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Hillege LE, Trepka KR, Ziemons J, Aarnoutse R, Guthrie BGH, de Vos-Geelen J, Valkenburg-van Iersel L, van Hellemond IEG, Baars A, Vestjens JHMJ, Penders J, Deutschbauer A, Atreya CE, Kidder WA, Turnbaugh PJ, Smidt ML. Metagenomic analysis during capecitabine therapy reveals microbial chemoprotective mechanisms and predicts drug toxicity in colorectal cancer patients. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.11.24315249. [PMID: 39484258 PMCID: PMC11527039 DOI: 10.1101/2024.10.11.24315249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Purpose Unpredictable chemotherapy side effects are a major barrier to successful treatment. Cell culture and mouse experiments indicate that the gut microbiota is influenced by and influences anti-cancer drugs. However, metagenomic data from patients paired to careful side effect monitoring remains limited. Herein, we focus on the oral fluoropyrimidine capecitabine (CAP). We investigate CAP-microbiome interactions through metagenomic sequencing of longitudinal stool sampling from a cohort of advanced colorectal cancer (CRC) patients. Methods We established a prospective cohort study including 56 patients with advanced CRC treated with CAP monotherapy across 4 centers in the Netherlands. Stool samples and clinical questionnaires were collected at baseline, during cycle 3, and post-treatment. Metagenomic sequencing to assess microbial community structure and gene abundance was paired with transposon mutagenesis, targeted gene deletion, and media supplementation experiments. An independent US cohort was used for model validation. Results CAP treatment significantly altered gut microbial composition and pathway abundance, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, and media supplementation confirmed that menaquinol biosynthesis protects Escherichia coli from drug toxicity. Microbial menaquinol biosynthesis genes were associated with decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted hand-foot syndrome and dose reductions in an independent cohort. Conclusion These results suggest treatment-associated increases in microbial vitamin biosynthesis serve a chemoprotective role for bacterial and host cells, with implications for toxicities outside the gastrointestinal tract. We provide a proof-of-concept for the use of microbiome profiling and machine learning to predict drug toxicities across independent cohorts. These observations provide a foundation for future human intervention studies, more in-depth mechanistic dissection in preclinical models, and extension to other cancer treatments.
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Affiliation(s)
- Lars E Hillege
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Surgery, Maastricht University Medical Center+; Maastricht, Netherlands
| | - Kai R Trepka
- Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA
| | - Janine Ziemons
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Surgery, Maastricht University Medical Center+; Maastricht, Netherlands
| | - Romy Aarnoutse
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Surgery, Maastricht University Medical Center+; Maastricht, Netherlands
| | - Benjamin G H Guthrie
- Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA
| | - Judith de Vos-Geelen
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+; Maastricht, The Netherlands
| | - Liselot Valkenburg-van Iersel
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+; Maastricht, The Netherlands
| | | | - Arnold Baars
- Department of Medical Oncology, Hospital Gelderse Vallei; Ede, The Netherlands
| | | | - John Penders
- NUTRIM - Institute of Nutrition and Translational Research in Metabolism, Maastricht University; Maastricht, The Netherlands
- Department of Medical Microbiology, Infectious Diseases, and Infection Prevention, Maastricht University Medical Center+; Maastricht, The Netherlands
| | - Adam Deutschbauer
- Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory; Berkeley, USA
| | - Chloe E Atreya
- Department of Medicine, Division of Hematology and Oncology, University of California San Francisco; San Francisco, USA
- UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA
| | - Wesley A Kidder
- Department of Medicine, Division of Hematology and Oncology, University of California San Francisco; San Francisco, USA
- UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA
| | - Peter J Turnbaugh
- Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA
- Chan Zuckerberg Biohub-San Francisco; San Francisco, USA
| | - Marjolein L Smidt
- GROW - Research Institute for Oncology and Reproduction, Maastricht University; Maastricht, Netherlands
- Department of Surgery, Maastricht University Medical Center+; Maastricht, Netherlands
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Kallapura G, Prakash AS, Sankaran K, Manjappa P, Chaudhary P, Ambhore S, Dhar D. Microbiota based personalized nutrition improves hyperglycaemia and hypertension parameters and reduces inflammation: a prospective, open label, controlled, randomized, comparative, proof of concept study. PeerJ 2024; 12:e17583. [PMID: 38948211 PMCID: PMC11214429 DOI: 10.7717/peerj.17583] [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: 01/19/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Background Recent studies suggest that gut microbiota composition, abundance and diversity can influence many chronic diseases such as type 2 diabetes. Modulating gut microbiota through targeted nutrition can provide beneficial effects leading to the concept of personalized nutrition for health improvement. In this prospective clinical trial, we evaluated the impact of a microbiome-based targeted personalized diet on hyperglycaemic and hyperlipidaemic individuals. Specifically, BugSpeaks®-a microbiome profile test that profiles microbiota using next generation sequencing and provides personalized nutritional recommendation based on the individual microbiota profile was evaluated. Methods A total of 30 participants with type 2 diabetes and hyperlipidaemia were recruited for this study. The microbiome profile of the 15 participants (test arm) was evaluated using whole genome shotgun metagenomics and personalized nutritional recommendations based on their microbiota profile were provided. The remaining 15 participants (control arm) were provided with diabetic nutritional guidance for 3 months. Clinical and anthropometric parameters such as HbA1c, systolic/diastolic pressure, c-reactive protein levels and microbiota composition were measured and compared during the study. Results The test arm (microbiome-based nutrition) showed a statistically significant decrease in HbA1c level from 8.30 (95% confidence interval (CI), [7.74-8.85]) to 6.67 (95% CI [6.2-7.05]), p < 0.001 after 90 days. The test arm also showed a 5% decline in the systolic pressure whereas the control arm showed a 7% increase. Incidentally, a sub-cohort of the test arm of patients with >130 mm Hg systolic pressure showed a statistically significant decrease of systolic pressure by 14%. Interestingly, CRP level was also found to drop by 19.5%. Alpha diversity measures showed a significant increase in Shannon diversity measure (p < 0.05), after the microbiome-based personalized dietary intervention. The intervention led to a minimum two-fold (Log2 fold change increase in species like Phascolarctobacterium succinatutens, Bifidobacterium angulatum, and Levilactobacillus brevis which might have a beneficial role in the current context and a similar decrease in species like Alistipes finegoldii, and Sutterella faecalis which have been earlier shown to have some negative effects in the host. Overall, the study indicated a net positive impact of the microbiota based personalized dietary regime on the gut microbiome and correlated clinical parameters.
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Kaźmierczak-Siedlecka K, Bulman N, Ulasiński P, Sobocki BK, Połom K, Marano L, Kalinowski L, Skonieczna-Żydecka K. Pharmacomicrobiomics of cell-cycle specific anti-cancer drugs - is it a new perspective for personalized treatment of cancer patients? Gut Microbes 2023; 15:2281017. [PMID: 37985748 PMCID: PMC10730203 DOI: 10.1080/19490976.2023.2281017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/05/2023] [Indexed: 11/22/2023] Open
Abstract
Intestinal bacteria are equipped with an enzyme apparatus that is involved in the active biotransformation of xenobiotics, including drugs. Pharmacomicrobiomics, a new area of pharmacology, analyses interactions between bacteria and xenobiotics. However, there is another side to the coin. Pharmacotherapeutic agents can significantly modify the microbiota, which consequently affects their efficacy. In this review, we comprehensively gathered scientific evidence on the interplay between anticancer therapies and gut microbes. We also underlined how such interactions might impact the host response to a given therapy. We discuss the possibility of modulating the gut microbiota to increase the effectiveness/decrease the incidence of adverse events during tumor therapy. The anticipation of the future brings new evidence that gut microbiota is a target of interest to increase the efficacy of therapy.
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Affiliation(s)
- Karolina Kaźmierczak-Siedlecka
- Department of Medical Laboratory Diagnostics – Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdańsk, Poland
| | - Nikola Bulman
- Department of Medical Laboratory Diagnostics – Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdańsk, Poland
| | - Paweł Ulasiński
- Unit of Surgery with Unit of Oncological Surgery in Koscierzyna, Kościerzyna, Poland
| | - Bartosz Kamil Sobocki
- Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdańsk, Poland
| | - Karol Połom
- Academy of Medical and Social Applied Sciences, Elbląg, Poland
| | - Luigi Marano
- Academy of Medical and Social Applied Sciences, Elbląg, Poland
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics – Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdańsk, Poland
- BioTechMed Centre/Department of Mechanics of Materials and Structures, Gdansk University of Technology, Gdansk, Poland
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Long D, Mao C, Zhang Z, Zou J, Zhu Y. Visual analysis of colorectal cancer and gut microbiota: A bibliometric analysis from 2002 to 2022. Medicine (Baltimore) 2023; 102:e35727. [PMID: 37933041 PMCID: PMC10627710 DOI: 10.1097/md.0000000000035727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/29/2023] [Indexed: 11/08/2023] Open
Abstract
A growing number of studies have shown that gut microbiota (GM) plays an essential role in the occurrence and development of colorectal cancer (CRC). The current body of research exploring the relationship between CRC and GM is vast. Nevertheless, bibliometric studies in this area have not yet been reported. This study aimed to explore the hotspots and frontiers of research on GM and CRC in the past 20 years, which may provide a reference for researchers in this field. The Web of Science Core Collection database was searched for publications on CRC and GM from 2002 to 2022. The scientometric softwares CiteSpace and VOSviewer were used to visually analyze the countries, institutions, authors, journals, and keywords involved in the literature. Keywords co-occurrence, cluster, and burst analysis were utilized to further explore the current state and development trends of research on GM and CRC. A total of 2158 publications were included in this study, with a noticeably rising annual publication trend. The majority of these papers are from 80 nations, primarily China and the USA. J Yu was the most active author and WS Garrett has the highest citation. Among all institutions, Shanghai Jiao Tong University has the largest number of papers. Most of the publications were published in the International Journal of Molecular Sciences, with Science being the most frequently cited journal. The 4 main clusters mainly involved probiotics, inflammation, molecular mechanisms, and research methods. Current research hotspots included "Fusobacterium nucleatum," "Escherichia coli," etc. Newly emerging research has focused predominantly on immune response, gene expression, and recent strategies for the treatment of CRC with GM. The relationship between GM and CRC will continue to be a hot research area. Changes in the composition of GM in patients with CRC, the potential molecular mechanisms as well as probiotics and natural products used in the treatment of CRC have been the focus of current research and hotspots for future studies.
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Affiliation(s)
- Dan Long
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Chenhan Mao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhensheng Zhang
- The First Traditional Chinese Medicine Hospital of Zhanjiang City, Zhanjiang, Guangdong, China
| | - Junjun Zou
- The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ying Zhu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Wang AJ, Song D, Hong YM, Liu NN. Multi-omics insights into the interplay between gut microbiota and colorectal cancer in the "microworld" age. Mol Omics 2023; 19:283-296. [PMID: 36916422 DOI: 10.1039/d2mo00288d] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial heterogeneous disease largely due to both genetic predisposition and environmental factors including the gut microbiota, a dynamic microbial ecosystem inhabiting the gastrointestinal tract. Elucidation of the molecular mechanisms by which the gut microbiota interacts with the host may contribute to the pathogenesis, diagnosis, and promotion of CRC. However, deciphering the influence of genetic variants and interactions with the gut microbial ecosystem is rather challenging. Despite recent advancements in single omics analysis, the application of multi-omics approaches to integrate multiple layers of information in the microbiome and host to introduce effective prevention, diagnosis, and treatment strategies is still in its infancy. Here, we integrate host- and microbe-based multi-omics studies, respectively, to provide a strategy to explore potential causal relationships between gut microbiota and colorectal cancer. Specifically, we summarize the recent multi-omics studies such as metagenomics combined with metabolomics and metagenomics combined with genomics. Meanwhile, the sample size and sample types commonly used in multi-omics research, as well as the methods of data analysis, were also generalized. We highlight multiple layers of information from multi-omics that need to be verified by different types of models. Together, this review provides new insights into the clinical diagnosis and treatment of colorectal cancer patients.
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Affiliation(s)
- An-Jun Wang
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
| | - Dingka Song
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
| | - Yue-Mei Hong
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
| | - Ning-Ning Liu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
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Pandey H, Tang DWT, Wong SH, Lal D. Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities. Cancers (Basel) 2023; 15:cancers15030866. [PMID: 36765824 PMCID: PMC9913759 DOI: 10.3390/cancers15030866] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/03/2023] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.
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Affiliation(s)
- Himani Pandey
- Redcliffe Labs, Electronic City, Noida 201301, India
| | - Daryl W. T. Tang
- School of Biological Sciences, Nanyang Technological University, Singapore 308232, Singapore
| | - Sunny H. Wong
- Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Correspondence: (S.H.W.); (D.L.)
| | - Devi Lal
- Department of Zoology, Ramjas College, University of Delhi, Delhi 110007, India
- Correspondence: (S.H.W.); (D.L.)
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Changes in intestinal microbiota in postmenopausal oestrogen receptor-positive breast cancer patients treated with (neo)adjuvant chemotherapy. NPJ Breast Cancer 2022; 8:89. [PMID: 35906259 PMCID: PMC9338016 DOI: 10.1038/s41523-022-00455-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/05/2022] [Indexed: 11/08/2022] Open
Abstract
This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.
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Evaluation of Changes to the Oral Microbiome Based on 16S rRNA Sequencing among Children Treated for Cancer. Cancers (Basel) 2021; 14:cancers14010007. [PMID: 35008173 PMCID: PMC8750156 DOI: 10.3390/cancers14010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Childhood cancer survivors suffer from many oral complications during and after primary therapy. Our study focuses on changes in the oral microbiome of cancer survivors. Using 16S rRNA sequencing, we observed global and distinct changes in oral microbiome associated with a patient’s age and therapy duration, but not antibiotic therapy or cancer type. Observed changes in the oral microbiome could differentiate patients at higher risk of long-term oral complications. Abstract A child’s mouth is the gateway to many species of bacteria. Changes in the oral microbiome may affect the health of the entire body. The aim of the study was to evaluate the changes in the oral microbiome of childhood cancer survivors. Saliva samples before and after anti-cancer treatment were collected from 20 patients aged 6–18 years, diagnosed de novo with cancer in 2018–2019 (7 girls and 13 boys, 7.5–19 years old at the second time point). Bacterial DNA was extracted, and the microbial community profiles were assessed by 16S rRNA sequencing. The relative abundances of Cellulosilyticum and Tannerella genera were found to significantly change throughout therapy (p = 0.043 and p = 0.036, respectively). However, no differences in the alpha-diversity were observed (p = 0.817). The unsupervised classification revealed two clusters of patients: the first with significant changes in Campylobacter and Fusobacterium abundance, and the other with change in Neisseria. These two groups of patients differed in median age (10.25 vs. 16.16 years; p = 0.004) and the length of anti-cancer therapy (19 vs. 4 months; p = 0.003), but not cancer type or antibiotic treatment.
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Huang X, Li M, Hou S, Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021; 59:101. [PMID: 34738624 PMCID: PMC8577795 DOI: 10.3892/ijo.2021.5281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
A large body of evidence has revealed that the microbiome serves a role in all aspects of cancer, particularly cancer treatment. To date, studies investigating the relationship between the microbiome and systemic therapy for pancreatic ductal adenocarcinoma (PDAC) are lacking. PDAC is a high‑mortality malignancy (5‑year survival rate; <9% for all stages). Systemic therapy is one of the most important treatment choices for all patients; however, resistance or toxicity can affect its efficacy. Studies have supported the hypothesis that the microbiome is closely associated with the response to systemic therapy in PDAC, including the induction of drug resistance, or toxicity and therapy‑related changes in microbiota composition. The present review comprehensively summarized the role of the microbiome in systemic therapy for PDAC and the associated molecular mechanisms in an attempt to provide a novel direction for the improvement of treatment response and proposed potential directions for in‑depth research.
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Affiliation(s)
| | | | - Shengzhong Hou
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bole Tian
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Aarnoutse R, Ziemons J, de Vos-Geelen J, Valkenburg-van Iersel L, Wildeboer ACL, Vievermans A, Creemers GJM, Baars A, Vestjens HJHMJ, Le GN, Barnett DJM, Rensen SS, Penders J, Smidt ML. The Role of Intestinal Microbiota in Metastatic Colorectal Cancer Patients Treated With Capecitabine. Clin Colorectal Cancer 2021; 21:e87-e97. [PMID: 34801414 DOI: 10.1016/j.clcc.2021.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 09/29/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Previous pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment. PATIENTS AND METHODS Patients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region. RESULTS Thirty-three patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. Of the 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (β-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine. CONCLUSION This is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.
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Affiliation(s)
- Romy Aarnoutse
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Janine Ziemons
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Liselot Valkenburg-van Iersel
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Aurelia C L Wildeboer
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Anne Vievermans
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | | | - Arnold Baars
- Department of Medical Oncology, Hospital Gelderse Vallei, Ede, The Netherlands
| | | | - Giang N Le
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - David J M Barnett
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands; Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands; NUTRIM - School of Nutrition and Translational research In Metabolism, Maastricht University, Maastricht, The Netherlands
| | - John Penders
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands; NUTRIM - School of Nutrition and Translational research In Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Marjolein L Smidt
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.
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Huang X, Chen L, Li Z, Zheng B, Liu N, Fang Q, Jiang J, Rao T, Ouyang D. The efficacy and toxicity of antineoplastic antimetabolites: Role of gut microbiota. Toxicology 2021; 460:152858. [PMID: 34273448 DOI: 10.1016/j.tox.2021.152858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/01/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
The incidence and mortality of cancer are rapidly growing all over the world. Nowadays, antineoplastic antimetabolites still play a key role in the chemotherapy of cancer. However, the interindividual variations in the efficacy and toxicity of antineoplastic antimetabolites are nonnegligible challenges to their clinical applications. Although many studies have focused on genetic variation, the reasons for these interindividual variations have still not been fully understood. Gut microbiota is reported to be associated with the efficacy and toxicity of antineoplastic antimetabolites. In this review, we summarize the interaction of antineoplastic antimetabolites on gut microbiota and the influences of shifted gut microbiota profiles on the efficacy and toxicity of antineoplastic antimetabolites. The factors affecting the efficacy and toxicity of antineoplastic antimetabolites via gut microbiota are also discussed. In addition, we present our viewpoints that regulating the gut microbiota may increase the efficacy and decrease the toxicity of antineoplastic antimetabolites. This will help us better understand the new mechanism via gut microbiota and promote individualized use of antineoplastic antimetabolites.
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Affiliation(s)
- Xinyi Huang
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
| | - Lulu Chen
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, 411000, PR China
| | - Zhenyu Li
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China; Department of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, PR China
| | - Binjie Zheng
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
| | - Na Liu
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
| | - Qing Fang
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
| | - Jinsheng Jiang
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China; Sanjin Group Hunan Sanjin Pharmaceutical Co., Ltd., 320 Deshan Road, Hunan, 415000, PR China
| | - Tai Rao
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China.
| | - Dongsheng Ouyang
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China.
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12
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Ziemons J, Smidt ML, Damink SO, Rensen SS. Gut microbiota and metabolic aspects of cancer cachexia. Best Pract Res Clin Endocrinol Metab 2021; 35:101508. [PMID: 33648847 DOI: 10.1016/j.beem.2021.101508] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer cachexia is a metabolic syndrome characterized by unintended weight loss and muscle wasting. It has a strong negative impact on survival. Its underlying mechanisms involve systemic inflammation and insulin resistance, which are known to be influenced by the gut microbiota. Preclinical studies support a role for the gut microbiota in cancer cachexia by demonstrating that cachectic mice display: 1) various gut microbiota composition changes; 2) increased gut permeability and translocation of pro-inflammatory microbial compounds; 3) muscle atrophy-related processes linked to gut microbiota properties; 4) positive effects of microbiota-modulating interventions. Data on the relationships between gut microbiota, insulin resistance, and hepatic/adipose tissue metabolism in cachexia models are lacking. Nevertheless, the available data and existing evidence for the impact of gut microbiota on metabolic aberrations in human obesity urge for exploration of its role in human cancer cachexia. We provide practical recommendations and discuss the challenges for such future clinical studies.
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Affiliation(s)
- Janine Ziemons
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Marjolein L Smidt
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Steven Olde Damink
- Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands; NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of General-, Visceral- and Transplant Surgery, Uniklinikum Aachen, Aachen, Germany.
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands; NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
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13
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Gastrointestinal cancers: the role of microbiota in carcinogenesis and the role of probiotics and microbiota in anti-cancer therapy efficacy. Cent Eur J Immunol 2021; 45:476-487. [PMID: 33658894 PMCID: PMC7882408 DOI: 10.5114/ceji.2020.103353] [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: 03/22/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
The gut epithelium is a habitat of a variety of microorganisms, including bacteria, fungi, viruses and Archaea. With the advent of sophisticated molecular techniques and bioinformatics tools, more information on the composition and thus function of gut microbiota was revealed. The gut microbiota as an integral part of the intestinal barrier has been shown to be involved in shaping the mucosal innate and adaptive immune response and to provide protection against pathogens. Consequently, a set of biochemical signals exchanged within microbes and communication between the microbiota and the host have opened a new way of thinking about cancer biology. Probiotics are living organisms which administered in adequate amounts may bring health benefits and have the potential to be an integral part of the prevention/treatment strategies in clinical approaches. Here we provide a comprehensive review of data linking gut microbiota to cancer pathogenesis and its clinical course. We focus on gastrointestinal cancers, such as gastric, colorectal, pancreatic and liver cancer.
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14
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Bartolini I, Risaliti M, Ringressi MN, Melli F, Nannini G, Amedei A, Muiesan P, Taddei A. Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer: Focus on short and long-term outcomes. World J Gastroenterol 2020; 26:2498-2513. [PMID: 32523307 PMCID: PMC7265137 DOI: 10.3748/wjg.v26.i20.2498] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/27/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Human body is colonized by a huge amount of microorganisms mostly located in the gastrointestinal tract. These dynamic communities, the environment and their metabolites constitute the microbiota. Growing data suggests a causal role of a dysbiotic microbiota in several pathologies, such as metabolic and neurological disorders, immunity dysregulations and cancer, especially the well-studied colorectal cancer development. However, many were preclinical studies and a complete knowledge of the pathogenetic mechanisms in humans is still absent. The gut microbiota can exert direct or indirect effects in different phases of colorectal cancer genesis. For example, Fusobacterium nucleatum promotes cancer through cellular proliferation and some strains of Escherichia coli and Bacteroides fragilis produce genotoxins. However, dysbiosis may also cause a pro-inflammatory state and the stimulation of a Th17 response with IL-17 and IL-22 secretion that have a pro-oncogenic activity, as demonstrated for Fusobacterium nucleatum. Microbiota has a crucial role in several stages of postoperative course; dysbiosis in fact seems related with surgical site infections and Enterococcus faecalis (and other collagenase-producers microbes) are suggested as a cause of anastomotic leak. Consequently, unbalanced presence of some species, together with altered immune response may also have a prognostic role. Microbiota has also a substantial role in effectiveness of chemotherapy, chemoresistance and in the related side effects. In other words, a complete knowledge of the fine pathological mechanisms of gut microbiota may provide a wide range of new diagnostic tools other than therapeutic targets in the light of tailored medicine.
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Affiliation(s)
- Ilenia Bartolini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Matteo Risaliti
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Maria Novella Ringressi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Filippo Melli
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Paolo Muiesan
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Antonio Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
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15
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Aarnoutse R, Ziemons J, Penders J, Rensen SS, de Vos-Geelen J, Smidt ML. The Clinical Link between Human Intestinal Microbiota and Systemic Cancer Therapy. Int J Mol Sci 2019; 20:E4145. [PMID: 31450659 PMCID: PMC6747354 DOI: 10.3390/ijms20174145] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Clinical interest in the human intestinal microbiota has increased considerably. However, an overview of clinical studies investigating the link between the human intestinal microbiota and systemic cancer therapy is lacking. This systematic review summarizes all clinical studies describing the association between baseline intestinal microbiota and systemic cancer therapy outcome as well as therapy-related changes in intestinal microbiota composition. A systematic literature search was performed and provided 23 articles. There were strong indications for a close association between the intestinal microbiota and outcome of immunotherapy. Furthermore, the development of chemotherapy-induced infectious complications seemed to be associated with the baseline microbiota profile. Both chemotherapy and immunotherapy induced drastic changes in gut microbiota composition with possible consequences for treatment efficacy. Evidence in the field of hormonal therapy was very limited. Large heterogeneity concerning study design, study population, and methods used for analysis limited comparability and generalization of results. For the future, longitudinal studies investigating the predictive ability of baseline intestinal microbiota concerning treatment outcome and complications as well as the potential use of microbiota-modulating strategies in cancer patients are required. More knowledge in this field is likely to be of clinical benefit since modulation of the microbiota might support cancer therapy in the future.
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Affiliation(s)
- Romy Aarnoutse
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands.
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands.
| | - Janine Ziemons
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
| | - John Penders
- Department of Medical Microbiology, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
| | - Marjolein L Smidt
- GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, 6202 AZ Maastricht, The Netherlands
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16
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Dai D, Wang T, Wu S, Gao NL, Chen WH. Metabolic Dependencies Underlie Interaction Patterns of Gut Microbiota During Enteropathogenesis. Front Microbiol 2019; 10:1205. [PMID: 31214144 PMCID: PMC6558107 DOI: 10.3389/fmicb.2019.01205] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 05/13/2019] [Indexed: 01/09/2023] Open
Abstract
In recent decades, increasing evidence has strongly suggested that gut microbiota play an important role in many intestinal diseases including inflammatory bowel disease (IBD) and colorectal cancer (CRC). The composition of gut microbiota is thought to be largely shaped by interspecies competition for available resources and also by cooperative interactions. However, to what extent the changes could be attributed to external factors such as diet of choice and internal factors including mutual relationships among gut microbiota, respectively, are yet to be elucidated. Due to the advances of high-throughput sequencing technologies, flood of (meta)-genome sequence information and high-throughput biological data are available for gut microbiota and their association with intestinal diseases, making it easier to gain understanding of microbial physiology at the systems level. In addition, the newly developed genome-scale metabolic models that cover significant proportion of known gut microbes enable researchers to analyze and simulate the system-level metabolic response in response to different stimuli in the gut, providing deeper biological insights. Using metabolic interaction network based on pair-wise metabolic dependencies, we found the same interaction pattern in two IBD datasets and one CRC datasets. We report here for the first time that the growth of significantly enriched bacteria in IBD and CRC patients could be boosted by other bacteria including other significantly increased ones. Conversely, the growth of probiotics could be strongly inhibited from other species, including other probiotics. Therefore, it is very important to take the mutual interaction of probiotics into consideration when developing probiotics or “microbial based therapies.” Together, our metabolic interaction network analysis can predict majority of the changes in terms of the changed directions in the gut microbiota during enteropathogenesis. Our results thus revealed unappreciated interaction patterns between species could underlie alterations in gut microbiota during enteropathogenesis, and between probiotics and other microbes. Our methods provided a new framework for studying interactions in gut microbiome and their roles in health and disease.
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Affiliation(s)
- Die Dai
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Teng Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Sicheng Wu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Na L Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Wei-Hua Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.,College of Life Science, Henan Normal University, Xinxiang, China.,Huazhong University of Science and Technology Ezhou Industrial Technology Research Institute, Ezhou, China
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17
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Review: Using physiologically based models to predict population responses to phytochemicals by wild vertebrate herbivores. Animal 2018; 12:s383-s398. [PMID: 30251623 DOI: 10.1017/s1751731118002264] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To understand how foraging decisions impact individual fitness of herbivores, nutritional ecologists must consider the complex in vivo dynamics of nutrient-nutrient interactions and nutrient-toxin interactions associated with foraging. Mathematical modeling has long been used to make foraging predictions (e.g. optimal foraging theory) but has largely been restricted to a single currency (e.g. energy) or using simple indices of nutrition (e.g. fecal nitrogen) without full consideration of physiologically based interactions among numerous co-ingested phytochemicals. Here, we describe a physiologically based model (PBM) that provides a mechanistic link between foraging decisions and demographic consequences. Including physiological mechanisms of absorption, digestion and metabolism of phytochemicals in PBMs allows us to estimate concentrations of ingested and interacting phytochemicals in the body. Estimated phytochemical concentrations more accurately link intake of phytochemicals to changes in individual fitness than measures of intake alone. Further, we illustrate how estimated physiological parameters can be integrated with the geometric framework of nutrition and into integral projection models and agent-based models to predict fitness and population responses of vertebrate herbivores to ingested phytochemicals. The PBMs will improve our ability to understand the foraging decisions of vertebrate herbivores and consequences of those decisions and may help identify key physiological mechanisms that underlie diet-based ecological adaptations.
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18
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Hendler R, Zhang Y. Probiotics in the Treatment of Colorectal Cancer. MEDICINES (BASEL, SWITZERLAND) 2018; 5:E101. [PMID: 30205429 PMCID: PMC6164107 DOI: 10.3390/medicines5030101] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/05/2018] [Accepted: 09/05/2018] [Indexed: 12/19/2022]
Abstract
The human microbiome plays many roles in inflammation, drug metabolism, and even the development of cancer that we are only beginning to understand. Colorectal cancer has been a focus for study in this field as its pathogenesis and its response to treatment have both been linked to the functioning of microbiota. This literature review evaluates the animal and human studies that have explored this relationship. By manipulating the microbiome with interventions such as probiotic administration, we may be able to reduce colorectal cancer risk and improve the safety and effectiveness of cancer therapy even though additional clinical research is still necessary.
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Affiliation(s)
- Robert Hendler
- Department of Hematology and Oncology, Stony Brook University Hospital, Stony Brook, New York, NY 11794, USA.
| | - Yue Zhang
- Department of Hematology and Oncology, Stony Brook University Hospital, Stony Brook, New York, NY 11794, USA.
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19
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Villéger R, Lopès A, Veziant J, Gagnière J, Barnich N, Billard E, Boucher D, Bonnet M. Microbial markers in colorectal cancer detection and/or prognosis. World J Gastroenterol 2018; 24:2327-2347. [PMID: 29904241 PMCID: PMC6000297 DOI: 10.3748/wjg.v24.i22.2327] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/03/2018] [Accepted: 05/18/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer worldwide. CRC is still associated with a poor prognosis among patients with advanced disease. On the contrary, due to its slow progression from detectable precancerous lesions, the prognosis for patients with early stages of CRC is encouraging. While most robust methods are invasive and costly, actual patient-friendly screening methods for CRC suffer of lack of sensitivity and specificity. Therefore, the development of sensitive, non-invasive and cost-effective methods for CRC detection and prognosis are necessary for increasing the chances of a cure. Beyond its beneficial functions for the host, increasing evidence suggests that the intestinal microbiota is a key factor associated with carcinogenesis. Many clinical studies have reported a disruption in the gut microbiota balance and an alteration in the faecal metabolome of CRC patients, suggesting the potential use of a microbial-based test as a non-invasive diagnostic and/or prognostic tool for CRC screening. This review aims to discuss the microbial signatures associated with CRC known to date, including dysbiosis and faecal metabolome alterations, and the potential use of microbial variation markers for non-invasive early diagnosis and/or prognostic assessment of CRC and advanced adenomas. We will finally discuss the possible use of these markers as predicators for treatment response and their limitations.
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Affiliation(s)
- Romain Villéger
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
| | - Amélie Lopès
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Research Biologics, Sanofi R&D, Vitry-Sur-Seine 94400, France
| | - Julie Veziant
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Chirurgie digestive, Centre Hospitalier Universitaire, Clermont-Ferrand 63000, France
| | - Johan Gagnière
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Chirurgie digestive, Centre Hospitalier Universitaire, Clermont-Ferrand 63000, France
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Elisabeth Billard
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Delphine Boucher
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
| | - Mathilde Bonnet
- Université Clermont Auvergne, Inserm U1071, USC-INRA 2018, M2iSH, CRNH Auvergne, Clermont-Ferrand 63000, France
- Université Clermont Auvergne, Institut Universitaire de Technologie de Clermont-Ferrand, Clermont-Ferrand 63000, France
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20
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Kather JN, Halama N, Jaeger D. Genomics and emerging biomarkers for immunotherapy of colorectal cancer. Semin Cancer Biol 2018; 52:189-197. [PMID: 29501787 DOI: 10.1016/j.semcancer.2018.02.010] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/19/2018] [Accepted: 02/28/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.
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Affiliation(s)
- Jakob Nikolas Kather
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Niels Halama
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Dirk Jaeger
- Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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21
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Raskov H, Burcharth J, Pommergaard HC. Linking Gut Microbiota to Colorectal Cancer. J Cancer 2017; 8:3378-3395. [PMID: 29151921 PMCID: PMC5687151 DOI: 10.7150/jca.20497] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health.
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Affiliation(s)
- Hans Raskov
- Speciallægecentret ved Diakonissestiftelsen, Frederiksberg, Denmark
| | - Jakob Burcharth
- Department of Surgery, Zealand University Hospital, University of Copenhagen, Denmark
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