Constructing personalized longitudinal holo'omes of colon cancer-prone humans and their modeling in flies and mice.

Myrofora Panagi,Konstantina Georgila,Yiorgos Apidianakis,Aristides G Eliopoulos

doi:10.18632/oncotarget.6463

Abstract

Specific host genes and intestinal microbes, dysbiosis, aberrant immune responses and lifestyle may contribute to intestinal inflammation and cancer, but each of these parameters does not suffice to explain why sporadic colon cancer develops at an old age and only in some of the people with the same profile. To improve our understanding, longitudinal multi-omic and personalized studies will help to pinpoint combinations of host genetic, epigenetic, microbiota and lifestyle-shaped factors, such as blood factors and metabolites that change as we age. The intestinal holo’ome – defined as the combination of host and microbiota genomes, transcriptomes, proteomes, and metabolomes – may be imbalanced and shift to disease when the wrong host gene expression profile meets the wrong microbiota composition. These imbalances can be triggered by the dietary- or lifestyle-shaped intestinal environment. Accordingly, personalized human intestinal holo’omes will differ significantly among individuals and between two critical points in time: long before and upon the onset of disease. Detrimental combinations of factors could therefore be pinpointed computationally and validated using animal models, such as mice and flies. Finally, treatment strategies that break these harmful combinations could be tested in clinical trials. Herein we provide an overview of the literature and a roadmap to this end.

Highlights

Among cancers that affect both men and women, colorectal cancer (CRC) is the second leading cause of death in the United States and Europe
The short-chain fatty acids (SCFAs) effects on Treg are mediated in part by histone acetylation of the FoxP3 locus leading to elevated expression of FoxP3, a transcription factor required for the differentiation of CD4+ T lymphocytes to Treg [104, 105]. These findings suggest that microbial metabolic products of diet epigenetically modulate host gene expression and hint to important links between commensal microbiota and epigenetic changes in the immune system that may influence the onset of inflammation and cancer in the intestine
Despite the lack of adaptive immune responses that may mediate the beneficial responses to Lactobacillus species, fly autochthonous bacteria, such as L. plantarum, and pathogens, such as Pseudomonas aeruginosa, induce regenerative inflammatory signaling via the highly conserved Jun N-terminal kinase (JNK) and STAT pathways, as part of the host defense response against intestinal infection [11, 117,118,119]

Summary

Introduction

Among cancers that affect both men and women, colorectal cancer (CRC) is the second leading cause of death in the United States and Europe. Based on data from human, mouse and Drosophila studies, the present review points to the importance of interactions among host gene expression, the intestinal microbiome and environment and systemic factors and metabolites, which comprise the intestinal holo’ome, an integral system controlling homeostasis, inflammation and cancer.

Results

Conclusion