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Gut microbiota in colorectal cancer: The importance of Parvimonas micra
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Tarmfloran hos patienter med kolorektalcancer : betydelsen av Parvimonas micra (Swedish)
Abstract [en]

Colorectal cancer (CRC) is a heterogenous disease consisting of multiple molecular subtypes, each of which has diverse treatment responses and prognoses. The importance of the gut microbiota in CRC development and progression has undergone increasing recognition in recent years, with a structural segregation in terms of microbial composition between CRC patients and healthy controls. However, many questions remain before a full understanding of the impact of the gut microbiota on CRC is reached. The overall aim of this thesis was to explore the role of gut microbes in CRC, including their potential as CRC biomarkers and associations with clinicopathological, immunological, and molecular traits of CRC. A particular focus was the CRC-associated oral pathogen Parvimonas micra.

To investigate faecal microbiota as a potential biomarker for CRC, we studied the presence of specific bacteria in faeces from CRC patients and controls using qPCR. We found higher levels of P. micra in faecal samples from CRC patients than from control patients. A test for high levels of P. micra was able to identify CRC with a specificity of 87.3% and a sensitivity of 60.5%. Adding the oral pathogen Fusobacterium nucleatum, colibactin-producing bacteria, and faecal haemoglobin to the test enhanced its sensitivity.

We further aimed to explore the associations of P. micra and F. nucleatum with molecular subtypes of CRC and the tumour immune response. The levels of P. micra and F. nucleatum, as analysed by qPCR in both faeces and tumour tissue from CRC patients, were found to be positively correlated. High levels of intratumoural P. micra and F. nucleatum were associated with tumours of the microsatellite instable subtype and BRAF-mutated tumours. For F. nucleatum, an additional association with right-sided tumours was found. Moreover, both P. micra and F. nucleatum in tumour tissue were associated with the immune-activated consensus molecular subtype (CMS) 1 subtype of CRC. In line with this finding, we found novel associations between intratumoural P. micra and specific immune traits, which were evaluated by flow cytometry, indicating an active immune response in CRC. These results were further confirmed using transcriptomics. However, no associations with specific immune traits were found for F. nucleatum.

We also investigated associations between faecal and intratumoural levels of P. micra and F. nucleatum and survival in CRC patients. CRC patients with high levels of intratumoural P. micra and F. nucleatum showed reduced five-year cancer-specific survival. This association remained significant for P. micra in multivariable analysis. No associations with cancer-specific survival were found for levels of P. micra and F. nucleatum in faeces.

To investigate the faecal microbial landscape of CRC patients on a larger scale, we used 16S rRNA sequencing. Network analysis revealed a cluster of associated bacteria, including P. micra and F. nucleatum, as well as other CRC-related pathogens such as Bacteroides fragilis, Peptostreptococcus stomatitis, and Porphyromonas spp. Furthermore, beta-diversity analysis indicated a significantly different gut microbial composition depending on tumour location and microsatellite instability status. Interestingly, three of the six annotated species most strongly associated with microsatellite instable tumours were also present in the cluster: P. micra, F. nucleatum, and P. stomatis.

In conclusion, our results suggest P. micra as a putative candidate for a future non-invasive microbial test panel for detection of CRC. Moreover, our results indicate that intratumoural P. micra and F. nucleatum are associated with immune-active subtypes of CRC, including microsatellite instable tumours and tumours of the CMS1 subtype, as well as decreased patient survival. Furthermore, P. micra and F. nucleatum were found to be associated with a cluster of other CRC-related oral pathogens. An improved understanding of the role of the gut microbiota in tumour progression may lead to the identification of important biomarkers for CRC disease and outcome, as well as potential targets for future therapy.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2286
Keywords [en]
Colorectal cancer, mucosal microbiota, Parvimonas micra, Fusobacterium nucleatum, immunity, survival
National Category
Biomedical Laboratory Science/Technology
Research subject
biomedical laboratory science
Identifiers
URN: urn:nbn:se:umu:diva-222737ISBN: 978-91-8070-300-0 (electronic)ISBN: 978-91-8070-299-7 (print)OAI: oai:DiVA.org:umu-222737DiVA, id: diva2:1847175
Public defence
2024-04-26, Hörsal Betula, byggnad 6M, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-04-05 Created: 2024-03-26 Last updated: 2024-03-28Bibliographically approved
List of papers
1. Parvimonas micra as a putative non-invasive faecal biomarker for colorectal cancer
Open this publication in new window or tab >>Parvimonas micra as a putative non-invasive faecal biomarker for colorectal cancer
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 15250Article in journal (Refereed) Published
Abstract [en]

The use of faecal microbial markers as non-invasive biomarkers for colorectal cancer (CRC) has been suggested, but not fully elucidated. Here, we have evaluated the importance of Parvimonas micra as a potential non-invasive faecal biomarker in CRC and its relation to other microbial biomarkers. The levels of P. micra, F. nucleatum and clbA+bacteria were quantified using qPCR in faecal samples from a population-based cohort of patients undergoing colonoscopy due to symptoms from the large bowel. The study included 38 CRC patients, 128 patients with dysplasia and 63 controls. The results were validated in a second consecutive CRC cohort including faecal samples from 238 CRC patients and 94 controls. We found significantly higher levels of P. micra in faecal samples from CRC patients compared to controls. A test for P. micra could detect CRC with a specificity of 87.3% and a sensitivity of 60.5%. In addition, we found that combining P. micra with other microbial markers, could further enhance test sensitivity. Our findings support the potential use of P. micra as a non-invasive biomarker for CRC. Together with other microbial faecal markers, P. micra may identify patients with "high risk" microbial patterns, indicating increased risk and incidence of cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-176065 (URN)10.1038/s41598-020-72132-1 (DOI)000573742900024 ()32943695 (PubMedID)2-s2.0-85091192879 (Scopus ID)
Available from: 2020-11-05 Created: 2020-11-05 Last updated: 2024-03-26Bibliographically approved
2. Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer
Open this publication in new window or tab >>Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer
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2022 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 71, p. 2565-2575Article in journal (Refereed) Published
Abstract [en]

The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and Fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and F. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. F. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69+ T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between F. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

Place, publisher, year, edition, pages
Springer, 2022
Keywords
Colorectal cancer, F. nucleatum, Immunity, Mucosal microbiota, P. micra
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-193335 (URN)10.1007/s00262-022-03179-4 (DOI)000770199300001 ()35301576 (PubMedID)2-s2.0-85126450770 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, AMP 21-1048Region Västerbotten, VLL-833541Swedish Cancer Society, 20 1271PjF
Available from: 2022-03-28 Created: 2022-03-28 Last updated: 2024-03-26Bibliographically approved
3. Tumour colonisation of Parvimonas micra is associated with decreased survival in colorectal cancer patients
Open this publication in new window or tab >>Tumour colonisation of Parvimonas micra is associated with decreased survival in colorectal cancer patients
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2022 (English)In: Cancers, ISSN 2072-6694, Vol. 14, no 23, article id 5937Article in journal (Refereed) Published
Abstract [en]

Increasing evidence suggests that the gut microbiota may impact colorectal cancer (CRC) development and progression. In this study, the tumour colonisation of two CRC-associated bacteria, Parvimonas micra and Fusobacterium nucleatum, was studied in relation to patient survival in a cohort of 257 CRC patients. Colonisation of P. micra and F. nucleatum was analysed in fresh frozen tumour tissue (n = 112) and in faeces (n = 250) by qPCR. When analysing tumour tissues, both P. micra and F. nucleatum were found to be associated with decreased five-year cancer-specific survival, an association that remained significant in multivariable analysis for P. micra. Furthermore, we found significant associations of high levels of P. micra and F. nucleatum with tumour molecular characteristics, i.e., tumours mutated in BRAFV600E, and tumours of the MSI subtype. The analysis of faecal samples showed weaker associations with prognosis and tumour molecular characteristics. In conclusion, our findings support a novel association of tumour colonisation of P. micra with decreased patient survival. A better understanding of the role of the gut microbiota in CRC might contribute to the advancement of prognostic tools and new targets for therapy.

Keywords
Fusobacterium nucleatum, Parvimonas micra, colorectal cancer, mucosal microbiota, survival
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-202632 (URN)10.3390/cancers14235937 (DOI)000896321500001 ()36497419 (PubMedID)2-s2.0-85143631346 (Scopus ID)
Funder
Swedish Cancer Society, 20 1271Sjöberg FoundationCancerforskningsfonden i Norrland, LP 22-2318Region Västerbotten
Available from: 2023-01-12 Created: 2023-01-12 Last updated: 2024-03-26Bibliographically approved
4. Parvimonas micra forms a distinct bacterial network with oral pathobionts in colorectal cancer patients
Open this publication in new window or tab >>Parvimonas micra forms a distinct bacterial network with oral pathobionts in colorectal cancer patients
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-222732 (URN)
Available from: 2024-03-26 Created: 2024-03-26 Last updated: 2024-03-27

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