Faecal microbiome as determinant of the effect of diet on colorectal-cancer risk: comparison of meat based versus pesco-vegetarian diets.

HDHL INTIMIC cofunded call “Interrelation of the Intestinal Microbiome, Diet and Health” (IM 2017)
Faecal microbiome as determinant of the effect of diet on colorectal-cancer risk: comparison of meat based versus pesco-vegetarian diets.
MeaTIc
2018-04-30
2021-10-30
Carlotta De Filippo
National Research Council (CNR)
Italy

Consortium

Partner Organization Partner Country
University of FlorenceItaly
French National Institute for Agricultural Research (INRA)France
French National Institute for Agricultural Research (INRA)France
Netherlands Organisation for Applied Scientific Research (TNO)The Netherlands

1. Overall project description


1.1 Summary

The aim of Meatic project is to understand the role of the gut microbiome as determinant of the effect of diet on colorectal cancer risk and to identify specific associated microbiome profiles. We compared in humans (WP1) and experimental animals (WP2-WP3-WP4), a high-risk meat-based diet (MBD) with a pesco-vegetarian diet (PVD) associated with a lower CRC risk and a MBD diet medium risk supplemented with α-tocopherol (MBD-T). In human study (WP1), cholesterol, triglyceride, and ferritin blood levels were significantly different comparing the three different diets. Considering the primary outcome, our results indicate that the MBD was associated with an increase in markers of colon cancer risk as faecal waters (FW) genotoxicity. Instead, a complete protection from the effect of the MBD was found upon supplementation of the meat-based diet with alpha-tocopherol. Regarding the microbial metabolome, we found significantly differences in the 3 diets by identifying specific metabolic biomarkers for the PVD diet compared to the meat-based diets, resulting more discriminating than those of the metataxonomic profiles.


For AOM induced rat carcinogenesis (WP2), urinary and faecal lipid peroxidation biomarkers indicate an increase in luminal lipid peroxidation in the colon of rats fed meat-based diets when compared to the Ctrl or the PVD, with no significant effect of α-tocopherol supplementation. In addition, gut permeability was decreased by the PVD, with no effect of MBD and MBD-T. The analysis on microbiota composition indicated that dietary intervention significantly modified bacterial communities generating clearly distinguishable profiles, especially for the PVD.  The metabolomics analysis identified a set of seven metabolites able to classify different diet groups and expanding those we found another set of 50 highly correlated.


For the Pirc rats (WP3), our results showed a significantly lower number of colon and total tumours in the rats treated with the PVD, while MBD and MBD-T presented similar numbers. Apoptosis in the normal mucosa was significantly higher in the PVD compared with the two groups fed with meat. Metataxonomic analysis indicated a significant difference of the bacterial community between the 3 diets, in particular of the PVD with respect to all others. In particular, we found Prevotellaceae, Lachnospiraceae, Ruminococcaceae abundance in PVD group, showing the strongest inverse relation to colon tumours. Metabolomics analyses identifies specific metabolomics profiles characteristic of the three diets. 


The faecal microbiota transplant (WP4) from Pirc rats fed the three different diets into germ–free rats in which colon carcinogenesis was induced with AOM, demonstrated that faecal microbiota with relative metabolites was able to transmit cancer risk: WT rats transplanted with the meat-based diet faeces, had a significantly higher number of preneoplastic lesions related with specific microbiome profile and relative metabolites.


1.2 Highlights

The MeatIC project is the first controlled dietary intervention study to understand the contribution of microbiome in red/processed meat-mediated CRC risk, that we conducted in parallel in humans and in three relevant models of colon carcinogenesis. The project is focused on the role of microbiome profile and relative microbial metabolites on CRC risk (in humans and animals) to determine whether reduced intake of red and processed meat is able to reduce the level of toxic metabolites. We compared in human’s volunteers and experimental animals (Chemically-induced carcinogenesis with Azoxymethane (AOM) in rats and colon carcinogenesis in Pirc rats, mutated in Apc gene), a high-risk meat-based diet (MBD) with a pesco-vegetarian diet (PVD) associated with a lower CRC risk. An additional arm is a MBD diet supplemented with tocopherol (MBD-T), possibly reducing risk.


Pirc rats fed the PVD diet, showed a significantly lower number of colon tumours than rats fed all the other diets. In the AOM-treated rats no differences were observed in the number preneoplastic lesions, but MDF with the PVD and CTRL diets were smaller than with the two meat-based diets. Oxidative stress parameters such as faecal TBARS, urinary DHN-MA and urinary 8-iso-PGF 2α were lower in PVD than in Meat-based diets-fed rats (both models, more or less). AOM-treated rats in the PVD group showed a significantly lower number of colon macrophagic infiltration (CD-68 positive cells) than in MBD group, while in the PVD-fed Pirc rats apoptosis in both the colon mucosa and tumours was higher than the MBD-group. Faecal metagenomic analysis showed that bacterial communities significantly differed on the basis of diet, with the exception of MBD and MBD-T samples which were similar. Metabolite profiles were also impacted by the different diets.


Moreover, to better understand the contribution of diet-induced gut microbiome changes on the CRC and to demonstrate causality between dysbiosis and pathology, we performed a transplant of faeces from rats fed the three diets into germ-free rats. The intestinal microbiome and relative metabolomics profiles associated with these diets has been correlated with carcinogenesis measuring surrogate biomarkers in the humans and tumorigenesis in rats fed the same diets. Strikingly, rats transplanted with the MBD-faeces had the highest number of MDF compared with all the other diets. In conclusion, these results demonstrate the protective properties of PVD diet and confirm the carcinogenetic activity of MBD-diets.


Regarding the human study, total cholesterol, triglyceride, and ferritin levels significantly changed between diets. Results indicate that the MBD was associated with an increase in markers of colon cancer risk as faecal waters (FW) genotoxicity, whereas no effect of the PVD was observed. Instead, a complete protection from the effect of the MBD was found upon supplementation of the meat-based diet with alpha-tocopherol. Regarding the analysis of the faecal microbiota, the profiles of the microbial metabolome are significantly different in the three diets identifying specific biomarkers for the PVD diet compared to the meat-based diets resulting more discriminating than those of the metataxonomic profiles relating to the bacterial component.


Our results further demonstrate that these impacts of the different diets on carcinogenicity are, at least in part, mediated by the intestinal microbiome.


4. Impact


4.1 List of publications

AuthorsTitleYear, Issue, PPPartners NumberDoiPdf
Sofi F, Dinu M, Pagliai G, Pierre F, Gueraud F, Bowman J, Gerard P, Longo V, Giovannelli L, Caderni G, de Filippo C.Fecal microbiome as determinant of the effect of diet on colorectal cancer risk: comparison of meat-based versus pesco-vegetarian diets (the MeaTIc study). 2019, 9;20(1):688. U1, U2, U3, U4, U510.1186/s13063-019-3801-xDownload
Vitali F*, Tortora K*, Di Paola M, Bartolucci G, Menicatti M, De Filippo C*, Caderni G. *Intestinal microbiota profiles in a genetic model of colon tumorigenesis correlates with colon cancer biomarkers.2022, Jan 26;12(1):1432U1-U210.1038/s41598-022-05249-0
Sharon I, Quijada NM, Pasolli E, Fabbrini M, Vitali F*, Agamennone V, Dötsch A, Selberherr E, Grau JH, Meixner M, Liere K, Ercolini D, de Filippo C*, Caderni G*, Brigidi P, Turroni S. The Core Human Microbiome: Does It Exist and How Can We Find It? A Critical Review of the Concept. 2022 Jul 13;14(14):2872U1-U210.3390/nu14142872

4.2 Presentation of the project

Target groupAuthorsMeans of communicationHyperlinkPdf
Scientists and NutritionistsDinu, G. Pagliai, I. Giangrandi, S. Lotti, B. Colombini, F. Cesari, G. Caderni, F. Vitali, C. De Filippo, S. Ristori, L. Giovannelli, F. Sofi. (partners U1 - U2) Effects of a meat-based diet versus pesco-vegetarian diet on biochemical parameters: results from the MeaTIc Study. “XLI CONGRESSO NAZIONALE SINU 2021” April 9-10th / 16-17th 2021, Virtual conferenceOral presentation (Virtual conference)Link
Scientists and NutritionistsRistori, M. Dinu, G. Pagliai, F. Sofi, G. Caderni, F. Vitali,C. M. Della Croce, V. Longo, C. De Filippo, L. Giovannelli (partners U1 - U2) . Comparison of meat-based versus pesco-vegetarian diets harmful metabolite content in faeces: preliminary results from the MeaTIc Study. “XLI CONGRESSO NAZIONALE SINU 2021” April 9-10th / 16-17th 2021, Virtual conference Oral presentation (Virtual conference)Link
ScientistsSofia Chioccioli, Francesco Vitali, Fabrice Pierre, Philippe Gérard, Jildau Bouwman, Serdar Özsezen, Francoise Gueraud, Giovanna Caderni, Carlotta De Filippo, Faecal microbiome as determinant of the effect of diet on colorectal-cancer risk: comparison of red meat based versus pesco-vegetarian diets in rodent models. XVI FISV Congress 3R: Research, Resilience, Reprise Reggia di Portici (Naples), Italy • 14-16 September 2022PosterLink

4.3 List of submitted patents and other outputs

Patent licencePartners involvedYearInternational eu or national patentCommentPdf

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This project has received funding from the European Union’s
H2020 Research and Innovation Programme under grant agreement n.696300

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