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Saadh MJ, Allela OQB, Kareem RA, Sanghvi G, Ballal S, Naidu KS, Bareja L, Chahar M, Gupta S, Sameer HN, Yaseen A, Athab ZH, Adil M. Exploring preventive and treatment strategies for oral cancer: Modulation of signaling pathways and microbiota by probiotics. Gene 2025; 952:149380. [PMID: 40089085 DOI: 10.1016/j.gene.2025.149380] [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: 10/24/2024] [Revised: 01/11/2025] [Accepted: 02/28/2025] [Indexed: 03/17/2025]
Abstract
The evidence suggests that the microbiome plays a crucial role in cancer development. The oral cavity has many microorganisms that can influence oral cancer progression. Understanding the mechanisms and signaling pathways of the oral, gum, and teeth microbiome in tumor progression can lead to new treatment strategies. Probiotics, which are friendly microorganisms, have shown potential as anti-cancer agents. These positive characteristics of probiotic strains make them suitable for cancer prevention or treatment. The oral-gut microbiome axis supports health and homeostasis, and imbalances in the oral microbiome can disrupt immune signaling pathways, epithelial barriers, cell cycles, apoptosis, genomic stability, angiogenesis, and metabolic processes. Changes in the oral microbiome in oral cancer may suggest using probiotics-based treatments for their direct or indirect positive roles in cancer development, progression, and metastasis, specifically oral squamous cell carcinoma (OSCC). Here, reported relationships between probiotics, oral microbiota, and oral cancer are summarized.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot 360003 Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401 Punjab, India
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali 140307 Punjab, 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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2
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Mizutani H, Fukui S, Oosuka K, Ikeda K, Kobayashi M, Shimada Y, Nakazawa Y, Nishiura Y, Suga D, Moritani I, Yamanaka Y, Inoue H, Nakagawa H, Dohi K, Kaiju H, Takaba K, Wada H, Shiraki K. Biliary microbiome profiling via 16 S rRNA amplicon sequencing in patients with cholangiocarcinoma, pancreatic carcinoma and choledocholithiasis. Sci Rep 2025; 15:16966. [PMID: 40374795 PMCID: PMC12081727 DOI: 10.1038/s41598-025-00976-6] [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: 01/05/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
Recent studies have revealed that oral, gut, and intratumoral microbial dysbiosis significantly affects tumor progression, therapy resistance, and prognosis in cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) patients. However, the biliary microbiome, which directly interacts with malignant tissues, remains poorly understood. In this study, we analyzed the bile microbiota from 17 CCA, 15 PDAC, and 40 choledocholithiasis (CDL) patients using bacterial 16 S rRNA and fungal ITS sequencing. Principal coordinate analysis revealed significant differences in microbial communities between the cancer and CDL groups. The microbial community structure in each group demonstrated a specific pattern. Linear discriminant analysis revealed Streptococcus, Sphingomonas, and Bacillus enrichment in CCA patients, Neisseria, Sphingomonas, and Caulobacter in PDAC patients were more prevalent compared with CDL patients. Caulobacter was more prevalent, wheares Campylobacter was less in PDAC patients than in CCA patients. Fungal DNA was detected in ~ 50% of the samples, with CCA and PDAC patients. KEGG pathway analysis revealed altered metabolic pathways, including peptidoglycan, sphingolipid, and fatty acid metabolism and bile acid metabolism, in CCA and PDAC patients. These findings highlight the potential role of the biliary microbiome in CCA and PDAC pathogenesis, offering new insights into disease mechanisms and biomarkers.
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Affiliation(s)
- Hiroki Mizutani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Shunsuke Fukui
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Kazuki Oosuka
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Kohei Ikeda
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Mayu Kobayashi
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yasuaki Shimada
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yuuichi Nakazawa
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yuuki Nishiura
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Daisuke Suga
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Isao Moritani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yutaka Yamanaka
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Hidekazu Inoue
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroyuki Kaiju
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Kei Takaba
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Hideo Wada
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Katsuya Shiraki
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan.
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan.
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3
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Xu Y, Shi C, Qian J, Yu X, Wang S, Shao L, Yu W. The gut microbiota is altered significantly in primary diffuse large b-cell lymphoma patients and relapse refractory diffuse large b-cell lymphoma patients. Clin Transl Oncol 2025; 27:2347-2353. [PMID: 39320604 DOI: 10.1007/s12094-024-03710-2] [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: 07/30/2024] [Accepted: 08/28/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE Studies have shown that the gut microbiota may affect anti-tumor immunity by regulating the host immune system and tumor microenvironment. To date, little is known about whether the gut microbiota underlies the occurrence of diffuse large B-cell lymphoma (DLBCL) and drug resistance. METHODS In the present study, we compared the gut microbiota structure of fecal samples from 26 patients with primary DLBCL, 28 patients with relapsed and refractory (RR) DLBCL, and 30 healthy people. RESULTS Notably, Fusobacteria (from phylum to species) was enriched in the primary group. A decrease of Fusobacterium and an increase of Enterococcus were found in the RR group. PICRUSt analysis found that genes related to cytochrome P450 were upregulated in the RR group compared to the primary group, which likely contributes to the occurrence of DLBCL and the formation of drug resistance. CONCLUSIONS Our study provides further evidence for the relationship between gut microbiota and DLBCL and the formation of drug resistance, highlighting the potential significance of the bacterial variations may be used as new biomarkers of DLBCL.
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Affiliation(s)
- Yu Xu
- Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China.
| | - Chang Shi
- Zhejiang provincial Key laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, China
| | - Jiejing Qian
- Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China
| | - Xiao Yu
- Zhejiang Provincial Clinical Research Center for Hematological disorder, Zhejiang University, Hangzhou, China
| | - Shasha Wang
- Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China
| | - Li Shao
- Zhejiang University Cancer Center, Zhejiang University , Hangzhou, China
| | - Wenjuan Yu
- Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China
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Chen Y, Nian F, Chen J, Jiang Q, Yuan T, Feng H, Shen X, Dong L. Metagenomic Microbial Signatures for Noninvasive Detection of Pancreatic Cancer. Biomedicines 2025; 13:1000. [PMID: 40299688 PMCID: PMC12025148 DOI: 10.3390/biomedicines13041000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 05/01/2025] Open
Abstract
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor early detection rates owing to the limited sensitivity and specificity of the current biomarker CA19-9. Gut microbiota dysbiosis plays a key role in PDAC pathogenesis. This study aimed to evaluate the noninvasive approach we developed, combining metagenome-derived microbial signatures with CA19-9, to improve PDAC detection. Methods: This study included 50 treatment-naïve patients with PDAC and their matched controls. Fecal samples were analyzed using shotgun metagenomic sequencing. Machine learning algorithms were used to develop and validate a diagnostic panel integrating microbial signatures and CA19-9 levels. Subgroup analyses were used to confirm the robustness of the microbial markers. Results: The combined models at both species and genus levels effectively distinguished patients with PDAC from healthy individuals, and their strong diagnostic efficacy and accuracy were demonstrated through rigorous validation. Conclusions: In conclusion, the combination of gut microbiome profiling and CA19-9 improves PDAC detection accuracy compared to the use of CA19-9 alone, showing promise for early and noninvasive diagnosis.
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Affiliation(s)
- Yueying Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Fulin Nian
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Jia Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Qiuyu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Tianli Yuan
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, University School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Haokang Feng
- Key Laboratory of Carcinogenesis and Cancer Invasion, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai 200032, China
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
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Stein-Thoeringer CK, Renz BW, De Castilhos J, von Ehrlich-Treuenstätt V, Wirth U, Tschaidse T, Hofmann FO, Koch DT, Beirith I, Ormanns S, Guba MO, Angele MK, Andrassy J, Niess H, D'Haese JG, Werner J, Ilmer M. Microbiome Dysbiosis With Enterococcus Presence in the Upper Gastrointestinal Tract Is a Risk Factor for Mortality in Patients Undergoing Surgery for Pancreatic Cancer. Ann Surg 2025; 281:615-623. [PMID: 38275104 DOI: 10.1097/sla.0000000000006210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
BACKGROUND Recent retrospective studies suggest a role for distinct microbiota in the perioperative morbidity and mortality of pancreatic head resections. OBJECTIVE We aimed to prospectively investigate the microbial colonization of critical operative sites of pancreatic head resections to identify microbial stratification factors for surgical and long-term oncologic outcomes. METHODS Prospective biomarker study applying 16S rRNA sequencing and microbial culturing to samples collected from various sites of the gastrointestinal tract and surgical sites of patients during pancreatic head resections at a German single high-volume pancreatic center. RESULTS A total of 101 patients were included {38 noncancer, 63 cancer patients [50 pancreatic ductal adenocarcinoma (PDAC) patients]} in the study. In a first data analysis series, 16S rRNA sequencing data were utilized from 96 patients to assess associations of microbiome profiles with clinical parameters and outcomes. In general, microbiome composition varied according to sampling site, cancer, age or preoperative endoscopic retrograde cholangiopancreatography (ERCP) intervention, notably for the bile microbiome. In the PDAC subcohort, the compositional variance of the bile or periampullary microbiome was significantly associated with postoperative complications such as intensive care unit admission; on a taxonomic level we observed Enterococcus spp. to be significantly more abundant in patients developing deep or organ-space surgical site infections (SSI). Elevated Enterococcus relative abundances in the upper gastrointestinal tract, in turn, were associated with 6 months mortality rates. In a second step, we focused on microbiological cultures collected from bile aspirates during surgery and investigated associations with perioperative complications and long-term survival. Notably, Enterococcus spp. were among the most prevalent pathobiont isolates observed in cancer patient bile specimens that were associated with severe SSIs, and thereby elevated mortality rates up to 24 months. Clinically relevant postoperative pancreatic fistulas or severe SSI were found as other major variables determining short-term mortality in this cancer patient cohort. In the context of adverse microbiological factors, a preoperative ERCP was also observed to segregate long-term survival, and it appeared to interact with the presence of Enterococcus spp. as highest mortality rates were observed in PDAC patients with both preoperative ERCP and presence of E. faecalis in bile aspirates. CONCLUSIONS The presence of Enterococcus spp. in bile ducts of PDAC patients undergoing pancreatic surgery represents a significant risk factor for perioperative infections and, thereby, elevated postoperative and long-term mortality. This finding supports previous data on the use of the antibiotic drug piperacillin-tazobactam as appropriate perioperative antibiotic prophylaxis for preventing adverse outcomes after pancreatoduodenectomy.
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Affiliation(s)
- Christoph K Stein-Thoeringer
- Laboratory of Translational Microbiome Science, Internal Medicine I, University Clinic Tuebingen, Germany
- CMFI Cluster of Excellence, University of Tuebingen, Germany
- DZIF (Deut. Zentrum für Infektionsforschung), HAARBI Partner Site Tuebingen, Germany
| | - Bernhard W Renz
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Juliana De Castilhos
- Laboratory of Translational Microbiome Science, Internal Medicine I, University Clinic Tuebingen, Germany
| | - Viktor von Ehrlich-Treuenstätt
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Ulrich Wirth
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Tengis Tschaidse
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Felix O Hofmann
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominik T Koch
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Iris Beirith
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Steffen Ormanns
- German Cancer Consortium (DKTK), Partner Site Munich, of the German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Markus O Guba
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Martin K Angele
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Joachim Andrassy
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Hanno Niess
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
| | - Jens Werner
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, of the German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Ilmer
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, of the German Cancer Research Center (DKFZ), Heidelberg, Germany
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Ramesh RPG, Yasmin H, Ponnachan P, Al-Ramadi B, Kishore U, Joseph AM. Phenotypic heterogeneity and tumor immune microenvironment directed therapeutic strategies in pancreatic ductal adenocarcinoma. Front Immunol 2025; 16:1573522. [PMID: 40230862 PMCID: PMC11994623 DOI: 10.3389/fimmu.2025.1573522] [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: 02/09/2025] [Accepted: 03/04/2025] [Indexed: 04/16/2025] Open
Abstract
Pancreatic cancer is an aggressive tumor with high metastatic potential which leads to decreased survival rate and resistance to chemotherapy and immunotherapy. Nearly 90% of pancreatic cancer comprises pancreatic ductal adenocarcinoma (PDAC). About 80% of diagnoses takes place at the advanced metastatic stage when it is unresectable, which renders chemotherapy regimens ineffective. There is also a dearth of specific biomarkers for early-stage detection. Advances in next generation sequencing and single cell profiling have identified molecular alterations and signatures that play a role in PDAC progression and subtype plasticity. Most chemotherapy regimens have shown only modest survival benefits, and therefore, translational approaches for immunotherapies and combination therapies are urgently required. In this review, we have examined the immunosuppressive and dense stromal network of tumor immune microenvironment with various metabolic and transcriptional changes that underlie the pro-tumorigenic properties in PDAC in terms of phenotypic heterogeneity, plasticity and subtype co-existence. Moreover, the stromal heterogeneity as well as genetic and epigenetic changes that impact PDAC development is discussed. We also review the PDAC interaction with sequestered cellular and humoral components present in the tumor immune microenvironment that modify the outcome of chemotherapy and radiation therapy. Finally, we discuss different therapeutic interventions targeting the tumor immune microenvironment aimed at better prognosis and improved survival in PDAC.
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Affiliation(s)
- Remya P. G. Ramesh
- Department of Veterinary Medicine, UAE University, Al Ain, United Arab Emirates
| | - Hadida Yasmin
- Immunology and Cell Biology Laboratory, Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal, India
| | - Pretty Ponnachan
- Department of Veterinary Medicine, UAE University, Al Ain, United Arab Emirates
| | - Basel Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Uday Kishore
- Department of Veterinary Medicine, UAE University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ann Mary Joseph
- Department of Veterinary Medicine, UAE University, Al Ain, United Arab Emirates
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Shimosaka M, Kondo J, Sonoda M, Kawaguchi R, Noda E, Nishikori K, Ogata A, Takamatsu S, Sasai K, Akita H, Eguchi H, Kamada Y, Okamoto S, Miyoshi E. Invasion of pancreatic ductal epithelial cells by Enterococcus faecalis is mediated by fibronectin and enterococcal fibronectin-binding protein A. Sci Rep 2025; 15:2585. [PMID: 39833342 PMCID: PMC11747100 DOI: 10.1038/s41598-025-86531-9] [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: 09/05/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025] Open
Abstract
The poor prognosis of pancreatic cancer is often attributed to difficulties of early detection due to a lack of appropriate risk factors. Previously, we demonstrated the presence of Enterococcus faecalis (E. faecalis) in pancreatic juice and tissues obtained from patients with cancers of the duodeno-pancreato-biliary region, suggesting the possible involvement of this bacterial species in chronic and malignant pancreatic diseases. However, it remains unclear if and how E. faecalis can infect pancreatic ductal cells. In this study, we used immortalized normal human pancreatic ductal epithelial cells (iPDECs) and pancreatic ductal cancer cell lines to demonstrate that E. faecalis adheres to and invades pancreatic ductal lineage epithelial cells. Inhibitors of micropinocytosis or clathrin- or caveolae-mediated endocytosis suppressed iPDEC invasion by E. faecalis. Mechanistically, bacterial expression of enterococcal fibronectin-binding protein A (EfbA) was correlated with adhesive potential of E. faecalis strains. Knockout of fibronectin 1, a binding partner of EfbA, in iPDECs resulted in suppressed E. faecalis adhesion and invasion, suggesting the importance of the EfbA-fibronectin axis in infection of pancreatic ductal epithelial lineage cells. Overall, these results suggest that E. faecalis can colonize pancreatic tissue by infecting iPDECs, at least in part, via the expression of the cell adhesion factor EfbA.
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Affiliation(s)
- Munefumi Shimosaka
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Jumpei Kondo
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Mamika Sonoda
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Rui Kawaguchi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Emika Noda
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kaho Nishikori
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Asuka Ogata
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ken Sasai
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shigefumi Okamoto
- Laboratory of Medical Microbiology and Microbiome, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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8
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Luan X, Wang X, Bian G, Li X, Gao Z, Liu Z, Zhang Z, Han T, Zhao J, Zhao H, Luan X, Zhu W, Dong L, Guo F. Exosome applications for the diagnosis and treatment of pancreatic ductal adenocarcinoma: An update (Review). Oncol Rep 2025; 53:13. [PMID: 39575479 PMCID: PMC11605277 DOI: 10.3892/or.2024.8846] [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: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.
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Affiliation(s)
- Xinchi Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuezhe Wang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Gang Bian
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Xiaoxuan Li
- Department of Oncology, Key Laboratory of Cancer Molecular and Translational Research, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China
| | - Ziru Gao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zijiao Liu
- School of Clinical and Basic Medicine and Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Zhishang Zhang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyue Han
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Jinpeng Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Hongjiao Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xinyue Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wuhui Zhu
- Department of Hepatobiliary surgery, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Lili Dong
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Feifei Guo
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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9
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Chen X, Guo X. Microbiome analysis reveals the potential mechanism of herbal sitz bath complementary therapy in accelerating postoperative recovery from perianal abscesses. IET Syst Biol 2025; 19:e12114. [PMID: 39846370 PMCID: PMC11771788 DOI: 10.1049/syb2.12114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/24/2025] Open
Abstract
The herbal sitz bath formula, as a complementary therapy, effectively alleviates postoperative wound pain and accelerates healing time in patients with perianal abscesses. To investigate its mechanism of action, this study conducted 16S rRNA gene sequencing and bioinformatics analysis on wound exudate samples from patients after perianal abscess surgery. Patients were randomly divided into two groups: one receiving the herbal sitz bath as an adjunctive therapy and the other without this adjunctive therapy. Samples were collected on the first and eighth days after surgery to compare the differences in microbial community composition between the two groups on the eighth day and between the first and eighth days within each group. The study revealed that the herbal sitz bath significantly altered the structure of the microbial community, increasing its diversity and abundance. By reducing Enterococcus and increasing Bifidobacterium, Faecalibacterium, and Ruminococcus, the therapy enhanced the wound's anti-infective capacity and accelerated healing. This study explored the potential mechanism of the herbal sitz bath formula as an adjunctive therapy in promoting postoperative recovery from perianal abscesses, providing valuable data for further research on the role of microorganisms in wound care. These findings contribute to optimising postoperative treatment regimens and facilitating patient recovery.
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Affiliation(s)
- Xinghua Chen
- Department of Traditional Chinese MedicineJinshan Hospital of Fudan UniversityShanghaiChina
| | - Xiutian Guo
- Department of AnorectalShanghai Municipal Hospital of Traditional Chinese Medicine (Affiliated to Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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10
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Lin Z, Assaraf YG, Kwok HF. Peptides for microbe-induced cancers: latest therapeutic strategies and their advanced technologies. Cancer Metastasis Rev 2024; 43:1315-1336. [PMID: 39008152 DOI: 10.1007/s10555-024-10197-4] [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: 02/26/2023] [Accepted: 06/14/2024] [Indexed: 07/16/2024]
Abstract
Cancer is a significant global health concern associated with multiple distinct factors, including microbial and viral infections. Numerous studies have elucidated the role of microorganisms, such as Helicobacter pylori (H. pylori), as well as viruses for example human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis C virus (HCV), in the development of human malignancies. Substantial attention has been focused on the treatment of these microorganism- and virus-associated cancers, with promising outcomes observed in studies employing peptide-based therapies. The current paper provides an overview of microbe- and virus-induced cancers and their underlying molecular mechanisms. We discuss an assortment of peptide-based therapies which are currently being developed, including tumor-targeting peptides and microbial/viral peptide-based vaccines. We describe the major technological advancements that have been made in the design, screening, and delivery of peptides as anticancer agents. The primary focus of the current review is to provide insight into the latest research and development in this field and to provide a realistic glimpse into the future of peptide-based therapies for microbe- and virus-induced neoplasms.
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Affiliation(s)
- Ziqi Lin
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Instituteof Technology, Haifa, 3200003, Israel
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR.
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11
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Gao Z, Luan X, Wang X, Han T, Li X, Li Z, Li P, Zhou Z. DNA damage response-related ncRNAs as regulators of therapy resistance in cancer. Front Pharmacol 2024; 15:1390300. [PMID: 39253383 PMCID: PMC11381396 DOI: 10.3389/fphar.2024.1390300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
The DNA damage repair (DDR) pathway is a complex signaling cascade that can sense DNA damage and trigger cellular responses to DNA damage to maintain genome stability and integrity. A typical hallmark of cancer is genomic instability or nonintegrity, which is closely related to the accumulation of DNA damage within cancer cells. The treatment principles of radiotherapy and chemotherapy for cancer are based on their cytotoxic effects on DNA damage, which are accompanied by severe and unnecessary side effects on normal tissues, including dysregulation of the DDR and induced therapeutic tolerance. As a driving factor for oncogenes or tumor suppressor genes, noncoding RNA (ncRNA) have been shown to play an important role in cancer cell resistance to radiotherapy and chemotherapy. Recently, it has been found that ncRNA can regulate tumor treatment tolerance by altering the DDR induced by radiotherapy or chemotherapy in cancer cells, indicating that ncRNA are potential regulatory factors targeting the DDR to reverse tumor treatment tolerance. This review provides an overview of the basic information and functions of the DDR and ncRNAs in the tolerance or sensitivity of tumors to chemotherapy and radiation therapy. We focused on the impact of ncRNA (mainly microRNA [miRNA], long noncoding RNA [lncRNA], and circular RNA [circRNA]) on cancer treatment by regulating the DDR and the underlying molecular mechanisms of their effects. These findings provide a theoretical basis and new insights for tumor-targeted therapy and the development of novel drugs targeting the DDR or ncRNAs.
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Affiliation(s)
- Ziru Gao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xinchi Luan
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xuezhe Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Tianyue Han
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiaoyuan Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zeyang Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zhixia Zhou
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
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12
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Jiang H, Tian Y, Xu L, Chen X, Huang Y, Wu J, Wang T, Liu T, Wu X, Ye C, Wu H, Ye W, Fang L, Zhang Y. Alterations of the bile microbiome is associated with progression-free survival in pancreatic ductal adenocarcinoma patients. BMC Microbiol 2024; 24:235. [PMID: 38956452 PMCID: PMC11218221 DOI: 10.1186/s12866-024-03371-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/17/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. METHODS Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16 S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. RESULTS PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. CONCLUSION PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.
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Affiliation(s)
- Hang Jiang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yitong Tian
- Zhejiang University, Hangzhou, Zhejiang Province, 310058, China
| | - Linwei Xu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Xing Chen
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Yurun Huang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jia Wu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
| | - Tingzhang Wang
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China
- NMPA Key Laboratory for Testing and Risk Warning of Pharmaceutical Microbiology, Hangzhou, China
| | - Tingting Liu
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China
- NMPA Key Laboratory for Testing and Risk Warning of Pharmaceutical Microbiology, Hangzhou, China
| | - Xitian Wu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chao Ye
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Hao Wu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Wenkai Ye
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Luo Fang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
| | - Yuhua Zhang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
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13
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Pust MM, Rocha Castellanos DM, Rzasa K, Dame A, Pishchany G, Assawasirisin C, Liss A, Fernandez-Del Castillo C, Xavier RJ. Absence of a pancreatic microbiome in intraductal papillary mucinous neoplasm. Gut 2024; 73:1131-1141. [PMID: 38429112 PMCID: PMC11187374 DOI: 10.1136/gutjnl-2023-331012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 02/06/2024] [Indexed: 03/03/2024]
Abstract
OBJECTIVE This study aims to validate the existence of a microbiome within intraductal papillary mucinous neoplasm (IPMN) that can be differentiated from the taxonomically diverse DNA background of next-generation sequencing procedures. DESIGN We generated 16S rRNA amplicon sequencing data to analyse 338 cyst fluid samples from 190 patients and 19 negative controls, the latter collected directly from sterile syringes in the operating room. A subset of samples (n=20) and blanks (n=5) were spiked with known concentrations of bacterial cells alien to the human microbiome to infer absolute abundances of microbial traces. All cyst fluid samples were obtained intraoperatively and included IPMNs with various degrees of dysplasia as well as other cystic neoplasms. Follow-up culturing experiments were conducted to assess bacterial growth for microbiologically significant signals. RESULTS Microbiome signatures of cyst fluid samples were inseparable from those of negative controls, with no difference in taxonomic diversity, and microbial community composition. In a patient subgroup that had recently undergone invasive procedures, a bacterial signal was evident. This outlier signal was not characterised by higher taxonomic diversity but by an increased dominance index of a gut-associated microbe, leading to lower taxonomic evenness compared with the background signal. CONCLUSION The 'microbiome' of IPMNs and other pancreatic cystic neoplasms does not deviate from the background signature of negative controls, supporting the concept of a sterile environment. Outlier signals may appear in a small fraction of patients following recent invasive endoscopic procedures. No associations between microbial patterns and clinical or cyst parameters were apparent.
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Affiliation(s)
- Marie-Madlen Pust
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Kara Rzasa
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Andrea Dame
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Gleb Pishchany
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
| | - Charnwit Assawasirisin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew Liss
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
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14
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Schwarcz S, Kovács P, Nyerges P, Ujlaki G, Sipos A, Uray K, Bai P, Mikó E. The bacterial metabolite, lithocholic acid, has antineoplastic effects in pancreatic adenocarcinoma. Cell Death Discov 2024; 10:248. [PMID: 38782891 PMCID: PMC11116504 DOI: 10.1038/s41420-024-02023-1] [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: 09/06/2023] [Revised: 05/08/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024] Open
Abstract
Lithocholic acid (LCA) is a secondary bile acid. LCA enters the circulation after bacterial synthesis in the gastrointestinal tract, reaches distantly located cancer cells, and influences their behavior. LCA was considered carcinogenic, but recent studies demonstrated that LCA has antitumor effects. We assessed the possible role of LCA in pancreatic adenocarcinoma. At the serum reference concentration, LCA induced a multi-pronged antineoplastic program in pancreatic adenocarcinoma cells. LCA inhibited cancer cell proliferation and induced mesenchymal-to-epithelial (MET) transition that reduced cell invasion capacity. LCA induced oxidative/nitrosative stress by decreasing the expression of nuclear factor, erythroid 2-like 2 (NRF2) and inducing inducible nitric oxide synthase (iNOS). The oxidative/nitrosative stress increased protein nitration and lipid peroxidation. Suppression of oxidative stress by glutathione (GSH) or pegylated catalase (pegCAT) blunted LCA-induced MET. Antioxidant genes were overexpressed in pancreatic adenocarcinoma and decreased antioxidant levels correlated with better survival of pancreatic adenocarcinoma patients. Furthermore, LCA treatment decreased the proportions of cancer stem cells. Finally, LCA induced total and ATP-linked mitochondrial oxidation and fatty acid oxidation. LCA exerted effects through the farnesoid X receptor (FXR), vitamin D receptor (VDR), and constitutive androstane receptor (CAR). LCA did not interfere with cytostatic agents used in the chemotherapy of pancreatic adenocarcinoma. Taken together, LCA is a non-toxic compound and has antineoplastic effects in pancreatic adenocarcinoma.
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Affiliation(s)
- Szandra Schwarcz
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Petra Nyerges
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Gyula Ujlaki
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
| | - Karen Uray
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
- HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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15
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Zhao F, Chen A, Wu X, Deng X, Yang J, Xue J. Heterogeneous changes in gut and tumor microbiota in patients with pancreatic cancer: insights from clinical evidence. BMC Cancer 2024; 24:478. [PMID: 38622651 PMCID: PMC11020926 DOI: 10.1186/s12885-024-12202-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 03/28/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Pancreatic cancer is the foremost contributor to cancer-related deaths globally, and its prevalence continues to rise annually. Nevertheless, the underlying mechanisms behind its development remain unclear and necessitate comprehensive investigation. METHODS In this study, a total of 29 fresh stool samples were collected from patients diagnosed with pancreatic cancer. The gut microbial data of healthy controls were obtained from the SRA database (SRA data number: SRP150089). Additionally, 28 serum samples and diseased tissues were collected from 14 patients with confirmed pancreatic cancer and 14 patients with chronic pancreatitis. Informed consent was obtained from both groups of patients. Microbial sequencing was performed using 16s rRNA. RESULTS The results showed that compared with healthy controls, the species abundance index of intestinal flora in patients with pancreatic cancer was increased (P < 0.05), and the number of beneficial bacteria at the genus level was reduced (P < 0.05). Compared with patients with chronic pancreatitis, the expression levels of CA242 and CA199 in the serum of patients with pancreatic cancer were increased (P < 0.05). The bacterial richness index of tumor microorganisms in patients with pancreatic cancer increased, while the diversity index decreased(P < 0.05). Furthermore, there was a change in the species composition at the genus level. Additionally, the expression level of CA242 was found to be significantly positively correlated with the relative abundance of Acinetobacter(P < 0.05). CONCLUSION Over all, the expression levels of serum tumor markers CA242 and CA19-9 in patients with pancreatic cancer are increased, while the beneficial bacteria in the intestine and tumor microenvironment are reduced and pathogenic bacteria are increased. Acinetobacter is a specific bacterial genus highly expressed in pancreatic cancer tissue.
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Affiliation(s)
- Feng Zhao
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 55, Daxuecheng Middle Road, ShaPingBa District, 400016, Chongqing, People's Republic of China
| | - Anli Chen
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, 401331, Chongqing, People's Republic of China
| | - Xiaotian Wu
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, 401331, Chongqing, People's Republic of China
| | - Xiangyu Deng
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, 401331, Chongqing, People's Republic of China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, 401147, Chongqing, People's Republic of China.
| | - Jianjiang Xue
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 55, Daxuecheng Middle Road, ShaPingBa District, 400016, Chongqing, People's Republic of China.
- Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, 401331, Chongqing, People's Republic of China.
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16
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Liu J, Yan Q, Li S, Jiao J, Hao Y, Zhang G, Zhang Q, Luo F, Zhang Y, Lv Q, Zhang W, Zhang A, Song H, Xin Y, Ma Y, Owusu L, Ma X, Yin P, Shang D. Integrative metagenomic and metabolomic analyses reveal the potential of gut microbiota to exacerbate acute pancreatitis. NPJ Biofilms Microbiomes 2024; 10:29. [PMID: 38514648 PMCID: PMC10957925 DOI: 10.1038/s41522-024-00499-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 03/13/2024] [Indexed: 03/23/2024] Open
Abstract
Early dysbiosis in the gut microbiota may contribute to the severity of acute pancreatitis (AP), however, a comprehensive understanding of the gut microbiome, potential pathobionts, and host metabolome in individuals with AP remains elusive. Hence, we employed fecal whole-metagenome shotgun sequencing in 82 AP patients and 115 matched healthy controls, complemented by untargeted serum metabolome and lipidome profiling in a subset of participants. Analyses of the gut microbiome in AP patients revealed reduced diversity, disrupted microbial functions, and altered abundance of 77 species, influenced by both etiology and severity. AP-enriched species, mostly potential pathobionts, correlated positively with host liver function and serum lipid indicators. Conversely, many AP-depleted species were short-chain fatty acid producers. Gut microflora changes were accompanied by shifts in the serum metabolome and lipidome. Specifically, certain gut species, like enriched Bilophila wadsworthia and depleted Bifidobacterium spp., appeared to contribute to elevated triglyceride levels in biliary or hyperlipidemic AP patients. Through culturing and whole-genome sequencing of bacterial isolates, we identified virulence factors and clinically relevant antibiotic resistance in patient-derived strains, suggesting a predisposition to opportunistic infections. Finally, our study demonstrated that gavage of specific pathobionts could exacerbate pancreatitis in a caerulein-treated mouse model. In conclusion, our comprehensive analysis sheds light on the gut microbiome and serum metabolome in AP, elucidating the role of pathobionts in disease progression. These insights offer valuable perspectives for etiologic diagnosis, prevention, and intervention in AP and related conditions.
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Affiliation(s)
- Jianjun Liu
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Qiulong Yan
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | | | - Juying Jiao
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Yiming Hao
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Guixin Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qingkai Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fei Luo
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Yue Zhang
- Puensum Genetech Institute, Wuhan, China
| | - Qingbo Lv
- Puensum Genetech Institute, Wuhan, China
| | - Wenzhe Zhang
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | | | - Huiyi Song
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yi Xin
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yufang Ma
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Lawrence Owusu
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xiaochi Ma
- Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Peiyuan Yin
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
- College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
- College of Integrative Medicine, Dalian Medical University, Dalian, China.
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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17
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Subramanian SK, Brahmbhatt B, Bailey-Lundberg JM, Thosani NC, Mutha P. Lifestyle Medicine for the Prevention and Treatment of Pancreatitis and Pancreatic Cancer. Diagnostics (Basel) 2024; 14:614. [PMID: 38535034 PMCID: PMC10968821 DOI: 10.3390/diagnostics14060614] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 04/14/2025] Open
Abstract
The incidence of pancreatitis and pancreatic cancer is on the upswing in the USA. These conditions often lead to higher healthcare costs due to the complex nature of diagnosis and the need for specialized medical interventions, surgical procedures, and prolonged medical management. The economic ramification encompasses direct healthcare expenses and indirect costs related to productivity losses, disability, and potential long-term care requirements. Increasing evidence underscores the importance of a healthy lifestyle in preventing and managing these conditions. Lifestyle medicine employs evidence-based interventions to promote health through six key pillars: embracing a whole-food, plant-predominant dietary pattern; regular physical activity; ensuring restorative sleep; managing stress effectively; removing harmful substances; and fostering positive social connections. This review provides a comprehensive overview of lifestyle interventions for managing and preventing the development of pancreatitis and pancreatic cancer.
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Affiliation(s)
- Sruthi Kapliyil Subramanian
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
| | - Bhaumik Brahmbhatt
- Mayo Clinic, Division of Gastroenterology and Hepatology, Jacksonville, FL 32224, USA;
| | - Jennifer M. Bailey-Lundberg
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA;
| | - Nirav C. Thosani
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
| | - Pritesh Mutha
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
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18
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Di Carlo P, Serra N, Fasciana TMA, Giammanco A, D’Arpa F, Rea T, Napolitano MS, Lucchesi A, Cascio A, Sergi CM. Microbial profile in bile from pancreatic and extra-pancreatic biliary tract cancer. PLoS One 2024; 19:e0294049. [PMID: 38381746 PMCID: PMC10880987 DOI: 10.1371/journal.pone.0294049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 09/11/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Dysbiotic biliary bacterial profile is reported in cancer patients and is associated with survival and comorbidities, raising the question of its effect on the influence of anticancer drugs and, recently, the suggestion of perichemotherapy antibiotics in pancreatic cancer patients colonized by the Escherichia coli and Klebsiella pneumoniae. OBJECTIVE In this study, we investigated the microbial communities that colonize tumours and which bacteria could aid in diagnosing pancreatic and biliary cancer and managing bile-colonized patients. METHODS A retrospective study on positive bile cultures of 145 Italian patients who underwent cholangiopancreatography with PC and EPC cancer hospitalized from January 2006 to December 2020 in a QA-certified academic surgical unit were investigated for aerobic/facultative-anaerobic bacteria and fungal organisms. RESULTS We found that among Gram-negative bacteria, Escherichia coli and Pseudomonas spp were the most frequent in the EPC group, while Escherichia coli, Klebsiella spp, and Pseudomonas spp were the most frequent in the PC group. Enterococcus spp was the most frequent Gram-positive bacteria in both groups. Comparing the EPC and PC, we found a significant presence of patients with greater age in the PC compared to the EPC group. Regarding Candida spp, we found no significant but greater rate in the PC group compared to the EPC group (11.7% vs 1.96%). We found that Alcaligenes faecalis was the most frequent bacteria in EPC than the PC group, among Gram-negative bacterial species. CONCLUSIONS Age differences in gut microbiota composition may affect biliary habitats in our cancer population, especially in patients with pancreatic cancer. Alcaligenes faecalis isolated in the culture of bile samples could represent potential microbial markers for a restricted follow-up to early diagnosis of extra-pancreatic cancer. Finally, the prevalence of Candida spp in pancreatic cancer seems to trigger new aspects about debate about the role of fungal microbiota into their relationship with pancreatic cancer.
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Affiliation(s)
- Paola Di Carlo
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence "G. D’Alessandro”, University of Palermo, Palermo, Italy
| | - Nicola Serra
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Teresa Maria Assunta Fasciana
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence "G. D’Alessandro”, University of Palermo, Palermo, Italy
| | - Anna Giammanco
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence "G. D’Alessandro”, University of Palermo, Palermo, Italy
| | - Francesco D’Arpa
- Department of General Surgery and Emergency, University of Palermo, Palermo, Italy
| | - Teresa Rea
- Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Maria Santa Napolitano
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence "G. D’Alessandro”, University of Palermo, Palermo, Italy
| | - Alessandro Lucchesi
- Hematology Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) “Dini Amadori”, Meldola, Forl-Cesena, Italy
| | - Antonio Cascio
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence "G. D’Alessandro”, Infectious Disease Unit, University of Palermo, Palermo, Italy
| | - Consolato Maria Sergi
- Lab. Med. and Pathology, Children’s Hospital of Eastern Ontario (CHEO), Ottawa, Canada
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19
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Shirai H, Tsukada K. Understanding bacterial infiltration of the pancreas through a deformable pancreatic duct. J Biomech 2024; 162:111883. [PMID: 38064997 DOI: 10.1016/j.jbiomech.2023.111883] [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: 07/26/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 01/16/2024]
Abstract
Tiny amount of bacteria are found in the pancreas in pancreatitis and cancer, which seemed involved in inflammation and carcinogenesis. However, bacterial infiltration from the duodenum is inhibited by the physical defense mechanisms such as bile flow and the sphincter of Oddi. To understand how the bacteria possibly infiltrate the pancreas through a deformable pancreatic duct, influenced by the periodic contractions of the sphincter of Oddi, a mathematical model of bacterial infiltration is developed that considered large deformation, fluid flow, and bacterial transport in a deformable pancreatic duct. In addition, the sphincter's contraction wave is modeled by including its propagation from the pancreas toward the duodenum. Simulated structure of the deformed duct with the relaxed sphincter and simulated bile distribution agreed reasonably well with the literature, validating the model. Bacterial infiltration from the duodenum in a deformable pancreatic duct, following the sphincter's contraction, is counteracted by a gradual peristalsis-like deformation of the pancreatic duct, due to an antegrade contraction wave propagation from the pancreas to the duodenum, Parametric sensitivity analysis demonstrated that bacterial infiltration is increased with lower bile and pancreatic juice flow rate, greater contraction amplitude and frequency, thinner wall thickness, and retrograde contraction wave propagation. Since contraction waves following retrograde propagation are increased in patients with common bile duct stones and pancreatitis, they may possibly be factors for continuum inflammation of pancreas. (224 words).
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Affiliation(s)
- Hiroaki Shirai
- Graduate School of Science and Technology, Keio University, 3-14-1 Hiyoshi Kohoku-ku, Yokohama-shi, Kanagawa 223-8522, Japan.
| | - Kosuke Tsukada
- Graduate School of Science and Technology, Keio University, 3-14-1 Hiyoshi Kohoku-ku, Yokohama-shi, Kanagawa 223-8522, Japan; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi Kohoku-ku, Yokohama-shi, Kanagawa 223-8522, Japan
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20
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Yang X, Zhang Z, Shen X, Xu J, Weng Y, Wang W, Xue J. Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma. Cell Oncol (Dordr) 2023; 46:1645-1658. [PMID: 37261698 DOI: 10.1007/s13402-023-00831-8] [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] [Accepted: 05/15/2023] [Indexed: 06/02/2023] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of the intratumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and the host immune response. Here, we explore whether intervention with butyrate-producing probiotics can limit PDAC progression. METHODS Based on the TCGA (PAAD) database, we analyzed the differential communities of intratumoral microbiota in PDAC patients with long survival and short survival and explored the relevant mechanisms of Clostridium butyricum and its metabolite butyrate in the treatment of PDAC. Treatment with Clostridium butyricum or butyrate in combination with the ferroptosis inducer RSL3 in a PDAC mouse model has an inhibitory effect on PDAC progression. The potential molecular mechanisms were verified by flow cytometry, RNA-seq, Western blotting, qRT‒PCR and immunofluorescence. RESULTS We found that the tumoral butyrate-producing microbiota was linked to a better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility in PDAC. CONCLUSION Our study reveals a novel antitumor mechanism of butyrate and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.
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Affiliation(s)
- Xiaotong Yang
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Zhengyan Zhang
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Xuqing Shen
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Junyi Xu
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Yawen Weng
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Wei Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No 100, Haining Road, Shanghai, 200080, China.
| | - Jing Xue
- State Key Laboratory of Systems Medicine for Cancer , Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China.
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21
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He J, Li H, Jia J, Liu Y, Zhang N, Wang R, Qu W, Liu Y, Jia L. Mechanisms by which the intestinal microbiota affects gastrointestinal tumours and therapeutic effects. MOLECULAR BIOMEDICINE 2023; 4:45. [PMID: 38032415 PMCID: PMC10689341 DOI: 10.1186/s43556-023-00157-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/08/2023] [Indexed: 12/01/2023] Open
Abstract
The intestinal microbiota is considered to be a forgotten organ in human health and disease. It maintains intestinal homeostasis through various complex mechanisms. A significant body of research has demonstrated notable differences in the gut microbiota of patients with gastrointestinal tumours compared to healthy individuals. Furthermore, the dysregulation of gut microbiota, metabolites produced by gut bacteria, and related signal pathways can partially explain the mechanisms underlying the occurrence and development of gastrointestinal tumours. Therefore, this article summarizes the latest research progress on the gut microbiota and gastrointestinal tumours. Firstly, we provide an overview of the composition and function of the intestinal microbiota and discuss the mechanisms by which the intestinal flora directly or indirectly affects the occurrence and development of gastrointestinal tumours by regulating the immune system, producing bacterial toxins, secreting metabolites. Secondly, we present a detailed analysis of the differences of intestinal microbiota and its pathogenic mechanisms in colorectal cancer, gastric cancer, hepatocellular carcinoma, etc. Lastly, in terms of treatment strategies, we discuss the effects of the intestinal microbiota on the efficacy and toxic side effects of chemotherapy and immunotherapy and address the role of probiotics, prebiotics, FMT and antibiotic in the treatment of gastrointestinal tumours. In summary, this article provides a comprehensive review of the pathogenic mechanisms of and treatment strategies pertaining to the intestinal microbiota in patients with gastrointestinal tumours. And provide a more comprehensive and precise scientific basis for the development of microbiota-based treatments for gastrointestinal tumours and the prevention of such tumours.
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Affiliation(s)
- Jikai He
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Haijun Li
- Department of Gastrointestinal Surgery, Inner Mongolia Autonomous Region People's Hospital, Hohhot, 010017, Inner Mongolia, China
| | - Jiaqi Jia
- Graduate School of Youjiang Medical University for Nationalities, No. 98 Chengcheng Road, Youjiang District, Baise City, 533000, China
| | - Yang Liu
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Ning Zhang
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Rumeng Wang
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China
| | - Wenhao Qu
- Graduate School of Youjiang Medical University for Nationalities, No. 98 Chengcheng Road, Youjiang District, Baise City, 533000, China
| | - Yanqi Liu
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot City, 010050, Inner Mongolia, China.
| | - Lizhou Jia
- Central Laboratory, Bayannur Hospital, Bayannur, 015000, Inner Mongolia, China.
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22
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Merali N, Chouari T, Terroire J, Jessel MD, Liu DSK, Smith JH, Wooldridge T, Dhillon T, Jiménez JI, Krell J, Roberts KJ, Rockall TA, Velliou E, Sivakumar S, Giovannetti E, Demirkan A, Annels NE, Frampton AE. Bile Microbiome Signatures Associated with Pancreatic Ductal Adenocarcinoma Compared to Benign Disease: A UK Pilot Study. Int J Mol Sci 2023; 24:16888. [PMID: 38069211 PMCID: PMC10706407 DOI: 10.3390/ijms242316888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/18/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3-V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.
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Affiliation(s)
- Nabeel Merali
- Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Tarak Chouari
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Julien Terroire
- Surrey Institute for People-Centred AI, University of Surrey, Guildford GU2 7XH, UK
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Maria-Danae Jessel
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Daniel S. K. Liu
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - James-Halle Smith
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
| | - Tyler Wooldridge
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Tony Dhillon
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - José I. Jiménez
- Department of Life Sciences, Imperial College London, London SW7 2AZ, UK
| | - Jonathan Krell
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Keith J. Roberts
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, UK
| | - Timothy A. Rockall
- Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
| | - Eirini Velliou
- Centre for 3D Models of Health and Disease, Division of Surgery and Interventional Science, University College London (UCL), London W1W 7TY, UK
| | - Shivan Sivakumar
- Oncology Department, Institute of Immunology and Immunotherapy, Birmingham Medical School, University of Birmingham, Birmingham B15 2TT, UK
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme PI, 56017 Pisa, Italy
| | - Ayse Demirkan
- Surrey Institute for People-Centred AI, University of Surrey, Guildford GU2 7XH, UK
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Nicola E. Annels
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
| | - Adam E. Frampton
- Minimal Access Therapy Training Unit (MATTU), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford GU2 7XX, UK
- Section of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
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23
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Ungkulpasvich U, Hatakeyama H, Hirotsu T, di Luccio E. Pancreatic Cancer and Detection Methods. Biomedicines 2023; 11:2557. [PMID: 37760999 PMCID: PMC10526344 DOI: 10.3390/biomedicines11092557] [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: 08/21/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The pancreas is a vital organ with exocrine and endocrine functions. Pancreatitis is an inflammation of the pancreas caused by alcohol consumption and gallstones. This condition can heighten the risk of pancreatic cancer (PC), a challenging disease with a high mortality rate. Genetic and epigenetic factors contribute significantly to PC development, along with other risk factors. Early detection is crucial for improving PC outcomes. Diagnostic methods, including imagining modalities and tissue biopsy, aid in the detection and analysis of PC. In contrast, liquid biopsy (LB) shows promise in early tumor detection by assessing biomarkers in bodily fluids. Understanding the function of the pancreas, associated diseases, risk factors, and available diagnostic methods is essential for effective management and early PC detection. The current clinical examination of PC is challenging due to its asymptomatic early stages and limitations of highly precise diagnostics. Screening is recommended for high-risk populations and individuals with potential benign tumors. Among various PC screening methods, the N-NOSE plus pancreas test stands out with its high AUC of 0.865. Compared to other commercial products, the N-NOSE plus pancreas test offers a cost-effective solution for early detection. However, additional diagnostic tests are required for confirmation. Further research, validation, and the development of non-invasive screening methods and standardized scoring systems are crucial to enhance PC detection and improve patient outcomes. This review outlines the context of pancreatic cancer and the challenges for early detection.
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Affiliation(s)
| | | | | | - Eric di Luccio
- Hirotsu Bioscience Inc., 22F The New Otani Garden Court, 4-1 Kioi-cho, Chiyoda-ku, Tokyo 102-0094, Japan; (U.U.); (H.H.); (T.H.)
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24
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Bangolo AI, Trivedi C, Jani I, Pender S, Khalid H, Alqinai B, Intisar A, Randhawa K, Moore J, De Deugd N, Faisal S, Suresh SB, Gopani P, Nagesh VK, Proverbs-Singh T, Weissman S. Impact of gut microbiome in the development and treatment of pancreatic cancer: Newer insights. World J Gastroenterol 2023; 29:3984-3998. [PMID: 37476590 PMCID: PMC10354587 DOI: 10.3748/wjg.v29.i25.3984] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/24/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
The gut microbiome plays an important role in the variation of pharmacologic response. This aspect is especially important in the era of precision medicine, where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy. The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research. Pancreatic adenocarcinoma (PAC) has a poor prognosis even in those with potentially resectable disease, and treatment options are very limited. Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs, in the treatment of PAC. A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC. This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.
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Affiliation(s)
- Ayrton I Bangolo
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Chinmay Trivedi
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ishan Jani
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Silvanna Pender
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Hirra Khalid
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Budoor Alqinai
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Alina Intisar
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Karamvir Randhawa
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Joseph Moore
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Nicoleta De Deugd
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shaji Faisal
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Suchith Boodgere Suresh
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Parva Gopani
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Vignesh K Nagesh
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Tracy Proverbs-Singh
- Department of Gastrointestinal Malignancies, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Simcha Weissman
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
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25
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Jing Y, Feng B, Gao J, Li J, Zhou G, Sun Z, Wang Y. BLAB2CancerKD: a knowledge graph database focusing on the association between lactic acid bacteria and cancer, but beyond. Database (Oxford) 2023; 2023:7176387. [PMID: 37221044 DOI: 10.1093/database/baad036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/25/2023]
Abstract
In a broad sense, lactic acid bacteria (LAB) is a general term for Gram-positive bacteria that can produce lactic acid by utilizing fermentable carbohydrates. It is widely used in essential fields such as industry, agriculture, animal husbandry and medicine. At the same time, LAB are closely related to human health. They can regulate human intestinal flora and improve gastrointestinal function and body immunity. Cancer, a disease in which some cells grow out of control and spread to other body parts, is one of the leading causes of human death worldwide. In recent years, the potential of LAB in cancer treatment has attracted attention. Mining knowledge from the scientific literature significantly accelerates its application in cancer treatment. Using 7794 literature studies of LAB cancer as source data, we have processed 16 543 biomedical concepts and 23 091 associations by using automatic text mining tools combined with manual curation of domain experts. An ontology containing 31 434 pieces of structured data is constructed. Finally, based on ontology, a knowledge graph (KG) database, which is called Beyond 'Lactic acid bacteria to Cancer Knowledge graph Database' (BLAB2CancerKD), is constructed by using KG and web technology. BLAB2CancerKD presents all the relevant knowledge intuitively and clearly in various data presentation forms, and the interactive system function also makes it more efficient. BLAB2CancerKD will be continuously updated to advance the research and application of LAB in cancer therapy. Researchers can visit BLAB2CancerKD at. Database URL http://110.40.139.2:18095/.
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Affiliation(s)
- Yi Jing
- Faculty of Science, The University of New South Wales, High Street, Sydney, New South Wales 2052, Australia
- Inner Mongolia Autonomous Region Key Laboratory of Big Data Research and Application for Agriculture and Animal Husbandry, Zhaowuda Road No. 306, Hohhot 010018, China
| | - Baiyang Feng
- Inner Mongolia Autonomous Region Key Laboratory of Big Data Research and Application for Agriculture and Animal Husbandry, Zhaowuda Road No. 306, Hohhot 010018, China
- College of Computer and Information Engineering, Inner Mongolia Agricultural University, Erdos East Street No. 29, Hohhot 010011, China
| | - Jing Gao
- Inner Mongolia Autonomous Region Key Laboratory of Big Data Research and Application for Agriculture and Animal Husbandry, Zhaowuda Road No. 306, Hohhot 010018, China
- College of Computer and Information Engineering, Inner Mongolia Agricultural University, Erdos East Street No. 29, Hohhot 010011, China
- Inner Mongolia Autonomous Region Big Data Center, Chilechuan Street No. 1, Hohhot 010091, China
| | - Jin Li
- Inner Mongolia Autonomous Region Key Laboratory of Big Data Research and Application for Agriculture and Animal Husbandry, Zhaowuda Road No. 306, Hohhot 010018, China
- College of Computer and Information Engineering, Inner Mongolia Agricultural University, Erdos East Street No. 29, Hohhot 010011, China
| | - Ganghui Zhou
- Inner Mongolia Autonomous Region Key Laboratory of Big Data Research and Application for Agriculture and Animal Husbandry, Zhaowuda Road No. 306, Hohhot 010018, China
- College of Computer and Information Engineering, Inner Mongolia Agricultural University, Erdos East Street No. 29, Hohhot 010011, China
| | - Zhihong Sun
- College of Food Science and Engineering, Inner Mongolia Agricultural University, Zhaowuda Road No. 306, Hohhot 010018, China
| | - Yufei Wang
- The Affiliated Hospital of Inner Mongolia Medical University, Tongdao North road No.1, Hohhot 010050, China
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26
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Chai Y, Huang Z, Shen X, Lin T, Zhang Y, Feng X, Mao Q, Liang Y. Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response. Microorganisms 2023; 11:1240. [PMID: 37317214 PMCID: PMC10221276 DOI: 10.3390/microorganisms11051240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 06/16/2023] Open
Abstract
The microbiota is present in many parts of the human body and plays essential roles. The most typical case is the occurrence and development of cancer. Pancreatic cancer (PC), one of the most aggressive and lethal types of cancer, has recently attracted the attention of researchers. Recent research has revealed that the microbiota regulates PC carcinogenesis via an altered immune response. Specifically, the microbiota, in several sites, including the oral cavity, gastrointestinal tract, and pancreatic tissue, along with the numerous small molecules and metabolites it produces, influences cancer progression and treatment by activating oncogenic signaling, enhancing oncogenic metabolic pathways, altering cancer cell proliferation, and triggering chronic inflammation that suppresses tumor immunity. Diagnostics and treatments based on or in combination with the microbiota offer novel insights to improve efficiency compared with existing therapies.
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Affiliation(s)
- Yihan Chai
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Zhengze Huang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Xuqiu Shen
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Tianyu Lin
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Yiyin Zhang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Xu Feng
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
| | - Qijiang Mao
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310028, China
| | - Yuelong Liang
- Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310028, China
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Ruze R, Song J, Yin X, Chen Y, Xu R, Wang C, Zhao Y. Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review. Signal Transduct Target Ther 2023; 8:139. [PMID: 36964133 PMCID: PMC10039087 DOI: 10.1038/s41392-023-01376-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/31/2023] [Accepted: 02/15/2023] [Indexed: 03/26/2023] Open
Abstract
Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
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Binda C, Gibiino G, Sbrancia M, Coluccio C, Cazzato M, Carloni L, Cucchetti A, Ercolani G, Sambri V, Fabbri C. Microbiota in the Natural History of Pancreatic Cancer: From Predisposition to Therapy. Cancers (Basel) 2022; 15:cancers15010001. [PMID: 36611999 PMCID: PMC9817971 DOI: 10.3390/cancers15010001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/28/2022] [Accepted: 12/13/2022] [Indexed: 12/29/2022] Open
Abstract
Early microbiome insights came from gut microbes and their role among intestinal and extraintestinal disease. The latest evidence suggests that the microbiota is a true organ, capable of several interactions throughout the digestive system, attracting specific interest in the biliopancreatic district. Despite advances in diagnostics over the last few decades and improvements in the management of this disease, pancreatic cancer is still a common cause of cancer death. Microbiota can influence the development of precancerous disease predisposing to pancreatic cancer (PC). At the same time, neoplastic tissue shows specific characteristics in terms of diversity and phenotype, determining the short- and long-term prognosis. Considering the above information, a role for microbiota has also been hypothesized in the different phases of the PC approach, providing future revolutionary therapeutic insights. Microbiota-modulating therapies could open new issues in the therapeutic landscape. The aim of this narrative review is to assess the most updated evidence on microbiome in all the steps regarding pancreatic adenocarcinoma, from early development to response to antineoplastic therapy and long-term prognosis.
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Affiliation(s)
- Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Giulia Gibiino
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
- Correspondence: ; Tel.: +39-3488609557
| | - Monica Sbrancia
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Chiara Coluccio
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Maria Cazzato
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
| | - Lorenzo Carloni
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- General and Oncologic Surgery, Morgagni—Pierantoni Hospital, AUSL Romagna, 47121 Forlì, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- General and Oncologic Surgery, Morgagni—Pierantoni Hospital, AUSL Romagna, 47121 Forlì, Italy
| | - Vittorio Sambri
- Department of Medical and Surgical Sciences—DIMEC, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
- Microbiology Unit, Hub Laboratory, AUSL della Romagna, 47121 Cesena, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì-Cesena, Italy
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Xiang X, Lu J, Xu X, Hou X, Diao E, Qian S, Song H, Liang L, He Y, Shang Y. Rapid identification of novel specific molecular targets for PCR detection of four Enterococcus species. Lebensm Wiss Technol 2022. [DOI: 10.1016/j.lwt.2022.114356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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30
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Zhou W, Chen X, Fan Q, Yu H, Jiang W. Using proton pump inhibitors increases the risk of hepato-biliary-pancreatic cancer. A systematic review and meta-analysis. Front Pharmacol 2022; 13:979215. [PMID: 36188583 PMCID: PMC9515471 DOI: 10.3389/fphar.2022.979215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background: More and more studies are focusing on the adverse effects and damage caused by PPI abuse, we carried out a systematic review and meta-analysis for assessing whether the proton pump inhibitor (PPI) leads to hepato-biliary-pancreatic cancer. Methods: PubMed, EMBASE and Web of Science were searched until 1 July 2022, 25 studies (17 case-control and 8 cohort studies; 2741853 individuals) included in this study. Pooled Odd Ratios (ORs) were used for random effect models. Sensitivity analysis and dose-response analysis, subgroup analysis were all conducted. Results: The aggregate OR of the meta-analysis was 1.69 (95% confidence interval (CI): 1.42–2.01, p = 0.01) and heterogeneity (I2 = 98.9%, p < 0.001) was substantial. According to stratified subgroup analyses, the incidence of hepato-biliary-pancreatic cancer was associated, expect for study design, study quality and region. Risk of hepato-biliary-pancreatic cancer is highest when people is treated with normal doses of PPI. The risks decrease and become insignificant when the cumulative defined daily dose (cDDD) increases. Conclusion: The use of PPI may be associated with an increased risk of hepato-biliary-pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of hepato-biliary-pancreatic cancer.
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Affiliation(s)
- Wence Zhou
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, Gansu, China
- *Correspondence: Wence Zhou,
| | - Xinlong Chen
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Qigang Fan
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Haichuan Yu
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Wenkai Jiang
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
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31
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Di Carlo P, Serra N, Alduina R, Guarino R, Craxì A, Giammanco A, Fasciana T, Cascio A, Sergi CM. A systematic review on omics data (metagenomics, metatranscriptomics, and metabolomics) in the role of microbiome in gallbladder disease. Front Physiol 2022; 13:888233. [PMID: 36111147 PMCID: PMC9468903 DOI: 10.3389/fphys.2022.888233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/11/2022] [Indexed: 12/04/2022] Open
Abstract
Microbiotas are the range of microorganisms (mainly bacteria and fungi) colonizing multicellular, macroscopic organisms. They are crucial for several metabolic functions affecting the health of the host. However, difficulties hamper the investigation of microbiota composition in cultivating microorganisms in standard growth media. For this reason, our knowledge of microbiota can benefit from the analysis of microbial macromolecules (DNA, transcripts, proteins, or by-products) present in various samples collected from the host. Various omics technologies are used to obtain different data. Metagenomics provides a taxonomical profile of the sample. It can also be used to obtain potential functional information. At the same time, metatranscriptomics can characterize members of a microbiome responsible for specific functions and elucidate genes that drive the microbiotas relationship with its host. Thus, while microbiota refers to microorganisms living in a determined environment (taxonomy of microorganisms identified), microbiome refers to the microorganisms and their genes living in a determined environment and, of course, metagenomics focuses on the genes and collective functions of identified microorganisms. Metabolomics completes this framework by determining the metabolite fluxes and the products released into the environment. The gallbladder is a sac localized under the liver in the human body and is difficult to access for bile and tissue sampling. It concentrates the bile produced in the hepatocytes, which drains into bile canaliculi. Bile promotes fat digestion and is released from the gallbladder into the upper small intestine in response to food. Considered sterile originally, recent data indicate that bile microbiota is associated with the biliary tract's inflammation and carcinogenesis. The sample size is relevant for omic studies of rare diseases, such as gallbladder carcinoma. Although in its infancy, the study of the biliary microbiota has begun taking advantage of several omics strategies, mainly based on metagenomics, metabolomics, and mouse models. Here, we show that omics analyses from the literature may provide a more comprehensive image of the biliary microbiota. We review studies performed in this environmental niche and focus on network-based approaches for integrative studies.
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Affiliation(s)
- Paola Di Carlo
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence G. D’Alessandro, Section of Infectious Disease, University of Palermo, Palermo, Italy
| | - Nicola Serra
- Department of Public Health, University “Federico II”, Naples, Italy
| | - Rosa Alduina
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Riccardo Guarino
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Antonio Craxì
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence G. D’Alessandro, Section of Gastroenterology, University of Palermo, Palermo, Italy
| | - Anna Giammanco
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence G. D’Alessandro, Section of Microbiology, University of Palermo, Palermo, Italy
| | - Teresa Fasciana
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence G. D’Alessandro, Section of Microbiology, University of Palermo, Palermo, Italy
| | - Antonio Cascio
- Department of Health Promotion, Maternal-Childhood, Internal Medicine of Excellence G. D’Alessandro, Section of Infectious Disease, University of Palermo, Palermo, Italy
| | - Consolato M. Sergi
- Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, Ottawa, ON, Canada
- Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada
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The Oncobiome in Gastroenteric and Genitourinary Cancers. Int J Mol Sci 2022; 23:ijms23179664. [PMID: 36077063 PMCID: PMC9456244 DOI: 10.3390/ijms23179664] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022] Open
Abstract
Early evidence suggests a strong association of microorganisms with several human cancers, and great efforts have been made to understand the pathophysiology underlying microbial carcinogenesis. Bacterial dysbiosis causes epithelial barrier failure, immune dysregulation and/or genotoxicity and, consequently, creates a tumor-permissive microenvironment. The majority of the bacteria in our body reside in the gastrointestinal tract, known as gut microbiota, which represents a complex and delicate ecosystem. Gut microbes can reach the pancreas, stomach and colon via the bloodstream. Oral bacterial translocations can also occur. In the stomach, pancreas and colon, low microbial diversity is associated with cancer, in particular with a bad prognosis. The urogenital tract also harbors unique microbiota, distinct from the gut microbiota, which might have a role in the urinary and female/male reproductive cancers’ pathogenesis. In healthy women, the majority of bacteria reside in the vagina and cervix and unlike other mucosal sites, the vaginal microbiota exhibits low microbial diversity. Genital dysbiosis might have an active role in the development and/or progression of gynecological malignancies through mechanisms including modulation of oestrogen metabolism. Urinary dysbiosis may influence the pathogenesis of bladder cancer and prostate cancer in males. Modulation of the microbiome via pre, pro and postbiotics, fecal or vaginal microbiota transplantation and engineering bacteria might prove useful in improving cancer treatment response and quality of life. Elucidating the complex host-microbiome interactions will result in prevention and therapeutic efficacy interventions.
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Iwasa M, Eguchi A, Tamai Y, Shigefuku R, Nakagawa R, Hasegawa H, Kondo J, Morikawa M, Miyoshi E, Nakagawa H. Elevation of enterococcus-specific antibodies associated with bacterial translocation is predictive of survival rate in chronic liver disease. Front Med (Lausanne) 2022; 9:982128. [PMID: 36035413 PMCID: PMC9403143 DOI: 10.3389/fmed.2022.982128] [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: 06/30/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION/PURPOSE The gut-liver axis contributes to disease progression, a rise in infection rate, organ failure and a poor overall outcome in chronic liver diseases (CLD). Monitoring of the gut-liver axis is critical in understanding disease status, but biomarkers have not been elucidated. The aim of this study is to determine the level of serum antibodies against Enterococcus (E.) faecalis in evaluating patients with CLD, including those treated with rifaximin (a minimally absorbed antibiotic), and in patients with alcohol-associated liver disease (ALD). MATERIALS AND METHODS We enrolled 109 CLD patients (cohort 1), 30 hepatic encephalopathy patients treated with rifaximin (cohort 2), 53 inpatients with ALD undergoing alcohol cessation (cohort 3) and 33 healthy subjects. To assess the consequences of E. faecalis translocation, we developed an assay for the detection of a serum antibody against E. faecalis capsular polysaccharide (E.CPS). RESULTS Serum E.CPS antibody titer was elevated only in those patients with advanced CLD and ALD. The E.CPS antibody titer was an independent prognostic factor (p < 0.05), while Mac-2 binding protein and albumin-bilirubin score were not independent predictors of survival. The improvement of predictive model in integrated factors was significant [continuous net reclassification index (value 0.699, p < 0.05) and integrated discrimination improvement (value 0.164, p = 0.051)]. Furthermore, rifaximin treatment led to a decrease of serum E.CPS antibody titer resulting in a significantly longer overall rate of survival. CONCLUSION The E.CPS antibody titer appears to be a strong predictor of survival in CLD patients. Serum E.CPS levels decrease in CLD patients receiving rifaximin, and may be associated with an overall improvement in rate of survival.
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Affiliation(s)
- Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | | | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Jumpei Kondo
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | | | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
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34
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Ali A, Ara A, Kashyap MK. Gut microbiota: Role and Association with Tumorigenesis in Different Malignancies. Mol Biol Rep 2022; 49:8087-8107. [PMID: 35543828 DOI: 10.1007/s11033-022-07357-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023]
Abstract
The microbiota has been associated with different cancer and may vary from patient to patient. A specific microbial strain can alter the progression of cancer and therapeutic outcome in response to anti-cancer therapy. The variations in microbiota contributed due to the individual microbiome of the microorganism are responsible for diverse clinical outcomes. The expansion of microbiota subpopulation during dysbiosis can lead to toxin production, inducing inflammation and cancer. The microbiota can be a dual-edged sword because it can be tumor-suppressive or oncogenic in the case of the gut. The transition of cancer cells from early to late-stage also impacts the composition of the microbiota, and this alteration could change the behavior of cancer. Multi-omics platforms derived data from an individual's multi-dimensional data (DNA, mRNA, microRNA, protein, metabolite, microbiota, and microbiome), i.e., individualome, to exploit it for personalized tailored treatment for different cancers in a precise manner. A number of studies suggest the importance of microbiota and its add-in suitability to existing treatment options for different malignancies. Furthermore, in vitro, and in vivo studies and cancer clinical trials suggest that probiotics have driven modulation of gut microbiota and other sites discourage the aggressive behavior and progression of different cancers.
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Affiliation(s)
- Altamas Ali
- Department of Biosciences, Jamia Millia Islamia (A central University), Jamia Nagar, 110025, New Delhi, India
| | - Anam Ara
- Department of Biosciences, Jamia Millia Islamia (A central University), Jamia Nagar, 110025, New Delhi, India
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute/Amity Medical School, Amity University Haryana, Amity Education Valley, Panchgaon (Manesar), Gurugram, HR, 122413, India.
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35
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Inamura K, Hamada T, Bullman S, Ugai T, Yachida S, Ogino S. Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science. Gut 2022; 71:gutjnl-2022-327209. [PMID: 35820782 PMCID: PMC9834441 DOI: 10.1136/gutjnl-2022-327209] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023]
Abstract
Cancer is generally regarded as a localised disease, with the well-established role of the tumour microenvironment. However, the realm of cancer goes beyond the tumour microenvironment, and cancer should also be regarded as a systemic and environmental disease. The exposome (ie, the totality of exposures), which encompasses diets, supplements, smoking, alcohol, other lifestyle factors, medications, etc, likely alters the microbiome (inclusive of bacteria, viruses, archaea, fungi, parasites, etc) and immune system in various body sites and influences tumour phenotypes. The systemic metabolic/inflammatory status, which is likely influenced by exposures and intestinal physiological changes, may affect tissue microenvironment of colorectum and any other organs. Germline genomic factors can modify disease phenotypes via gene-by-environment interactions. Although challenges exist, it is crucial to advance not only basic experimental research that can analyse the effects of exposures, microorganisms and microenvironmental components on tumour evolution but also interdisciplinary human population research that can dissect the complex pathogenic roles of the exposome, microbiome and immunome. Metagenomic, metatranscriptomic and metabolomic analyses should be integrated into well-designed population research combined with advanced methodologies of artificial intelligence and molecular pathological epidemiology. Ideally, a prospective cohort study design that enables biospecimen (such as stool) collection before disease detection should be considered to address reverse causation and recall biases. Robust experimental and observational research together can provide insights into dynamic interactions between environmental exposures, microbiota, tumour and immunity during carcinogenesis processes, thereby helping us develop precision prevention and therapeutic strategies to ultimately reduce the cancer burden.
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Affiliation(s)
- Kentaro Inamura
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Medicine, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Susan Bullman
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Tomotaka Ugai
- Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Shinichi Yachida
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
- Division of Genomic Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Shuji Ogino
- Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA
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Li R, Hu Y, Hou S. An Exploration of Oral-Gut Pathogens Mediating Immune Escape of Pancreatic Cancer via miR-21/PTEN Axis. Front Microbiol 2022; 13:928846. [PMID: 35814712 PMCID: PMC9258743 DOI: 10.3389/fmicb.2022.928846] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022] Open
Abstract
Oral-gut pathogens are closely associated with pancreatic cancer, such as Campylobacter jejuni, Clostridium difficile, Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Helicobacter pylori, Porphyromonas gingivalis, and Vibrio cholera, but the related mechanisms remain not well understood. Phosphatase and tensin homolog (PTEN, a widely known tumor suppressor) play a key role in the anti-cancer immune system. Pancreatic cancer cells with PTEN loss are often in the immunosuppressive tumor microenvironment regulated by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2 macrophages, which are regarded as the mechanism in the immune escape of cancers. The miR-21, as an oncogene in human cancers, plays an important role in pancreatic cancer progression, downregulates the levels of PTEN, and may promote cancer to evade host immune surveillance. Some oral-gut pathogens have been found to promote miR-21 expression and reduce PTEN expression. On the other hand, most gut pathogens infection is thought to produce reactive oxygen species (ROS) or activate inflammatory cytokines, which may also induce ROS-mediated miR-21 expression. These pathogens' infection is involved with the cell density of MDSCs, Tregs, and M2 macrophages. Therefore, it is quite reasonable to propose that oral-gut pathogens possibly promote pancreatic cancer escaping from host immune surveillance by activating the miR-21/PTEN axis and immune-suppressive cells. The present exploration suggests that an increased understanding of the pattern of the effects of gut pathogens on the miR-21/PTEN axis will lead to better insights into the specific mechanisms associated with the immune escape of pancreatic cancer caused by oral-gut microbiota.
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Li Z, Liu Y, Zhang L. Role of the microbiome in oral cancer occurrence, progression and therapy. Microb Pathog 2022; 169:105638. [PMID: 35718272 DOI: 10.1016/j.micpath.2022.105638] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 02/07/2023]
Abstract
The oral cavity, like other digestive or mucosal sites, contains a site-specific microbiome that plays a significant role in maintaining health and homeostasis. Strictly speaking, the gastrointestinal tract starts from the oral cavity, with special attention paid to the specific flora of the oral cavity. In healthy people, the microbiome of the oral microenvironment is governed by beneficial bacteria, that benefit the host by symbiosis. When a microecological imbalance occurs, changes in immune and metabolic signals affect the characteristics of cancer, as well as chronic inflammation, disruption of the epithelial barrier, changes in cell proliferation and cell apoptosis, genomic instability, angiogenesis, and epithelial barrier destruction and metabolic regulation. These pathophysiological changes could result in oral cancer. Rising evidence suggests that oral dysbacteriosis and particular microbes may play a positive role in the evolution, development, progression, and metastasis of oral cancer, for instance, oral squamous cell carcinoma (OSCC) through direct or indirect action.
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Affiliation(s)
- Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
| | - Yuan Liu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
| | - Ling Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200000, China.
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Amara S, Yang LV, Tiriveedhi V, Muzaffar M. Complex Role of Microbiome in Pancreatic Tumorigenesis: Potential Therapeutic Implications. Cells 2022; 11:1900. [PMID: 35741028 PMCID: PMC9221309 DOI: 10.3390/cells11121900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality with limited diagnostic and therapeutic options. Although immunotherapy has shown promise in the treatment of several cancers, its role in pancreatic cancer is rather limited. Several studies have focused on determining the role of the tumor microenvironment with cancer-cell-intrinsic events and tumor-infiltrating immune cellular properties. However, in the past decade, there has been emerging research aimed at delineating the role of the host microbiome, including the metabolites from microbes and host responses, on pancreatic tumorigenesis. Importantly, there is emerging evidence suggesting the beneficial role of a gut microbiome transplant to improve immunotherapeutic outcomes in cancer patients. In this review, we summarize the recent understanding of the role of the microbiome in pancreatic cancer progression, along with its clinical diagnostic and therapeutic implications.
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Affiliation(s)
- Suneetha Amara
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (L.V.Y.); (M.M.)
| | - Li V. Yang
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (L.V.Y.); (M.M.)
| | - Venkataswarup Tiriveedhi
- Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA;
- Department of Pharmacology, Vanderbilt University, Nashville, TN 37212, USA
| | - Mahvish Muzaffar
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (L.V.Y.); (M.M.)
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Zhao G, Zhang T, Liu W, Edderkaoui M, Hu R, Li J, Pandol SJ, Fu X, Han YP. Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation. Cancers (Basel) 2022; 14:1407. [PMID: 35326559 PMCID: PMC8946475 DOI: 10.3390/cancers14061407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer is driven by risk factors such as diabetes and chronic pancreatic injury, which are further associated with gut dysbiosis. Intestinal toxins such as bile acids and bacterial endotoxin (LPS), in excess and persistence, can provoke chronic inflammation and tumorigenesis. Of interest is that many intestinal toxins are negatively charged acidic components in essence, which prompted us to test whether oral administration of cationic resin can deplete intestinal toxins and ameliorate pancreatic cancer. Here, we found that increased plasma levels of endotoxin and bile acids in Pdx1-Cre: LSL-KrasG12D/+ mice were associated with the transformation of the pancreatic ductal carcinoma (PDAC) state. Common bile-duct-ligation or LPS injection impeded autolysosomal flux, leading to Yap accumulation and malignant transformation. Conversely, oral administration of cholestyramine to sequestrate intestinal endotoxin and bile acids resumed autolysosomal flux for Yap degradation and attenuated metastatic incidence. Conversely, chloroquine treatment impaired autolysosomal flux and exacerbated malignance, showing jeopardization of p62/ Sqxtm1 turnover, leading to Yap accumulation, which is also consistent with overexpression of cystatin A (CSTA) in situ with pancreatic cancer cells and metastatic tumor. At cellular levels, chenodeoxycholic acid or LPS treatment activated the ligand-receptor-mediated AKT-mTOR pathway, resulting in autophagy-lysosomal stress for YAP accumulation and cellular dissemination. Thus, this work indicates a potential new strategy for intervention of pancreatic metastasis through sequestration of intestinal acidic toxins by oral administration of cationic resins.
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Affiliation(s)
- Guangfu Zhao
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Tianci Zhang
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Wei Liu
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Mouad Edderkaoui
- Cedars-Sinai Medical Center, Los Angeles, CA 90001, USA; (M.E.); (S.J.P.)
| | - Richard Hu
- Olive View-UCLA Medical Center, Los Angeles, CA 90001, USA;
| | - Jun Li
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu 610083, China;
| | - Stephen J. Pandol
- Cedars-Sinai Medical Center, Los Angeles, CA 90001, USA; (M.E.); (S.J.P.)
| | - Xiangsheng Fu
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu 610083, China;
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
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Halimi A, Gabarrini G, Sobkowiak MJ, Ateeb Z, Davanian H, Gaiser RA, Arnelo U, Valente R, Wong AY, Moro CF, Del Chiaro M, Özenci V, Chen MS. Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties. Gut Microbes 2022; 13:1983101. [PMID: 34816784 PMCID: PMC8632270 DOI: 10.1080/19490976.2021.1983101] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Emerging research suggests gut microbiome may play a role in pancreatic cancer initiation and progression, but cultivation of the cancer microbiome remains challenging. This pilot study aims to investigate the possibility to cultivate pancreatic microbiome from pancreatic cystic lesions associated with invasive cancer. Intra-operatively acquired pancreatic cyst fluid samples showed culture-positivity mainly in the intraductal papillary mucinous neoplasm (IPMN) group of lesions. MALDI-TOF MS profiling analysis shows Gammaproteobacteria and Bacilli dominate among individual bacteria isolates. Among cultivated bacteria, Gammaproteobacteria, particularly Klebsiella pneumoniae, but also Granulicatella adiacens and Enterococcus faecalis, demonstrate consistent pathogenic properties in pancreatic cell lines tested in ex vivo co-culture models. Pathogenic properties include intracellular survival capability, cell death induction, or causing DNA double-strand breaks in the surviving cells resembling genotoxic effects. This study provides new insights into the role of the pancreatic microbiota in the intriguing link between pancreatic cystic lesions and cancer.
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Affiliation(s)
- Asif Halimi
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden,Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Giorgio Gabarrini
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | | | - Zeeshan Ateeb
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Haleh Davanian
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | | | - Urban Arnelo
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden,Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Roberto Valente
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden,Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Alicia Y.W. Wong
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden,Department of Clinical Microbiology F 72, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Carlos Fernández Moro
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden,Department of Clinical Pathology/Cytology, Karolinska University Hospital, Huddinge, Sweden
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
| | - Volkan Özenci
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden,Department of Clinical Microbiology F 72, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Margaret Sällberg Chen
- Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden,CONTACT Margaret Sällberg Chen Department of Dental Medicine, Karolinska Institutet, Huddinge14141, Sweden
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Merali N, Chouari T, Kayani K, Rayner CJ, Jiménez JI, Krell J, Giovannetti E, Bagwan I, Relph K, Rockall TA, Dhillon T, Pandha H, Annels NE, Frampton AE. A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:1020. [PMID: 35205769 PMCID: PMC8870349 DOI: 10.3390/cancers14041020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.
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Affiliation(s)
- Nabeel Merali
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Tarak Chouari
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Kayani Kayani
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Charles J. Rayner
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - José I. Jiménez
- Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK;
| | - Jonathan Krell
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK;
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Fondazione Pisa per la Scienza, 56017 San Giuliano, Italy
| | - Izhar Bagwan
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Kate Relph
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Timothy A. Rockall
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
| | - Tony Dhillon
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Hardev Pandha
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Nicola E. Annels
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
| | - Adam E. Frampton
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK; (N.M.); (T.A.R.)
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK; (T.C.); (K.K.); (C.J.R.)
- Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7WG, UK; (I.B.); (K.R.); (T.D.); (H.P.); (N.E.A.)
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK;
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Grochowska M, Perlejewski K, Laskus T, Radkowski M. The Role of Gut Microbiota in Gastrointestinal Tract Cancers. Arch Immunol Ther Exp (Warsz) 2022; 70:7. [PMID: 35112169 PMCID: PMC8810472 DOI: 10.1007/s00005-021-00641-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023]
Abstract
Disturbances in gastrointestinal (GI) microbiota could play a significant role in the development of GI cancers, but the underlying mechanisms remain largely unclear. While some bacteria seem to facilitate carcinogenesis, others appear to be protective. So far only one bacterium (Helicobacter pylori) has been classified by the International Agency for Cancer Research as carcinogenic in humans but many other are the subject of intense research. Most studies on the role of microbiota in GI tract oncogenesis focus on pancreatic and colorectal cancers with the following three species: Helicobacter pylori, Escherichia coli, and Porphyromonas gingivalis as likely causative factors. This review summarizes the role of bacteria in GI tract oncogenesis.
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Affiliation(s)
- Marta Grochowska
- Department of Immunopathology, Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Karol Perlejewski
- Department of Immunopathology, Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marek Radkowski
- Department of Immunopathology, Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
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Itoyama S, Noda E, Takamatsu S, Kondo J, Kawaguchi R, Shimosaka M, Fukuoka T, Motooka D, Nakamura S, Tanemura M, Mitsufuji S, Iwagami Y, Akita H, Tobe T, Kamada Y, Eguchi H, Miyoshi E. Enterococcus spp. have higher fitness for survival, in a pH-dependent manner, in pancreatic juice among duodenal bacterial flora. JGH Open 2022; 6:85-90. [PMID: 35071793 PMCID: PMC8762619 DOI: 10.1002/jgh3.12703] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/15/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Bacterial infection is involved in the progression of many gastrointestinal diseases, including those of pancreas; however, how and which bacteria colonize in pancreatic juice and tissue have yet to be elucidated. Recently, we reported that Enterococcus faecalis exists in the pancreatic juice and tissues of patients with chronic pancreatic disease. Here, we investigated the survival of E. faecalis in duodenal juice with different pH conditions. METHODS Pancreatic juice samples from 62 patients with cancers of the duodeno-pancreato-biliary region were evaluated for the presence of E. faecalis. 16S ribosomal RNA polymerase chain reaction and 16S-based metagenome analyses were performed to determine the bacterial composition. The survival of E. faecalis in various pancreatic juice conditions was evaluated. RESULTS Of 62 samples, 27% (17/62) were positive for Enterococcus spp., among which 71% (12/17) contained E. faecalis. Enterococcus spp. showed the highest fitness for survival in alkaline pancreatic juice among various bacterial species. The microbiome of pancreatic juice from patients with pancreatic and bile duct cancer showed diversity, but Enterococcus spp. were enriched among duodenal tumors and intraductal papillary mucinous neoplasms. CONCLUSIONS Alkalinity is one of the important factors for the selective survival of E. faecalis among microbiota. E. faecalis can colonize the pancreatic duct when the pancreatic juice condition is altered.
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Affiliation(s)
- Saki Itoyama
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Emika Noda
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Jumpei Kondo
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Rui Kawaguchi
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Munefumi Shimosaka
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Tomoya Fukuoka
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Daisuke Motooka
- Research Institute for Microbial DiseasesOsaka UniversitySuitaOsakaJapan
| | - Shota Nakamura
- Research Institute for Microbial DiseasesOsaka UniversitySuitaOsakaJapan
| | - Masahiro Tanemura
- Department of SurgeryRinku General Medical CenterIzumisanoOsakaJapan
| | - Suguru Mitsufuji
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Yoshifumi Iwagami
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Hirofumi Akita
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Toru Tobe
- Laboratory of Molecular Medical MicrobiologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic HepatologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Hidetoshi Eguchi
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineSuitaOsakaJapan
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Schepis T, De Lucia SS, Nista EC, Manilla V, Pignataro G, Ojetti V, Piccioni A, Gasbarrini A, Franceschi F, Candelli M. Microbiota in Pancreatic Diseases: A Review of the Literature. J Clin Med 2021; 10:5920. [PMID: 34945216 PMCID: PMC8704740 DOI: 10.3390/jcm10245920] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023] Open
Abstract
The gut microbiota is a critical element in the balance between human health and disease. Its impairment, defined as dysbiosis, is associated with gastroenterological and systemic diseases. Pancreatic secretions are involved in the composition and changes of the gut microbiota, and the gut microbiota may colonize the pancreatic parenchyma and be associated with the occurrence of diseases. The gut microbiota and the pancreas influence each other, resulting in a "gut microbiota-pancreas axis". Moreover, the gut microbiota may be involved in pancreatic diseases, both through direct bacterial colonization and an indirect effect of small molecules and toxins derived from dysbiosis. Pancreatic diseases such as acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and pancreatic cancer are common gastroenterological diseases associated with high morbidity and mortality. The involvement of the microbiota in pancreatic diseases is increasingly recognized. Therefore, modifying the intestinal bacterial flora could have important therapeutic implications on these pathologies. The aim of this study is to review the literature to evaluate the alterations of the gut microbiota in pancreatic diseases, and the role of the microbiota in the treatment of these diseases.
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Affiliation(s)
- Tommaso Schepis
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (T.S.); (S.S.D.L.); (E.C.N.); (V.M.); (A.G.)
| | - Sara S. De Lucia
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (T.S.); (S.S.D.L.); (E.C.N.); (V.M.); (A.G.)
| | - Enrico C. Nista
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (T.S.); (S.S.D.L.); (E.C.N.); (V.M.); (A.G.)
| | - Vittoria Manilla
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (T.S.); (S.S.D.L.); (E.C.N.); (V.M.); (A.G.)
| | - Giulia Pignataro
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (G.P.); (V.O.); (A.P.); (F.F.)
| | - Veronica Ojetti
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (G.P.); (V.O.); (A.P.); (F.F.)
| | - Andrea Piccioni
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (G.P.); (V.O.); (A.P.); (F.F.)
| | - Antonio Gasbarrini
- Medical and Surgical Science Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (T.S.); (S.S.D.L.); (E.C.N.); (V.M.); (A.G.)
| | - Francesco Franceschi
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (G.P.); (V.O.); (A.P.); (F.F.)
| | - Marcello Candelli
- Emergency Medicine Department, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore di Roma, 00168 Roma, Italy; (G.P.); (V.O.); (A.P.); (F.F.)
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Sędzikowska A, Szablewski L. Human Gut Microbiota in Health and Selected Cancers. Int J Mol Sci 2021; 22:13440. [PMID: 34948234 PMCID: PMC8708499 DOI: 10.3390/ijms222413440] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 12/24/2022] Open
Abstract
The majority of the epithelial surfaces of our body, and the digestive tract, respiratory and urogenital systems, are colonized by a vast number of bacteria, archaea, fungi, protozoans, and viruses. These microbiota, particularly those of the intestines, play an important, beneficial role in digestion, metabolism, and the synthesis of vitamins. Their metabolites stimulate cytokine production by the human host, which are used against potential pathogens. The composition of the microbiota is influenced by several internal and external factors, including diet, age, disease, and lifestyle. Such changes, called dysbiosis, may be involved in the development of various conditions, such as metabolic diseases, including metabolic syndrome, type 2 diabetes mellitus, Hashimoto's thyroidis and Graves' disease; they can also play a role in nervous system disturbances, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and depression. An association has also been found between gut microbiota dysbiosis and cancer. Our health is closely associated with the state of our microbiota, and their homeostasis. The aim of this review is to describe the associations between human gut microbiota and cancer, and examine the potential role of gut microbiota in anticancer therapy.
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Affiliation(s)
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, ul. Chalubinskiego 5, 02-004 Warsaw, Poland;
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Ibragimova S, Ramachandran R, Ali FR, Lipovich L, Ho SB. Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis. Front Cell Dev Biol 2021; 9:725821. [PMID: 34869313 PMCID: PMC8633417 DOI: 10.3389/fcell.2021.725821] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
The recent increases in cancer incidences have been linked to lifestyle changes that result in obesity and metabolic syndrome. It is now evident that these trends are associated with the profound changes that occur in the intestinal microbiome, producing altered microbial population signatures that interact, directly or indirectly, with potentially pro-carcinogenic molecular pathways of transcription, proliferation, and inflammation. The effects of the entire gut microbial population on overall health are complex, but individual bacteria are known to play important and definable roles. Recent detailed examinations of a large number of subjects show a tight correlation between habitual diets, fecal microbiome signatures, and markers of metabolic health. Diets that score higher in healthfulness or diversity such as plant-based diets, have altered ratios of specific bacteria, including an increase in short-chain fatty acid producers, which in turn have been linked to improved metabolic markers and lowered cancer risk. Contrarily, numerous studies have implicated less healthy, lower-scoring diets such as the Western diet with reduced intestinal epithelial defenses and promotion of specific bacteria that affect carcinogenic pathways. In this review, we will describe how different dietary patterns affect microbial populations in the gut and illustrate the subsequent impact of bacterial products and metabolites on molecular pathways of cancer development, both locally in the gut and systemically in distant organs.
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Affiliation(s)
- Shakhzada Ibragimova
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, UAE
| | - Revathy Ramachandran
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, UAE
| | - Fahad R Ali
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, UAE
| | - Leonard Lipovich
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, UAE
| | - Samuel B Ho
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, UAE.,Department of Medicine, Mediclinic City Hospital, Dubai Healthcare City, Dubai, UAE
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Sammallahti H, Kokkola A, Rezasoltani S, Ghanbari R, Asadzadeh Aghdaei H, Knuutila S, Puolakkainen P, Sarhadi VK. Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients. Int J Mol Sci 2021; 22:12978. [PMID: 34884776 PMCID: PMC8658013 DOI: 10.3390/ijms222312978] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.
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Affiliation(s)
- Heidelinde Sammallahti
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Arto Kokkola
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Sama Rezasoltani
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Science, Tehran P.O. Box 1411713135, Iran;
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 1985717411, Iran;
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Pauli Puolakkainen
- Department of Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland; (A.K.); (P.P.)
| | - Virinder Kaur Sarhadi
- Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland;
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Terzić-Vidojević A, Veljović K, Popović N, Tolinački M, Golić N. Enterococci from Raw-Milk Cheeses: Current Knowledge on Safety, Technological, and Probiotic Concerns. Foods 2021; 10:2753. [PMID: 34829034 PMCID: PMC8624194 DOI: 10.3390/foods10112753] [Citation(s) in RCA: 12] [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: 10/07/2021] [Revised: 11/03/2021] [Accepted: 11/08/2021] [Indexed: 12/22/2022] Open
Abstract
The present study is focused on the safety, technological characteristics, and probiotic evaluation of Enterococcus species from different artisanal raw milk dairy products, mainly cheeses with ripening. Apart from proteolytic and lipolytic activities, most enterococci show the ability to metabolize citrate and convert it to various aromatic compounds. Long-ripened cheeses therefore have a specific flavor that makes them different from cheeses produced from thermally treated milk with commercial starter cultures. In addition, enterococci are producers of bacteriocins effective against spoilage and pathogenic bacteria, so they can be used as food preservatives. However, the use of enterococci in the dairy industry should be approached with caution. Although originating from food, enterococci strains may carry various virulence factors and antibiotic-resistance genes and can have many adverse effects on human health. Still, despite their controversial status, the use of enterococci in the food industry is not strictly regulated since the existence of these so-called desirable and undesirable traits in enterococci is a strain-dependent characteristic. To be specific, the results of many studies showed that there are some enterococci strains that are safe for use as starter cultures or as probiotics since they do not carry virulence factors and antibiotic-resistance genes. These strains even exhibit strong health-promoting effects such as stimulation of the immune response, anti-inflammatory activity, hypocholesterolemic action, and usefulness in prevention/treatment of some diseases.
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Affiliation(s)
- Amarela Terzić-Vidojević
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia; (K.V.); (N.P.); (M.T.); (N.G.)
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Basu M, Philipp LM, Baines JF, Sebens S. The Microbiome Tumor Axis: How the Microbiome Could Contribute to Clonal Heterogeneity and Disease Outcome in Pancreatic Cancer. Front Oncol 2021; 11:740606. [PMID: 34631577 PMCID: PMC8495218 DOI: 10.3389/fonc.2021.740606] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by a poor prognosis with a 5-year survival rate of only around 10% and an ongoing increase in death rate. Due to the lack of early and specific symptoms, most patients are diagnosed at an advanced or even metastasized stage, essentially limiting curative treatment options. However, even curative resection of the primary tumor and adjuvant therapy often fails to provide a long-term survival benefit. One reason for this dismal situation can be seen in the evolution of therapy resistances. Furthermore, PDAC is characterized by high intratumor heterogeneity, pointing towards an abundance of cancer stem cells (CSCs), which are regarded as essential for tumor initiation and drug resistance. Additionally, it was shown that the gut microbiome is altered in PDAC patients, promotes Epithelial-Mesenchymal-Transition (EMT), determines responses towards chemotherapy, and affects survival in PDAC patients. Given the established links between CSCs and EMT as well as drug resistance, and the emerging role of the microbiome in PDAC, we postulate that the composition of the microbiome of PDAC patients is a critical determinant for the abundance and plasticity of CSC populations and thus tumor heterogeneity in PDAC. Unravelling this complex interplay might pave the way for novel treatment strategies.
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Affiliation(s)
- Meghna Basu
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute of Experimental Medicine, Kiel University, Kiel, Germany
| | - Lisa-Marie Philipp
- Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel University, Kiel, Germany
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute of Experimental Medicine, Kiel University, Kiel, Germany
| | - Susanne Sebens
- Institute for Experimental Cancer Research, University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Kiel University, Kiel, Germany
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Tonini V, Zanni M. Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 2021; 27:5851-5889. [PMID: 34629806 PMCID: PMC8475010 DOI: 10.3748/wjg.v27.i35.5851] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.
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Affiliation(s)
- Valeria Tonini
- Department of Medical Sciences and Surgery, University of Bologna- Emergency Surgery Unit, IRCCS Sant’Orsola Hospital, Bologna 40121, Italy
| | - Manuel Zanni
- University of Bologna, Emergency Surgery Unit, IRCCS Sant'Orsola Hospital, Bologna 40121, Italy
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