination of gut microbiota metabolites and anti-mouse PD-1 mAb on glioma has been investigated. Methods RNA-seq assay in glioma cell and biomedical databases, including ONCOMINE, GEPIA and TCGA were incorporated. Subsequently, the inhibitory effect of sodium butyrate on glioma cells and its related mechanisms were assessed through Counting Kit-8 (CCK-8), Flow Cytometry, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments. In vitro, an orthotopic mouse glioma model was established. MRI imaging, Immunohistochemistry, and Immune cell flow cytometry were used to investigate the therapeutic effects of combined sodium butyrate and PD-1 inhibitor treatment on glioma-bearing mice. Results We discovered that deacetylation-associated gene expression is significantly increased in glioma patients and affects patient survival time. Moreover, we found sodium butyrate promoted glioma cell apoptosis, disrupted the cell cycle, and inhibited tumor growth. Additionally, sodium butyrate may upregulate PD-L1 expression in glioma cells by modulating the PI3K/AKT pathway. The experimental results demonstrated that this combination therapy significantly reduced tumor volume and prolonged survival in an orthotopic murine glioma model. Moreover, combination therapy led to an increase in the proportion of probiotic bacteria in the mouse gut microbiota, resulting in elevated levels of antitumor metabolites and a decrease in metabolites that affect immune cell function.
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Affiliation(s)
- Sui Li
- West China School of Pharmacy, Sichuan University, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Wang
- Bioinformatics Department, Jiangsu Sanshu Biotechnology Co., Ltd., Nantong, China
| | - MingYu Han
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Huali Fan
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangdong, China
| | - Huile Gao
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Guobo Li
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Zheng Xu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Department of Clinical Medicine, Zhengzhou University, Henan, China
| | - JunRong Du
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fu Peng
- West China School of Pharmacy, Sichuan University, Chengdu, China
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
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15
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Zhou P, Wu Y, Shen J, Duan T, Che L, Zhang Y, Zhao Y, Yan H. Gestational Inulin Supplementation in Low-/High-Fat Sow Diets: Effects on Growth Performance, Lipid Metabolism, and Meat Quality of Offspring Pigs. Foods 2025; 14:1314. [PMID: 40282717 PMCID: PMC12027208 DOI: 10.3390/foods14081314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025] Open
Abstract
This study investigated whether the supplementation of prebiotic inulin to gestating sows programmatically affects offspring growth performance and meat quality while exploring its epigenetic effects through histone acetylation modulation. After mating, sixty multiparous sows (Landrace × Yorkshire; parity 2-3) were assigned to a 2 × 2 factorial arrangement with inulin (0% vs. 1.5%) and fat (0% or 5%) supplementation until farrowing. Post-weaning, five litters (10 piglets per litter) per treatment were selected and maintained in their original litter for fattening under standardized feeding. The results demonstrated that maternal inulin supplementation during gestation accomplished the following: (1) Increased offspring liver index by 13.4% at weaning and 6.8% at finishing (p < 0.05) while reducing the finishing-phase backfat thickness by 11.6% (p < 0.01), with a significant inulin × fat interaction attenuating fat-induced abdominal lipid accumulation at weaning (p = 0.05). (2) Decreased longissimus dorsi muscle lightness (L*) by 4.5% in finishing pigs (p = 0.02) without altering the other meat quality parameters. (3) Suppressed offspring liver lipid deposition at birth and finishing (p < 0.05), concomitant with upregulated hepatic PGC-1α and CPT1A expression (p < 0.05). (4) Elevated neonatal serum butyrate by 15.6% (p = 0.06) while inhibiting hepatic histone deacetylase (HDAC) activity and enhancing histone H3/H4 acetylation (p < 0.01). These findings suggest that maternal inulin supplementation during gestation mitigates offspring hepatic lipid deposition through butyrate-mediated epigenetic regulation, where microbial-derived butyrate from inulin fermentation inhibits HDAC activity, enhances histone acetylation levels, and upregulates fatty acid β-oxidation gene expression. This study provides novel mechanistic insights into how maternal dietary fiber nutrition programs offspring development through epigenetic reprogramming.
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Affiliation(s)
- Pan Zhou
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
| | - Yachao Wu
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
| | - Jianbo Shen
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
| | - Tao Duan
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
| | - Long Che
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, No. 6 North Longzihu Road, Zhengdong New District, Zhengzhou 450046, China;
| | - Yong Zhang
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
| | - Yang Zhao
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China
| | - Honglin Yan
- School of Life Science and Agro-Forestry, Southwest University of Science and Technology, 59 Qinglong Road, Mianyang 621010, China; (P.Z.); (Y.W.); (J.S.); (T.D.); (Y.Z.)
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16
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Oumata N, Zhong Q, Zhang Y, Galons H, Andrei G, Zeng M. Emerging drugs for Epstein-Barr virus associated-diseases. Eur J Med Chem 2025; 287:117386. [PMID: 39952101 DOI: 10.1016/j.ejmech.2025.117386] [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: 12/13/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Epstein-Barr virus (EBV) is the first identified oncogenic virus. It causes three types of diseases: lymphomas, carcinomas, and autoimmune diseases. It is estimated that two hundred thousand deaths are due to EBV each year. After a primary infection, EBV can remain latent lifelong. Reactivation to lytic phase can be induced by various drugs including small organic molecules, biologics, or a combination of both. In this review, we identified the most relevant results obtained with small organic compounds against Epstein-Barr virus-associated diseases. Specific treatments targeting Epstein-Barr Nuclear Antigen 1 are emerging concerning small organic molecules and showed promising results against several EBV-related malignancies.
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Affiliation(s)
- Nassima Oumata
- Université Paris Cité, CNRS, INSERM, UTCBS, 4 avenue de l'observatoire, 75006, Paris, France.
| | - Qian Zhong
- Sun Yat-sen University Cancer Center, 651 Dong Feng Road, East Guangzhou, 510060, China.
| | - Yongmin Zhang
- Sorbonne Université, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France; Fuyang Institute & School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311422, Zhejiang, China.
| | - Hervé Galons
- Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France
| | - Graciela Andrei
- Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
| | - Musheng Zeng
- Sun Yat-sen University Cancer Center, 651 Dong Feng Road, East Guangzhou, 510060, China.
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17
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Tang R, Zha H, Liu R, Lv J, Cao D, Li L. Sodium butyrate attenuates liver fibrogenesis via promoting H4K8 crotonylation. Mol Cell Biochem 2025:10.1007/s11010-025-05274-3. [PMID: 40180786 DOI: 10.1007/s11010-025-05274-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/27/2025] [Indexed: 04/05/2025]
Abstract
Sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor derived from dietary sources, demonstrates its potential in improving liver fibrosis in mice. This study explored NaB's impact on liver fibrosis through histone crotonylation. In vitro, NaB significantly inhibited the growth of TGF-β-stimulated LX2 hepatic stellate cells and reduced the expression of fibrotic markers ACTA2, the encoding gene of αSMA, and COL1A1 proportionally to the dosage. In vivo, NaB treatment of CCl4-induced ICR mice led to notable gains in liver function and a marked suppression in liver fibrosis. NaB inhibited Hdac2 and Hdac3 expression leading to increased H4K8 crotonylation, and modulated key fibrosis-related genes, providing a mechanistic basis for its therapeutic potential. Trichostatin A (TSA) exhibited similar effects to NaB, supporting the importance of HDAC inhibition in modulating these pathways. Overall, NaB's modulation of HDAC activity and histone crotonylation reveals a novel mechanism underlying its impact on liver fibrosis, highlighting its promise as a treatment for liver disease.
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Affiliation(s)
- Ruiqi Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Hua Zha
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Rongrong Liu
- Center of Pediatric Hematology-oncology, Pediatric Leukemia Diagnostic, Therapeutic Technology Research Center of Zhejiang Province, National Clinical Research Center for Child Health, Children's Hospital, Zhejiang University School of Medicine, 57 Zhuganxiang Rd., Yan-an St., Hangzhou, 310003, China
| | - Jiawen Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Dan Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China.
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, China.
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18
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Liu S, Liu J, Xiang J, Yan R, Li S, Fan Q, Lu L, Wu J, Xue Y, Fu T, Liu J, Li Z. Restorative Effects of Short-Chain Fatty Acids on Corneal Homeostasis Disrupted by Antibiotic-Induced Gut Dysbiosis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:770-796. [PMID: 39732390 DOI: 10.1016/j.ajpath.2024.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/02/2024] [Accepted: 11/14/2024] [Indexed: 12/30/2024]
Abstract
The gut microbiota plays a crucial regulatory role in various physiological processes, yet its impact on corneal homeostasis remains insufficiently understood. Here, the effects of antibiotic-induced gut dysbiosis (AIGD) and germ-free conditions were investigated on circadian gene expression, barrier integrity, nerve density, and immune cell activity in the corneas of mice. Both AIGD and germ-free conditions significantly disrupted the overall transcriptomic profile and circadian transcriptomic oscillations in the cornea, as indicated by RNA sequencing. These molecular disturbances were accompanied by a reduction in corneal epithelial thickness, nerve density, corneal sensitivity, and compromised barrier function. Notably, supplementation with short-chain fatty acids (SCFAs) significantly restored corneal integrity in AIGD mice. Further single-cell sequencing revealed that SCFA receptors G-protein-coupled receptor 109A (Hcar2), olfactory receptor 78 (Olfr78), and G-protein-coupled receptor 43 (Ffar2) are expressed in corneal epithelial basal cells, embryonically derived macrophages, perivascular cells, and γδ T cells, respectively. In conclusion, this study demonstrated that the gut microbiota plays a critical role in corneal physiology by regulating circadian gene expression and maintaining barrier function. These findings enhance our understanding of the gut-eye axis, highlighting the cornea as a target for microbiota-derived metabolic signals and underlining the potential therapeutic value of SCFAs in treating corneal dysfunction.
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Affiliation(s)
- Sijing Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiangman Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Jiayan Xiang
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruyu Yan
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Senmao Li
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Qiwei Fan
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, China
| | - Liyuan Lu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiaxin Wu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yunxia Xue
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ting Fu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jun Liu
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhijie Li
- International Ocular Surface Research Center, Key Laboratory for Regenerative Medicine, Institute of Ophthalmology, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
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19
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Banjarnahor S, Scherpinski LA, Keller M, König J, Maas R. Differential uptake of arginine derivatives by the human heteromeric amino acid transporter b 0,+AT-rBAT (SLC7A9-SLC3A1). NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4419-4434. [PMID: 39480524 PMCID: PMC11978698 DOI: 10.1007/s00210-024-03510-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024]
Abstract
L-arginine and its (patho-)physiologically active derivatives, L-homoarginine and asymmetric dimethylarginine (ADMA), show significant differences in their renal clearance. The underlying molecular mechanisms remain to be elucidated, but selective tubular transport protein-mediated mechanisms likely play a role. In the present study, we investigate the human heteromeric transporter b0,+AT-rBAT (encoded by the SLC7A9 and SLC3A1 genes) as a potential candidate because it is localized in the luminal membrane of human proximal tubule cells and capable of mediating the cellular uptake of amino acids, including L-arginine. Double-transfected Madin-Darby canine kidney (MDCK) cells stably expressing human b0,+AT-rBAT exhibited significant uptake of L-arginine and L-homoarginine, with apparent Km values of 512.6 and 197.0 μM, respectively. On the contrary, ADMA uptake was not saturated up to 4000 μM, with a transport rate > 5 nmol × mg protein-1 × min-1. With an IC50 value of 115.8 μM, L-arginine inhibited L-homoarginine uptake. Conversely, L-arginine only exhibited a partial inhibitory effect on ADMA uptake. Taken together, our data indicate that b0,+AT-rBAT may contribute to the differential renal handling of L-arginine, L-homoarginine, and ADMA.
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Affiliation(s)
- Sofna Banjarnahor
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
- Research Centre for Pharmaceutical Ingredient and Traditional Medicine, Cibinong Science Center, National Research and Innovation Agency (BRIN), 16911, Cibinong, Jawa Barat, Indonesia
| | - Lorenz A Scherpinski
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Max Keller
- Institute of Pharmacy, Universität Regensburg, 93040, Regensburg, Germany
| | - Jörg König
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
- FAU NeW Research Center New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Renke Maas
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
- FAU NeW Research Center New Bioactive Compounds, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
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20
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Xiao W, Chen Q, Liu C, Yu Y, Liu T, Jin Y, Ma H, Chen S, Jiang C. Gut microbiota in cancer: From molecular mechanisms to precision medicine applications. IMETA 2025; 4:e70017. [PMID: 40236776 PMCID: PMC11995170 DOI: 10.1002/imt2.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 04/17/2025]
Abstract
The gut microbiota-cancer interaction functions through multi-level biological mechanisms, forming the basis for both diagnostic and therapeutic applications. Current technical and biological challenges drive the field toward precision medicine approaches, aiming to integrate multi-dimensional data for optimized, personalized cancer treatments.
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Affiliation(s)
- Weihua Xiao
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Qiong Chen
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chunjiao Liu
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Yueer Yu
- Department of Tea Research InstituteZhejiang UniversityHangzhouChina
| | - Tianliang Liu
- HaploX BiotechnologyShenzhenChina
- LifeX Institute, School of Medical TechnologyGannan Medical UniversityGanzhouChina
| | - Yang Jin
- Institute for Cancer Genetics and InformaticsOslo University HospitalOsloNorway
| | - Haifen Ma
- Department of Pathology, Beilun Branch of the First Affiliated Hospital, College of MedicineZhejiang UniversityNingboChina
| | - Shifu Chen
- HaploX BiotechnologyShenzhenChina
- LifeX Institute, School of Medical TechnologyGannan Medical UniversityGanzhouChina
| | - Chao Jiang
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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21
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Golshani M, Taylor JA, Woolbright BL. Understanding the microbiome as a mediator of bladder cancer progression and therapeutic response. Urol Oncol 2025; 43:254-265. [PMID: 39117491 DOI: 10.1016/j.urolonc.2024.07.004] [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: 04/02/2024] [Revised: 05/17/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024]
Abstract
Bladder cancer (BCa) remains a significant source of morbidity and mortality. BCa is one of the most expensive tumors to treat, in part because of a lack of nonsurgical options. The recent advent of immunotherapy, alone or in combination with other compounds, has improved therapeutic options. Resistance to immunotherapy remains common, and many patients do not have durable response. Recent advances indicate immunotherapy efficacy may be tied in part to the endogenous bacteria present in our body, more commonly referred to as the microbiome. Laboratory and clinical data now support the idea that a healthy microbiome is critical to effective response to immunotherapy. At the same time, pathogenic interactions between the microbiome and immune cells can also serve to drive formation of tumors, increasing the complexity of these interactions. Given the rising importance of immunotherapy in BCa, understanding how we might be able to alter the microbiome to improve therapeutic efficacy offers a novel route to improved patient care. The goal of this review is to examine our current understanding of microbial interactions with the immune system and cancer with an emphasis on BCa. We will further attempt to define both current gaps in knowledge and future directions that may yield beneficial results to the field.
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Affiliation(s)
- Mahgol Golshani
- School of Medicine, University of Kansas Medical Center, Kansas City, KS
| | - John A Taylor
- Department of Urology, University of Kansas Medical Center, Kansas City, KS; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS
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22
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Wang R, Wang Z, Zhang M, Zhong D, Zhou M. Application of photosensitive microalgae in targeted tumor therapy. Adv Drug Deliv Rev 2025; 219:115519. [PMID: 39955076 DOI: 10.1016/j.addr.2025.115519] [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: 11/27/2024] [Revised: 01/02/2025] [Accepted: 01/18/2025] [Indexed: 02/17/2025]
Abstract
Microalgae present a novel and multifaceted approach to cancer therapy by modulating the tumor-associated microbiome (TAM) and the tumor microenvironment (TME). Through their ability to restore gut microbiota balance, reduce inflammation, and enhance immune responses, microalgae contribute to improved cancer treatment outcomes. As photosynthetic microorganisms, microalgae exhibit inherent anti-tumor, antioxidant, and immune-regulating properties, making them valuable in photodynamic therapy and tumor imaging due to their capacity to generate reactive oxygen species. Additionally, microalgae serve as effective drug delivery vehicles, leveraging their biocompatibility and unique structural properties to target the TME more precisely. Microalgae-based microrobots further expand their therapeutic potential by autonomously navigating complex biological environments, offering a promising future for precision-targeted cancer treatments. We position microalgae as a multifunctional agent capable of modulating TAM, offering novel strategies to enhance TME and improve the efficacy of cancer therapies.
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Affiliation(s)
- Ruoxi Wang
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310029, China; Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China; Zhejiang University-Ordos City Etuoke Banner Joint Research Center, Haining 314400, China
| | - Zhouyue Wang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining 314400, China
| | - Min Zhang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining 314400, China
| | - Danni Zhong
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Min Zhou
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310029, China; Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining 314400, China; Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China; Zhejiang University-Ordos City Etuoke Banner Joint Research Center, Haining 314400, China.
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23
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Watson JA, Nutten S, Groot A, Hoffmans R, Damen L, Olivier E, Barnett J, Patin A. Safety Assessment of Butyric Acid-Rich Triglyceride Oil: A Novel Palatable Formulation of Butyrate for the Pediatric Population. J Appl Toxicol 2025; 45:587-605. [PMID: 39609950 DOI: 10.1002/jat.4729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 11/30/2024]
Abstract
A novel, palatable butyric acid-rich triglyceride oil has been developed and is available as a food supplement for adults in the United States and Canada. A program of safety studies was conducted with butyric acid-rich triglyceride oil for the pediatric population. The oil was tested in a microbial reverse mutation assay Ames Test OECD471 (Organisation for Economic Co-operation and Development) in which all bacterial strains showed negative responses over the complete dose range in two independently repeated experiments. All values were within the laboratory historical control data ranges. Further, data from the human lymphocyte micronucleus assay (OECD487) in the presence or absence of a metabolic activator (S9-mix), the oil did not induce a biologically relevant increase in the number of binucleated cells with micronuclei; therefore, the oil is considered not to be clastogenic or aneugenic. In a 90-day rat repeat dose toxicity study (OECD408), there were no unscheduled deaths, no treatment-related clinical signs, or effects on body weight and body weight gain, food consumption, ophthalmology, FOB parameters (including motor activity), clinical chemistry including thyroid hormones, and sperm parameters. There were no related organ weight changes, macroscopic or microscopic findings. In an extended one-generation reproductive toxicology study (EOGRTS) OECD443, there were no biologically important changes in body weight or body weight gain observed in the P generation male rats during the dosing period. At the end of the dosing period, the mean body weights in the male rats were 98% and 98% of the control group value in the 3720 and 4650 mg/kg/day dose groups, respectively. No biologically important changes in maternal body weights or body weight gains were observed during the premating, gestation, or lactation periods at dose levels up to and including 4650 mg/kg/day. Clinical signs observed in the P generation males and females were within the historical data ranges and not test substance related. There were no test substance-related changes in any other tested outcomes analyzed in the P generation males and females at doses up to and including 4650 mg/kg/day. In the F1 Generation, preweaning clinical signs observed in the males and females were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the preweaning period at maternal dose levels up to and including 4650 mg/kg/day. In the postweaning period, there were also no clinical signs observed in males and females; all were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the postweaning period at maternal dose levels up to and including 4650 mg/kg/day including body weights. Taken together, data from these toxicity studies show that butyric acid-rich triglyceride oil is extremely safe with a "no observed adverse effect level" (NOAEL) considered to be 4650 mg/kg/day, the highest dose tested.
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Affiliation(s)
| | | | | | - Roy Hoffmans
- Charles River Laboratories, 's-Hertogenbosch, Netherlands
| | - Lars Damen
- Charles River Laboratories, 's-Hertogenbosch, Netherlands
| | | | - John Barnett
- Charles River Laboratories, Inc, Horsham, Pennsylvania, USA
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24
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Pérez Escriva P, Correia Tavares Bernardino C, Letellier E. De-coding the complex role of microbial metabolites in cancer. Cell Rep 2025; 44:115358. [PMID: 40023841 DOI: 10.1016/j.celrep.2025.115358] [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: 08/09/2024] [Revised: 12/11/2024] [Accepted: 02/06/2025] [Indexed: 03/04/2025] Open
Abstract
The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.
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Affiliation(s)
- Pau Pérez Escriva
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Catarina Correia Tavares Bernardino
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
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25
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Krueger ME, Boles JS, Simon ZD, Alvarez SD, McFarland NR, Okun MS, Zimmermann EM, Forsmark CE, Tansey MG. Comparative analysis of Parkinson's and inflammatory bowel disease gut microbiomes reveals shared butyrate-producing bacteria depletion. NPJ Parkinsons Dis 2025; 11:50. [PMID: 40108151 PMCID: PMC11923181 DOI: 10.1038/s41531-025-00894-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 02/19/2025] [Indexed: 03/22/2025] Open
Abstract
Epidemiological studies reveal that inflammatory bowel disease (IBD) is associated with an increased risk of Parkinson's disease (PD). Gut dysbiosis has been documented in both PD and IBD, however it is currently unknown whether gut dysbiosis underlies the epidemiological association between both diseases. To identify shared and distinct features of the PD and IBD microbiome, we recruited 54 PD, 26 IBD, and 16 healthy control individuals and performed the first joint analysis of gut metagenomes. Larger, publicly available PD and IBD metagenomic datasets were also analyzed to validate and extend our findings. Depletions in short-chain fatty acid (SCFA)-producing bacteria, including Roseburia intestinalis, Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium rectale, as well depletion in SCFA-synthesis pathways were detected across PD and IBD datasets, suggesting that depletion of these microbes in IBD may influence the risk for PD development.
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Affiliation(s)
- Maeve E Krueger
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Jake Sondag Boles
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Zachary D Simon
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
| | - Stephan D Alvarez
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
| | - Nikolaus R McFarland
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
- Department of Medicine, Division of Gastroenterology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Michael S Okun
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
- Department of Medicine, Division of Gastroenterology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Ellen M Zimmermann
- Department of Medicine, Division of Gastroenterology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Christopher E Forsmark
- Department of Medicine, Division of Gastroenterology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Malú Gámez Tansey
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA.
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.
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26
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Ouyang P, Qi J, Tong B, Li Y, Cao J, Wang L, Niu T, Qi X. Butyrate Ameliorates Graves' Orbitopathy Through Regulating Orbital Fibroblast Phenotypes and Gut Microbiota. Invest Ophthalmol Vis Sci 2025; 66:5. [PMID: 40035727 PMCID: PMC11892527 DOI: 10.1167/iovs.66.3.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 02/04/2025] [Indexed: 03/06/2025] Open
Abstract
Purpose Graves' orbitopathy (GO), the common extrathyroidal complication of Graves' disease (GD), is characterized by orbital fibroblast stimulation, adipogenesis, and hyaluronan production. Recently, gut microbiota and its metabolites have garnered attention for their possible involvement in GO. Methods This study utilized an animal model of GO and examined the effects of butyrate treatment on orbital fibroblast cells and gut microbiota. Ex vivo experiments were performed using orbital fibroblasts derived from healthy patients' and patients' with GO orbital tissue to evaluate vitality, activation, and adipogenesis in response to butyrate treatment. Gut microbiota diversity was also analyzed in butyrate-treated and untreated GO mice. Results In human orbital fibroblasts, butyrate treatment dramatically decreased the vitality of GO-derived fibroblasts without harming normal fibroblasts. Butyrate prevented activation and fibrotic processes induced by transforming growth factor beta 1 (TGF-β1) in GO and normal fibroblasts. Additionally, butyrate reduced lipid droplet formation and downregulated lipogenic markers in GO and normal orbital fibroblasts, inhibiting adipogenesis. In the GO mouse model, butyrate therapy improved orbital histological abnormalities and normalized serum thyroid hormone and antibody levels. The intestinal microbiome of butyrate-treated GO mice also changed significantly, with a reduction in certain bacteria (Bifidobacterium, GCA-900066575, and Parabacteroides) and an increase in others (Bacteroides and Rikenellaceae_RC9). Conclusions Butyrate ameliorates several of the symptoms of GO, lowering GO orbital fibroblast viability, adipogenesis, and TGF-β1-induced fibrosis without damaging normal fibroblasts. Butyrate normalizes thyroid function in a GO mouse model, improves histopathological alterations, and transforms gut microbiota populations, proving its potential in treating GO through the gut-thyroid axis.
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Affiliation(s)
- Pingbo Ouyang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jia Qi
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Boding Tong
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yunping Li
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiamin Cao
- Department of Ophthalmology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lujue Wang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tongxin Niu
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xin Qi
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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27
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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28
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Hirasawa T, Miyake K, Shinozuka K, Yonehara Y, Tsuda H. Curcumin pretreatment prevents butyrate-induced cell death and release of damage-associated molecular patterns on gingival epithelial Ca9-22 cells. J Oral Biosci 2025; 67:100613. [PMID: 39824384 DOI: 10.1016/j.job.2025.100613] [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: 10/15/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/20/2025]
Abstract
OBJECTIVES Exposure of gingival epithelial cells to butyrate, a short-chain fatty acid produced by dental plaque bacteria, cause cell death and subsequent damage-associated molecular pattern (DAMP) release. We investigated the effects of curcumin, a polyphenol extracted from turmeric, on butyrate-induced human gingival epithelial Ca9-22 cell death and DAMP release. METHODS Ca9-22 cells were pretreated with curcumin before butyrate exposure. Cell death was quantified using SYTOX green dye, and histone H3 acetylation was analyzed by Western blot. Conditioned media were collected to detect DAMPs by Western blot. We also assessed the effects of the histone acetyltransferase (HAT) inhibitor C646, instead of curcumin, on butyrate-induced cell death, DAMP release, and histone H3 acetylation, and examined the effects of curcumin pretreatment on cell death, DAMP release, and histone H3 acetylation induced by the histone deacetylase (HDAC) inhibitors, valproate and suberoylanilide hydroxamic acid (SAHA). RESULTS Curcumin pretreatment attenuated butyrate-induced Ca9-22 cell death, histone H3 acetylation, and release of the DAMPs. The C646 also attenuated butyrate-induced cell death, DAMP release, and histone H3 acetylation. Curcumin also suppressed cell death, DAMP release, and histone H3 acetylation triggered by the HDAC inhibitors (valproate and SAHA). CONCLUSIONS Curcumin pretreatment ameliorated butyrate-induced histone H3 acetylation, cell death, and DAMP release. As elevated histone acetylation by HDAC inhibitors correlates with increased cell death, while reduced acetylation by a HAT inhibitor is associated with their attenuation, protective effects of curcumin against butyrate-induced Ca9-22 cell death and subsequent DAMP release may occur via suppression of histone acetylation.
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Affiliation(s)
- Takayuki Hirasawa
- Division of Oral Structural and Functional Biology, Nihon University Graduate School of Dentistry, Tokyo, Japan; Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, Tokyo, Japan
| | - Kiwa Miyake
- Department of Oral and Maxillofacial Surgery I, Nihon University School of Dentistry, Tokyo, Japan
| | - Keiji Shinozuka
- Department of Oral and Maxillofacial Surgery I, Nihon University School of Dentistry, Tokyo, Japan
| | - Yoshiyuki Yonehara
- Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, Tokyo, Japan
| | - Hiromasa Tsuda
- Department of Biochemistry, Nihon University School of Dentistry, Tokyo, Japan; Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
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Amiri P, Hosseini SA, Saghafi-Asl M, Roshanravan N, Tootoonchian M. Expression of PGC-1α, PPAR-α and UCP1 genes, metabolic and anthropometric factors in response to sodium butyrate supplementation in patients with obesity: a triple-blind, randomized placebo-controlled clinical trial. Eur J Clin Nutr 2025; 79:249-257. [PMID: 39448815 DOI: 10.1038/s41430-024-01512-x] [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: 03/19/2024] [Revised: 09/04/2024] [Accepted: 09/16/2024] [Indexed: 10/26/2024]
Abstract
OBJECTIVES There is increasing evidence that gut metabolites have a role in the etiology of obesity. This study aimed to investigate the effects of sodium butyrate (NaB) supplementation on the expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α), PPAR-α, and uncoupling protein-1 (UCP-1) genes, as well as on the metabolic parameters and anthropometric indices in persons with obesity. METHODS In this triple-blind placebo-controlled randomized clinical trial, 50 individuals with obesity were randomly assigned to NaB (600 mg/day) + hypo-caloric diet or placebo group + hypo-caloric diet for 8 weeks. The study measured the participants' anthropometric characteristics, food consumption, and feelings of hunger in addition to the serum levels of metabolic indices and the mRNA expression of the PGC-1α, PPAR-α, and UCP-1 genes in peripheral blood mononuclear cells (PBMCs). RESULTS PGC-1α and UCP-1 genes expression significantly increased in NaB group compared to the placebo at the endpoint. A significant decrease in weight, BMI, and waist circumference (WC) was observed in NaB group. Among the metabolic factors, NaB significantly decreased fasting blood sugar (FBS) (P = 0.04), low-density lipoprotein cholesterol (LDL-C) (P = 0.038) and increased high-density lipoprotein cholesterol (HDL-C) (P = 0.016). NaB could not significantly change serum GLP-1 level. CONCLUSIONS This study unveiled NaB supplementation alone cannot have significant beneficial effects on anthropometric, and biochemical factors. NaB could affect anthropometric and metabolic risk variables associated with obesity only when prescribed, along with calorie restriction. CLINICAL TRIAL REGISTRATION This study was registered in the Iranian Registry of Clinical Trials ( https://en.irct.ir/trial/53968 ) on 31 January 2021 (registry number IRCT20190303042905N2).
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Affiliation(s)
- Parichehr Amiri
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Nutrition and Metabolic Diseases Research Center, Clinical Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Ahmad Hosseini
- Nutrition and Metabolic Diseases Research Center, Clinical Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Maryam Saghafi-Asl
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mitra Tootoonchian
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Tout I, Bougarn S, Toufiq M, Gopinath N, Hussein O, Sathappan A, Chin-Smith E, Rehaman F, Mathew R, Mathew L, Wang K, Liu L, Salhab A, Soloviov O, Tomei S, Hasan W, Da'as S, Bejaoui Y, Hajj NE, Maalej KM, Dermime S, Rasul K, Dellabona P, Casorati G, Turdo A, Todaro M, Stassi G, Ferrone S, Wang X, Maccalli C. The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses. J Transl Med 2025; 23:193. [PMID: 39962504 PMCID: PMC11834280 DOI: 10.1186/s12967-025-06176-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) initiating cells (CICs) possess self-renewal capabilities and are pivotal in tumor recurrence and resistance to conventional therapies, including immunotherapy. The mechanisms underlying their interaction with immune cells remain unclear. METHODS We conducted a multi-omics analysis-encompassing DNA methylation, total RNA sequencing, and microRNAs (miRNAs; N = 800) profiling on primary CICs and differentiated tumor cell lines, including autologous pairs. Functional immunological assays were performed to assess the impact of miRNA modulation. RESULTS CICs exhibited distinct methylation patterns, transcriptomic profiles, and miRNA expressions compared to differentiated tumor cells (p < 0.05 or 0.01). Notably, miRNA-15a and -196a were implicated in regulating tumorigenic pathways, such as epithelial-to-mesenchymal transition (EMT), TGF-β signaling, and immune modulation. The transfection of CICs with miRNA mimics led to the downregulation of oncogenic EMT markers (CRKL, lncRNA SOX2-OT, JUNB, SMAD3) and TGF-β pathway, resulting in a significant reduction of the in vitro proliferation and the tumorigenicity and migration in a zebrafish xenograft model. Additionally, miRNA-15a enhanced the expression of antigen processing machinery and decreased the expression of immune checkpoints (PD-L1, PD-L2, CTLA-4) and immunosuppressive cytokines (IL-4). The co-culture of HLA-matched lymphocytes with CICs overexpressing the miRNA-15a, elicited robust tumor-specific immune responses, characterized by a shift toward central and effector memory T cell phenotypes and prevented their terminal differentiation and exhaustion. The combination of miRNA modulation with Indoleamine 2,3-dioxygenase blockade and immunomodulating agents further potentiated these effects. CONCLUSIONS Our study demonstrates that the modulation of miRNA-15a in CICs not only suppresses the tumorigenic properties but also enhances their visibility to the immune system by upregulating antigen presentation and reducing immunomodulatory molecules. These findings suggest that combining miRNA modulation with epigenetic or immunomodulatory agents holds significant promise for overcoming treatment resistance in CRC.
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Affiliation(s)
- Issam Tout
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Salim Bougarn
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Mohammed Toufiq
- Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Neha Gopinath
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Ola Hussein
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
- College of Pharmacy, Qatar University, Doha, Qatar
| | | | - Evonne Chin-Smith
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Fazulur Rehaman
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Rebecca Mathew
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Lisa Mathew
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Kun Wang
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Li Liu
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Abdulrahman Salhab
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Oleksandr Soloviov
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sara Tomei
- Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Waseem Hasan
- Zebrafish Functional Genomics Core, Research Department, Sidra Medicine, Doha, Qatar
| | - Sahar Da'as
- Zebrafish Functional Genomics Core, Research Department, Sidra Medicine, Doha, Qatar
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Yosra Bejaoui
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Nady El Hajj
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Karama Makni Maalej
- Translational Cancer Research Facility, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Hamad Medical Corporation, Doha, Qatar
| | - Kakil Rasul
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Paolo Dellabona
- Experimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital, Milan, Italy
| | - Giulia Casorati
- Experimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital, Milan, Italy
| | - Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xinhui Wang
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina Maccalli
- Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.
- College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar.
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Guo J, Wang C, Li H, Ding C. Exploring the causal associations of the gut microbiota and plasma metabolites with ovarian cancer: an approach of mendelian randomization analysis combined with network pharmacology and molecular docking. J Ovarian Res 2025; 18:27. [PMID: 39948579 PMCID: PMC11823090 DOI: 10.1186/s13048-025-01610-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND While increasing evidence suggests that alterations in the gut microbiota and metabolites are associated with ovarian cancer (OC) risk, whether these associations imply causation remains to be identified. METHODS We conducted a two-sample Mendelian randomization (MR) study utilizing a large-scale genome-wide association study (GWAS) to explore the causal effects of the gut microbiota of 196/220 individuals and 1,400 plasma metabolites on OC and epithelial ovarian cancer (EOC) subtypes. Data on the gut microbiota were obtained from the MiBioGen consortium of 18,340 subjects and the Dutch Microbiome Project of 7,738 volunteers. Data on plasma metabolites were derived from a GWAS of plasma metabolites in 8,299 participants. Ovarian cancer (n = 25,509) and EOC subtypes were obtained from the Ovarian Cancer Association Consortium (OCAC). Metabolites and associated targets were analyzed via network pharmacology and molecular docking. RESULTS At the genus and species levels, we identified seven risk factors for the gut microbiota: the genus Dialister (P = 0.024), genus Ruminiclostridium5 (P = 0.0004), genus Phascolarctobacterium (P = 0.0217), species Bacteroides massiliensis (P = 0.011), species Phascolarctobacterium succinatutens (P = 0.0212), species Paraprevotella clara (P = 0.0247) and species Bacteroides dorei (P = 0.0054). In addition, five gut microbes at the genus and species levels were found to be protective: genus Family XIII AD3011 group (P = 0.006), genus Butyrivibrio (P = 0.0095), genus Oscillibacter (P = 0.0206), species Roseburia hominis (P = 0.0241), and species Bifidobacterium bifidum (P = 0.0224). For plasma metabolites, we revealed five positive and four negative correlations with OC. Among these, caffeic acid and caffeine metabolites and sphingomyelin and ceramide metabolites were identified as risk factors, whereas phenylalanine metabolites, butyric acid metabolites, and some lipid metabolites were recognized as protective factors. A series of sensitivity analyses revealed no abnormalities, including pleiotropy and heterogeneity analyses. CONCLUSION Our MR analysis demonstrated that the gut microbiota and metabolites are causally associated with OC, which has significant potential for the early detection and diagnosis of OC and EOC subtypes, providing valuable insights into this area of research.
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Affiliation(s)
- Junfeng Guo
- Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Chen Wang
- Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - He Li
- Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Chenhuan Ding
- Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
- Department of Traditional Chinese Medicine, School of Medicine, Pujiang Hospital, Minhang Campus of Renji Hospital, Shanghai Jiao Tong University, Shanghai, 201112, China.
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Bakshi J, Mishra KP. Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells. Cell Immunol 2025; 408:104912. [PMID: 39729961 DOI: 10.1016/j.cellimm.2024.104912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 12/29/2024]
Abstract
The gastrointestinal (GI) tract is susceptible to damage under high altitude hypoxic conditions, leading to gastrointestinal discomfort and intestinal barrier injury. Sodium butyrate, a short-chain fatty acid present as a metabolite in the gut, has emerged as a promising therapeutic agent due to its ability to act as an immunomodulatory agent and restore intestinal barrier integrity. This study aimed to explore the mechanism by which sodium butyrate exhibits anti inflammatory effect on intestinal epithelial cells. In vitro, Caco-2 epithelial cells and RAW 264.7 macrophages were used to investigate the protective role of sodium butyrate on Lipopolysaccharide (LPS) induced inflammation. Cell viability assays demonstrated that 1 mM (110.86 μg/mL) of sodium butyrate did not exhibit cytotoxicity on cells in vitro. Treatment with sodium butyrate suppressed reactive oxygen species levels and TNF-α production in LPS-stimulated macrophages, indicating its efficacy in mitigating inflammatory responses. Western blot analysis revealed that sodium butyrate attenuated the expression of iNOS in RAW 264.7 macrophage cells. Moreover, sodium butyrate also reversed the LPS induced over expression of HIF-1α, NLRP3, IL-1β as well as NF-kB in Caco-2 epithelial cells and also had a suppressive effect on IL-8 secretion after LPS stimulation. Immunocytochemistry demonstrated that sodium butyrate enhanced tight junction protein occludin expression in Caco-2 cells while also restoring the decreased permeability of the Caco-2 monolayer due to LPS. These results indicate that sodium butyrate may influence immune responses by suppressing inflammatory mediators and improving the integrity of the epithelial barrier. Understanding the intricate interactions between gut metabolites and host immune responses may help in the development of innovative therapeutic strategies to alleviate intestinal inflammation in high altitude environments.
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Affiliation(s)
- Jyotsana Bakshi
- Defence Institute of Physiology and Allied Sciences, Delhi 110054, India
| | - K P Mishra
- Defence Institute of Physiology and Allied Sciences, Delhi 110054, India.
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Zhang Y, Ji W, Qin H, Chen Z, Zhou Y, Zhou Z, Wang J, Wang K. Astragalus polysaccharides alleviate DSS-induced ulcerative colitis in mice by restoring SCFA production and regulating Th17/Treg cell homeostasis in a microbiota-dependent manner. Carbohydr Polym 2025; 349:122829. [PMID: 39643403 DOI: 10.1016/j.carbpol.2024.122829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 10/01/2024] [Indexed: 12/09/2024]
Abstract
Natural polysaccharides from Astragalus membranaceus have been shown to relieve ulcerative colitis (UC). However, the mechanism and causal relationship between the gut microbiota and Astragalus polysaccharides (APS) treatment of UC are unclear. The results of the present study showed that APS ameliorated colonic injury and the disruption of the gut microbiota and restored intestinal immune homeostasis in mice with DSS-induced colitis. Meanwhile, we found that APS treatment was ineffective in antibiotic-treated colitis mice but was effective when FMT (Fecal microbiota transplantation) was performed on UC mice using APS-treated mice as donors. APS increased the proportion of relevant microbiota that produce SCFAs and both direct administration of APS and administration of APS-adjusted gut microbiota significantly promoted the production of SCFAs in colitis mice. We demonstrated that APS dually inhibited NF-κB activation via the TLR4 and HDAC3 pathways and improved the balance in Th17/Treg cells in UC mice. In conclusion, our study revealed that APS is a promising prebiotic agent for the maintenance of intestinal health and demonstrated that APS may ameliorate colitis in a gut microbiota-dependent manner.
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Affiliation(s)
- Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Wenting Ji
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Hailong Qin
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China
| | - Zehong Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Yinxing Zhou
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China
| | - Zhihong Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Jinglin Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China.
| | - Kaiping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China.
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Okoro FO, Markus V. Artificial sweeteners and Type 2 Diabetes Mellitus: A review of current developments and future research directions. J Diabetes Complications 2025; 39:108954. [PMID: 39854925 DOI: 10.1016/j.jdiacomp.2025.108954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/12/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
While artificial sweeteners are Generally Regarded as Safe (GRAS), the scientific community remains divided on their safety status. The previous assumption that artificial sweeteners are inert within the body is no longer valid. Artificial sweeteners, known for their high intense sweetness and low or zero calories, are extensively used today in food and beverage products as sugar substitutes and are sometimes recommended for weight management and Type 2 Diabetes Mellitus (T2DM) patients. The general omission of information about the concentration of artificial sweeteners on market product labels makes it challenging to determine the amounts of artificial sweeteners consumed by people. Despite regulatory authorization for their usage, such as from the United States Food and Drug Administration (FDA), concerns remain about their potential association with metabolic diseases, such as T2DM, which the artificial sweeteners were supposed to reduce. This review discusses the relationship between artificial sweetener consumption and the risk of developing T2DM. With the increasing number of recent scientific studies adding to the debate on this subject matter, we assessed recent literature and up-to-date evidence. Importantly, we highlight future research directions toward furthering knowledge in this field of study.
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Affiliation(s)
- Francisca Obianuju Okoro
- Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia, 99138 TRNC, Mersin 10, Turkey
| | - Victor Markus
- Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia, 99138 TRNC, Mersin 10, Turkey.
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Honda T, Ishigami M, Ishizu Y, Imai N, Ito T, Yamamoto K, Yokoyama S, Muto H, Inukai Y, Kato A, Murayama A, Yoshio S, Ishikawa T, Fujishiro M, Kawashima H, Kato T. Gut microbes associated with functional cure of chronic hepatitis B. Hepatol Int 2025:10.1007/s12072-025-10776-9. [PMID: 39869245 DOI: 10.1007/s12072-025-10776-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) is prevalent worldwide and is difficult to eradicate. Current treatment strategies for chronic hepatitis B ultimately seek to achieve functional cure (FC); however, the factors contributing to FC remain unclear. We aimed to investigate the gut microbiota profiles of patients with chronic hepatitis B who achieved FC. METHODS Among 105 HBeAg-negative patients with chronic hepatitis B, 70 were enrolled, after excluding patients with cirrhosis or hepatocellular carcinoma and those receiving nucleoside analogs. The gut microbiota of patients who achieved FC was assessed and compared with that of patients with high-titer of HBV DNA (HBV DNA ≥ 3.3 log IU/mL) or low-titer of HBV DNA (HBV DNA < 3.3 log IU/mL). Furthermore, we used cell culture-generated HBV (HBVcc) as a model for HBV infection to evaluate the effects of short-chain fatty acids (SCFAs) produced by the identified bacteria. RESULTS There was no difference in the alpha or beta diversity of the gut microbiota between the FC group and the other groups. However, compared with the other groups, the FC group presented a greater relative abundance of bacteria that produce SCFAs, especially butyrate. In vitro studies demonstrated that 1.0 mM butyrate reduces HBsAg production in HBVcc-infected cells. Furthermore, butyrate administration was most effective at the post-HBV infection stage. CONCLUSIONS Our findings suggest that butyrate-producing bacteria contribute to FC in HBeAg-negative patients with chronic hepatitis B through butyrate-mediated inhibition of HBV production.
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Affiliation(s)
- Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hisanori Muto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yosuke Inukai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Asuka Kato
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Sachiyo Yoshio
- Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Kohnodai 1-7-1, Ichikawa, 272-8516, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan
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Yang J, Li G, Wang S, He M, Dong S, Wang T, Shi B, Rensen PCN, Wang Y. Butyrate Prevents Obesity Accompanied by HDAC9-Mediated Browning of White Adipose Tissue. Biomedicines 2025; 13:260. [PMID: 40002674 PMCID: PMC11852213 DOI: 10.3390/biomedicines13020260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism. METHODS We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro. RESULTS Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate. CONCLUSIONS Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9.
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Affiliation(s)
- Jing Yang
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Guoli Li
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Shan Wang
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Mingqian He
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Sijing Dong
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Ting Wang
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an 710061, China
| | - Binyin Shi
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Patrick C. N. Rensen
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands
| | - Yanan Wang
- Department of Endocrinology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China; (J.Y.)
- Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands
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Mabry SJ, Cao X, Zhu Y, Rowe C, Patel S, González-Arancibia C, Romanazzi T, Saleeby DP, Elam A, Lee HT, Turkmen S, Lauzon SN, Hernandez CE, Sun H, Wu H, Carter AM, Galli A. Fusobacterium nucleatum determines the expression of amphetamine-induced behavioral responses through an epigenetic phenomenon. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.15.633210. [PMID: 39868090 PMCID: PMC11761806 DOI: 10.1101/2025.01.15.633210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Amphetamines (AMPHs) are psychostimulants commonly used for the treatment of neuropsychiatric disorders. They are also misused (AMPH use disorder; AUD), with devastating outcomes. Recent studies have implicated dysbiosis in the pathogenesis of AUD. However, the mechanistic roles of microbes in AUD are unknown. Fusobacterium nucleatum (Fn) is a bacterium that increases in abundance in both rats and humans upon AMPH exposure. Fn releases short-chain fatty acids (SCFAs), bacterial byproducts thought to play a fundamental role in the gut-brain axis as well as the pathogenesis of AUD. We demonstrate that in gnotobiotic Drosophila melanogaster, colonization with Fn or dietary supplementation of the SCFA butyrate, a potent inhibitor of histone deacetylases (HDACs), enhances the psychomotor and rewarding properties of AMPH as well as its ability to promote male sexual motivation. Furthermore, solely HDAC1 RNAi targeted inhibition recapitulates these enhancements, pointing to a specific process underlying this Fn phenomenon. Of note is that the expression of these AMPH behaviors is determined by the increase in extracellular dopamine (DA) levels that result from AMPH-induced reversal of DA transporter (DAT) function, termed non-vesicular DA release (NVDR). The magnitude of AMPH-induced NVDR is dictated, at least in part, by DAT expression levels. Consistent with our behavioral data, we show that Fn, butyrate, and HDAC1 inhibition enhance NVDR by elevating DAT expression. Thus, the participation of Fn in AUD stems from its ability to release butyrate and inhibit HDAC1. These data offer a microbial target and probiotic interventions for AUD treatment.
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Affiliation(s)
- Samuel J Mabry
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | - Xixi Cao
- Oregon Health & Science University, School of Dentistry, Portland, Oregon
| | - Yanqi Zhu
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | - Caleb Rowe
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | - Shalin Patel
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | | | - Tiziana Romanazzi
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - David P Saleeby
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | - Anna Elam
- University of Alabama Birmingham, Department of Psychiatry, Birmingham, Alabama
| | - Hui-Ting Lee
- University of Alabama Birmingham, Department of Chemistry, Birmingham, Alabama
| | - Serhat Turkmen
- Howard Hughes Medical Institute, University of Alabama Birmingham, Department of Cell, Developmental, and Integrative Biology, Birmingham, Alabama
| | - Shelby N Lauzon
- Howard Hughes Medical Institute, University of Alabama Birmingham, Department of Cell, Developmental, and Integrative Biology, Birmingham, Alabama
| | - Cesar E Hernandez
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
| | - HaoSheng Sun
- Howard Hughes Medical Institute, University of Alabama Birmingham, Department of Cell, Developmental, and Integrative Biology, Birmingham, Alabama
| | - Hui Wu
- Oregon Health & Science University, School of Dentistry, Portland, Oregon
| | - Angela M Carter
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
- University of Alabama Birmingham, Center for Inter-systemic Networks and Enteric Medical Advances (CINEMA), Birmingham, Alabama
| | - Aurelio Galli
- University of Alabama Birmingham, Department of Surgery, Birmingham, Alabama
- University of Alabama Birmingham, Center for Inter-systemic Networks and Enteric Medical Advances (CINEMA), Birmingham, Alabama
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Saadh MJ, Allela OQB, Kareem RA, Sanghvi G, Menon SV, Sharma P, Tomar BS, Sharma A, Sameer HN, Hamad AK, Athab ZH, Adil M. From Gut to Brain: The Impact of Short-Chain Fatty Acids on Brain Cancer. Neuromolecular Med 2025; 27:10. [PMID: 39821841 DOI: 10.1007/s12017-025-08830-8] [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: 12/17/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025]
Abstract
The primary source of short-chain fatty acids (SCFAs), now recognized as critical mediators of host health, particularly in the context of neurobiology and cancer development, is the gut microbiota's fermentation of dietary fibers. Recent research highlights the complex influence of SCFAs, such as acetate, propionate, and butyrate, on brain cancer progression. These SCFAs impact immune modulation and the tumor microenvironment, particularly in brain tumors like glioma. They play a critical role in regulating cellular processes, including apoptosis, cell differentiation, and inflammation. Moreover, studies have linked SCFAs to maintaining the integrity of the blood-brain barrier (BBB), suggesting a protective role in preventing tumor infiltration and enhancing anti-tumor immunity. As our understanding of the gut-brain axis deepens, it becomes increasingly important to investigate SCFAs' therapeutic potential in brain cancer management. Looking into how SCFAs affect brain tumor cells and the environment around them could lead to new ways to prevent and treat these diseases, which could lead to better outcomes for people who are dealing with these challenging cancers.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Pawan Sharma
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Balvir S Tomar
- Institute of Pediatric Gastroenterology and Hepatology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Aanchal Sharma
- Department of Medical Lab Sciences, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Mederle AL, Semenescu A, Drăghici GA, Dehelean CA, Vlăduț NV, Nica DV. Sodium Butyrate: A Multifaceted Modulator in Colorectal Cancer Therapy. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:136. [PMID: 39859117 PMCID: PMC11766496 DOI: 10.3390/medicina61010136] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/06/2025] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
Background and Objectives: Sodium butyrate (NaB) is a potent modulator of cancer-related gene networks. However, its precise mechanisms of action and effects at elevated doses remain insufficiently explored. This study investigated the impact of NaB at physiologically relevant doses on key cellular metrics (viability, confluence, cell number, morphology, nuclear integrity) and a comprehensive set of apoptosis and proliferation regulators (including underexplored genes) in colorectal cancer (CRC) cells. Materials and Methods: Human HCT-116 cells were treated with increasing NaB concentrations (0-20 mM). Cell viability, confluence, number, morphology, and nuclear integrity were assessed using MTT and imaging assays. RT-PCR was used to determine changes in the expression of critical pro-apoptotic players (BAX, CASP3, PUMA, TP53), anti-apoptotic facilitators (BCL-2, MCL-1), cell division regulators (PCNA, Ki-67, CDKN1), and inflammation genes (NF-κB). Results: This study provides the first exploration of MCL-1 and PCNA modulation by NaB in the context of CRC and HCT-116 cells, offering significant translational insights. All treatments reduced cell viability, confluence, and number in a dose-dependent manner (p < 0.0001). Gene expression revealed dose-related increases in most pro-apoptotic markers (BAX, CASP3, PUMA; p < 0.001), and decreases for the other genes (p < 0.001). BAX emerged as the most responsive gene to NaB, while TP53 showed minimal sensitivity, supporting NaB's effectiveness in p53-compromised phenotypes. Nuclear condensation and fragmentation at higher NaB doses confirmed apoptotic induction. Conclusions: NaB can modulate critical apoptotic and cell cycle genes, disrupt tumor cell proliferation, and overcome resistance mechanisms associated with anti-apoptotic regulators such as MCL-1. By targeting both short-term and long-term anti-apoptotic defenses, NaB shows promise as a preventive and therapeutic agent in CRC, particularly in high-risk phenotypes with compromised p53 functionality. These findings support its potential for integration into combination therapies or dietary interventions aimed at enhancing colonic butyrate levels.
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Affiliation(s)
- Alexandra Laura Mederle
- Doctoral School, “Victor Babeș” University of Medicine and Pharmacy Timişoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania;
| | - Alexandra Semenescu
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania; (A.S.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy,“Victor Babeş” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania;
| | - George Andrei Drăghici
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania; (A.S.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy,“Victor Babeş” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania;
| | - Cristina Adriana Dehelean
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania; (A.S.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy,“Victor Babeş” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania;
| | - Nicolae-Valentin Vlăduț
- The National Institute of Research—Development for Machines and Installations Designed for Agriculture and Food Industry (INMA), Bulevardul Ion Ionescu de la Brad 6, 077190 București, Romania;
| | - Dragoş Vasile Nica
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy,“Victor Babeş” University of Medicine and Pharmacy Timișoara, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania;
- The National Institute of Research—Development for Machines and Installations Designed for Agriculture and Food Industry (INMA), Bulevardul Ion Ionescu de la Brad 6, 077190 București, Romania;
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40
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Slater AS, Hickey RM, Davey GP. Interactions of human milk oligosaccharides with the immune system. Front Immunol 2025; 15:1523829. [PMID: 39877362 PMCID: PMC11772441 DOI: 10.3389/fimmu.2024.1523829] [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: 11/06/2024] [Accepted: 12/17/2024] [Indexed: 01/31/2025] Open
Abstract
Human milk oligosaccharides (HMOs) are abundant, diverse and complex sugars present in human breast milk. HMOs are well-characterized barriers to microbial infection and by modulating the human microbiome they are also thought to be nutritionally beneficial to the infant. The structural variety of over 200 HMOs, including neutral, fucosylated and sialylated forms, allows them to interact with the immune system in various ways. Clinically, HMOs impact allergic diseases, reducing autoimmune and inflammatory responses, and offer beneficial support to the preterm infant immune health. This review examines the HMO composition and associated immunomodulatory effects, including interactions with immune cell receptors and gut-associated immune responses. These immunomodulatory properties highlight the potential for HMO use in early stage immune development and for use as novel immunotherapeutics. HMO research is rapidly evolving and promises innovative treatments for immune-related conditions and improved health outcomes.
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Affiliation(s)
- Alanna S. Slater
- Teagasc Food Research Centre, Moorepark, Fermoy, Ireland
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Rita M. Hickey
- Teagasc Food Research Centre, Moorepark, Fermoy, Ireland
| | - Gavin P. Davey
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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41
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Sarlak Z, Naderi N, Amidi B, Ghorbanzadeh V. Sodium Butyrate, A Gut Microbiota Derived Metabolite in Type 2 Diabetes Mellitus and Cardiovascular Disease: A Review. Cardiovasc Hematol Agents Med Chem 2025; 23:1-10. [PMID: 39206487 DOI: 10.2174/0118715257307380240820052940] [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: 01/30/2024] [Revised: 06/13/2024] [Accepted: 07/03/2024] [Indexed: 09/04/2024]
Abstract
Type 2 diabetes is characterized by elevated blood glucose levels, leading to an increased risk of cardiovascular diseases. Sodium butyrate, the sodium salt of the short-chain fatty acid butyric acid produced by gut microbiota fermentation, has shown promising effects on metabolic diseases, including type 2 diabetes and cardiovascular diseases. Sodium butyrate demonstrates anti-inflammatory, anti-oxidative, and lipid-lowering properties and can improve insulin sensitivity and reduce hepatic steatosis. In this review, we investigate how sodium butyrate influences cardiovascular complications of type 2 diabetes, including atherosclerosis (AS), heart failure (HF), hypertension, and angiogenesis. Moreover, we explore the pathophysiology of cardiovascular disease in type 2 diabetes, focusing on hyperglycemia, oxidative stress, inflammation, and genetic factors playing crucial roles. The review suggests that sodium butyrate can be a potential preventive and therapeutic agent for cardiovascular complications in individuals with type 2 diabetes.
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Affiliation(s)
- Zeynab Sarlak
- Department of Biology, Khorramabad branch, Islamic Azad University, Khorramabad, Iran
| | - Narges Naderi
- Cardiovascular Research Center, Shahid Rahimi Hospital, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Bardia Amidi
- Cardiovascular Research Center, Shahid Rahimi Hospital, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Vajihe Ghorbanzadeh
- Cardiovascular Research Center, Shahid Rahimi Hospital, Lorestan University of Medical Sciences, Khorramabad, Iran
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42
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Singh V, Shirbhate E, Kore R, Vishwakarma S, Parveen S, Veerasamy R, Tiwari AK, Rajak H. Microbial Metabolites-induced Epigenetic Modifications for Inhibition of Colorectal Cancer: Current Status and Future Perspectives. Mini Rev Med Chem 2025; 25:76-93. [PMID: 38982701 DOI: 10.2174/0113895575320344240625080555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/05/2024] [Accepted: 06/05/2024] [Indexed: 07/11/2024]
Abstract
Globally, one of the most prevalent cancers is colorectal cancer (CRC). Chemotherapy and surgery are two common conventional CRC therapies that are frequently ineffective and have serious adverse effects. Thus, there is a need for complementary and different therapeutic approaches. The use of microbial metabolites to trigger epigenetic alterations as a way of preventing CRC is one newly emerging field of inquiry. Small chemicals called microbial metabolites, which are made by microbes and capable of altering host cell behaviour, are created. Recent research has demonstrated that these metabolites can lead to epigenetic modifications such as histone modifications, DNA methylation, and non-coding RNA regulation, which can control gene expression and affect cellular behaviour. This review highlights the current knowledge on the epigenetic modification for cancer treatment, immunomodulatory and anti-carcinogenic attributes of microbial metabolites, gut epigenetic targeting system, and the role of dietary fibre and gut microbiota in cancer treatment. It also focuses on short-chain fatty acids, especially butyrates (which are generated by microbes), and their cancer treatment perspective, challenges, and limitations, as well as state-of-the-art research on microbial metabolites-induced epigenetic changes for CRC inhibition. In conclusion, the present work highlights the potential of microbial metabolites-induced epigenetic modifications as a novel therapeutic strategy for CRC suppression and guides future research directions in this dynamic field.
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Affiliation(s)
- Vaibhav Singh
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
| | - Ekta Shirbhate
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
| | - Rakesh Kore
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
| | - Subham Vishwakarma
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
| | - Shadiya Parveen
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
| | - Ravichandran Veerasamy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, Bedong, Kedah Darul Aman, 08100, Malaysia
| | - Amit K Tiwari
- UAMS College of Pharmacy; UAMS - University of Arkansas for Medical Sciences, AR 72205, USA
| | - Harish Rajak
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.), 495 009, India
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Affiliation(s)
- Yuen Jian Cheong
- Epigenetics and Signalling Programmes, Babraham Institute, Cambridge, UK
| | - Sophie Trefely
- Epigenetics and Signalling Programmes, Babraham Institute, Cambridge, UK.
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Guidi L, Martinez-Tellez B, Ortega Santos CP. Obesity, gut bacteria, and the epigenetic control of metabolic disease. NUTRITION IN THE CONTROL OF INFLAMMATION 2025:333-368. [DOI: 10.1016/b978-0-443-18979-1.00013-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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45
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Galli M, Liu LCY, Sim KH, Kok YJ, Wongtrakul-Kish K, Nguyen-Khuong T, Tate S, Bi X. SWATH-MS insights on sodium butyrate effect on mAbs production and redox homeostasis in CHO cells. AMB Express 2024; 14:140. [PMID: 39718710 DOI: 10.1186/s13568-024-01807-z] [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: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 12/25/2024] Open
Abstract
Sodium butyrate (NaBu), well-known as a histone deacetylase inhibitor and for its capacity to impede cell growth, can enhance the production of a specific protein, such as an antibody, in recombinant Chinese hamster ovary (CHO) cell cultures. In this study, two CHO cell lines, namely K1 and DG44, along with their corresponding mAb-producing lines, K1-Pr and DG44-Pr, were cultivated with or without NaBu. A SWATH-based profiling method was employed to analyze the proteome. Cells cultured in the presence of NaBu exhibited a reduction in mitosis and gene expression, supported by their culture data demonstrating growth inhibition. The presence of NaBu corresponded to upregulation of intracellular trafficking and secretion pathways, aligned with an observed increase in mAb production, and was associated with an elevated glycosylation pathway and a slight alteration in the glycosylation profile of the mAbs. Increased fatty acid oxidation, redox interactions, and lipid biosynthesis were also observed and are likely attributable to the metabolism of NaBu. A comprehensive understanding of the systemic effects of NaBu will facilitate the discovery of strategies to enhance or prolong the productivity of CHO cells.
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Affiliation(s)
- Mauro Galli
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Lillian Chia-Yi Liu
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Kae Hwan Sim
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Yee Jiun Kok
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Katherine Wongtrakul-Kish
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Terry Nguyen-Khuong
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | | | - Xuezhi Bi
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore.
- Duke-NUS Medical School, 8 College Rd, Singapore, 169857, Singapore.
- Singapore Institute of Technology, 10 Dover Dr, Singapore, 138683, Singapore.
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Corte-Iglesias V, Saiz ML, Andrade-Lopez AC, Salazar N, Bernet CR, Martin-Martin C, Borra JM, Lozano JJ, Aransay AM, Diaz-Corte C, Lopez-Larrea C, Suarez-Alvarez B. Propionate and butyrate counteract renal damage and progression to chronic kidney disease. Nephrol Dial Transplant 2024; 40:133-150. [PMID: 38794880 PMCID: PMC11852269 DOI: 10.1093/ndt/gfae118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. METHODS SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease, and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. RESULTS Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by tumour necrosis factor-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively, prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. CONCLUSIONS Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.
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Affiliation(s)
- Viviana Corte-Iglesias
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Maria Laura Saiz
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ana Cristina Andrade-Lopez
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Department of Nephrology, Hospital Universitario San Agustin, Avilés, Spain
| | - Nuria Salazar
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Villaviciosa, Spain
- Diet, Human Microbiota and Health Group, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
| | - Cristian Ruiz Bernet
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
| | - Cristina Martin-Martin
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Jesús Martinez Borra
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Juan-Jose Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Ana M Aransay
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Carmen Diaz-Corte
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Department of Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carlos Lopez-Larrea
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Beatriz Suarez-Alvarez
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Asturias, Spain
- Kidney Disease Spanish Network, RICORS2040, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Kim N, Yang C. Butyrate as a Potential Modulator in Gynecological Disease Progression. Nutrients 2024; 16:4196. [PMID: 39683590 DOI: 10.3390/nu16234196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 11/30/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
This review investigates the therapeutic potential of butyrate, a short-chain fatty acid (SCFA) produced by gut microbiota, in the prevention and treatment of various gynecological diseases, including polycystic ovary syndrome (PCOS), endometriosis, and gynecologic cancers like cervical and ovarian cancer. These conditions often pose treatment challenges, with conventional therapies offering limited and temporary relief, significant side effects, and a risk of recurrence. Emerging evidence highlights butyrate's unique biological activities, particularly its role as a histone deacetylase (HDAC) inhibitor, which allows it to modulate gene expression, immune responses, and inflammation. In PCOS, butyrate aids in restoring hormonal balance, enhancing insulin sensitivity, and reducing chronic inflammation. For endometriosis, butyrate appears to suppress immune dysregulation and minimize lesion proliferation. Additionally, in cervical and ovarian cancers, butyrate demonstrates anticancer effects through mechanisms such as cell cycle arrest, apoptosis induction, and suppression of tumor progression. Dietary interventions, particularly high-fiber and Mediterranean diets, that increase butyrate production are proposed as complementary approaches, supporting natural microbiota modulation to enhance therapeutic outcomes. However, butyrate's short half-life limits its clinical application, spurring interest in butyrate analogs and probiotics to maintain stable levels and extend its benefits. This review consolidates current findings on butyrate's multifaceted impact across gynecological health, highlighting the potential for microbiota-centered therapies in advancing treatment strategies and improving women's reproductive health.
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Affiliation(s)
- Nayeon Kim
- Department of Science Education, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Changwon Yang
- Department of Science Education, Ewha Womans University, Seoul 03760, Republic of Korea
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Swanson EC, Basting CM, Klatt NR. The role of pharmacomicrobiomics in HIV prevention, treatment, and women's health. MICROBIOME 2024; 12:254. [PMID: 39627860 PMCID: PMC11613800 DOI: 10.1186/s40168-024-01953-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/17/2024] [Indexed: 12/06/2024]
Abstract
In the absence of an effective vaccine or curative treatment for HIV, the global HIV/AIDS epidemic continues despite significant advances in treatment and prevention. Antiretroviral therapy (ART) drugs have transformed HIV from a terminal illness to a manageable chronic condition. Likewise, pre-exposure prophylaxis treatment (PrEP) has dramatically reduced transmission in some of the highest risk populations. However, quality of life and life expectancy in people living with HIV (PWH) still lag significantly behind the general population. The mechanisms that reduce the efficacy of PrEP and ART are multifaceted, but one factor that warrants additional attention is the impact of the microbiome on ART and PrEP efficacy, as well as pharmacokinetics more broadly. In this review, we assess the current state of research on the HIV-associated microbiome, how this impacts treatment efficacy, and how microbiome states can alter HIV susceptibility. We also explore how the mechanisms we propose could extend to the efficacy of other drugs and identify promising areas of research that remain understudied. Video Abstract.
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Affiliation(s)
- Erik C Swanson
- Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Christopher M Basting
- Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Nichole R Klatt
- Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
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Ma Y, Chen T, Sun T, Dilimulati D, Xiao Y. The oncomicrobiome: New insights into microorganisms in cancer. Microb Pathog 2024; 197:107091. [PMID: 39481695 DOI: 10.1016/j.micpath.2024.107091] [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: 07/10/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
The discoveries of the oncomicrobiome (intratumoral microbiome) and oncomicrobiota (intratumoral microbiota) represent significant advances in tumor research and have rapidly become of key interest to the field. Within tumors, microorganisms such as bacteria, fungi, viruses, and archaea form the oncomicrobiota and are primarily found within tumor cells, immunocytes, and the intercellular matrix. The oncomicrobiome exhibits marked heterogeneity and is associated with tumor initiation, progression, metastasis, and treatment response. Interactions between the oncomicrobiome and the immune system can modulate host antitumor immunity, influencing the efficacy of immunotherapies. Oncomicrobiome research also faces numerous challenges, including overcoming methodological issues such as low target abundance, susceptibility to contamination, and biases in sample handling and analysis methods across different studies. Furthermore, studies of the oncomicrobiome may be confounded by baseline differences in microbiomes among populations driven by both environmental and genetic factors. Most studies to date have revealed associations between the oncomicrobiome and tumors, but very few have established mechanistic links between the two. This review introduces the relevant concepts, detection methods, sources, and characteristics of the oncomicrobiome. We then describe the composition of the oncomicrobiome in common tumors and its role in shaping the tumor microenvironment. We also discuss the current problems and challenges to be overcome in this rapidly progressing field.
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Affiliation(s)
- Yingying Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingting Sun
- Department of Structure and Morphology, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China; Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, China
| | - Dilinuer Dilimulati
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yonghong Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Structure and Morphology, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China; Peking Union Medical College & Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, China.
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50
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Dizman N, Robert M, McQuade J. Beyond the Microbiome: The Role of the Metabolome and Diet in Antitumor Immunity. Eur Urol Focus 2024; 10:906-908. [PMID: 39894735 DOI: 10.1016/j.euf.2025.01.010] [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: 01/12/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Abstract
Microbiome-derived or -modulated metabolites (short-chain fatty acids, bile acids, and amino acids) could mediate antitumor immunity. Diet offers an actionable route for manipulating both the microbiome and the metabolome. Diet- and microbiome-directed trials with robust translational correlates are eagerly awaited.
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Affiliation(s)
- Nazli Dizman
- University of Texas MD Anderson Cancer Center Houston TX USA.
| | - Margaux Robert
- University of Texas MD Anderson Cancer Center Houston TX USA
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