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
2020-04-30
Carlotta De Filippo
Partner Organization Partner Country

1. Overall project description


1.1 Summary

Aim: The aim of the project is to understand the role of the intestinal microbiome as determinant of the effect of diet on colorectal cancer risk and to identify specific microbiome/metabolomic profiles associated with cancer risk. We  focus our project on red and processed meat based-diets whose consumption is considered a risk factor in colon carcinogenesis. Importantly, although various mechanisms have implicated in such risk, it is still not clear whether intestinal microbiota plays a role in this process.  We are comparing in humans  (WP1) and experimental animals (WP2-WP3), 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. Moreover, to better understand the contribution of diet-induced gut microbiome changes on the CRC and to demonstrate causality between dysbiosis and pathology, we will perform a transplant of faeces from rats fed the three diets into germ–free rats (WP4). The  intestinal microbiome and metabolomics profiles (WP5) associated with these diets will be correlated with carcinogenesis measuring surrogate biomarkers in the humans  and tumorigenesis in rats fed the same diets. Results:  The results are still preliminary since volunteers recruitment (WP1) and colon carcinogenesis in Pirc rats (mutated in Apc gene)  just begun. Chemically-induced carcinogenesis with Azoxymethane (AOM) in rats has been carried out and the first results evidentiate that regarding Faecal Waters toxicity and genotoxicity we found some significant differences between the different diets. In particular Colon Myeloperoxidase activity (MPO), a good indicator of inflammation, has been analysed on whole colon samples. The results show a significant decrease of MPO with the PVD diet, when compared to the Control diet (CON), but no significant effect of both meat based diets. Urinary DHN-MA, the major urinary metabolite of 4-HNE (indicator of lipid peroxidation, originating from omega-6 polyunsaturated fatty acids) has been measured, showing a significant increase of the excretion of DHN-MA for both meat-based diets when compared to CON, but no effect of the PVD diet. Metabolomics and microbiome analyses (WP5) will be performed during the 2nd year of the project. We carried out a preliminary study on the faecal microbiome (16S rDNA) in Pirc and wt rats fed a standard diet, assessing if Apc mutation had any effect in determining microbiota composition at different age period (1, 4, 11 months). We found that age was the most influential factor in Beta diversity & Alpha diversity; in particular, with rat aging, the microbiota becomes more complex and structured, showing, at month 4, an influence on bacterial community composition of the genotype. Impact:The results will provide fundamental insight into the role of microbiota in determining the effect of the diet, in particular red/processed meat intake, on CRC risk.


 


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 are conducting in parallel in humans and in three relevant models of colon carcinogenesis. The project is focused on the role of microbiome profile and colon metabolites on CRC risk (in human and animals) and will determine whether reduced intake of red and processed meat, will reduce the level of toxic metabolites. We are comparing 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. Moreover, to better understand the contribution of diet-induced gut microbiome changes on the CRC and to demonstrate causality between dysbiosis and pathology, we will perform a transplant of faeces from rats fed the three diets into germ–free rats. The intestinal microbiome and metabolomics profiles associated with these diets will be correlated with carcinogenesis measuring surrogate biomarkers in the humans and tumorigenesis in rats fed the same diets. The human intervention study has begun and is currently under investigation. As preliminary results of the first year of the project in animal models (chemically-induced carcinogenesis with AOM in rats) we found that analyzing Faecal Waters toxicity and genotoxicity, Colon myeloperoxidase activity (MPO) a good indicator of inflammation, is significantly decreased with the PVD diet, when compared to the controls diets. The analysis of urinary DHN-MA, the major urinary metabolite of 4-HNE (indicator of lipid peroxidation, originating from omega-6 polyunsaturated fatty acids) shows a significant increase of the excretion for both meat-based diets (MBD and MBD-T) when compared to Control diet, but no effect of the PVD diet.  We also carried out a preliminary study on the faecal microbiome (16S rDNA) in Pirc and wt rats fed a standard diet, assessing if Apc mutation had any effect in determining microbiota composition at different age period (1, 4, 11 months). We found that age was the most influential factor in Beta diversity & Alpha diversity, in particular with rat aging, the microbiota becomes more complex and structured, showing, at month 4th, an influence on bacterial community composition of the genotype. 


4. Impact


4.1 List of publications

AuthorsTitleYear, Issue, PPDoiPdf

4.2 Presentation of the project

Target groupAuthorsMeans of communicationHyperlinkPdf
Scientists G. Caderni, C. De Filippo JPI-HDHL The new Strategic Research Agenda (SRA) National consultation workshop Rome, Ministry of Health, Auditorium, Via Ribotta 5 September 14th, 2018Oral presentation

4.3 List of submitted patents and other outputs

Patent licencePartners involvedYearInternational eu or national patentCommentPdf

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