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

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.

Keywords: Drosophila; cancer; inflammation; microbiota.

Figure 1. A roadmap to identify detrimental synergisms within human holo’omes as causal for colon cancer and develop personalized therapeutic or preventive strategies.

A systems biology approach to assess shifts in intestinal holo’omes in humans and its link to colorectal pathologies will necessitate analysis of host intestine and microbial community genome, transcriptome, proteome metabolome and blood secretome. Using computational platforms, the genetic, metabolic, nutritional, microbial and immunological information accumulated, together with publicly available phenotypic and molecular function data, will be explored to obtain a ‘holistic’ view of key pathogenic processes and their hierarchies, to simulate the expected response to hypothetical interventions and develop new basic and translational research hypotheses. Reductionist approaches in Drosophila and mice - which can be genetically manipulated to express or lose the expression of specific genes in the intestine, while fed or injected with specific microbes and metabolites - could be used to assess detrimental synergisms of the intestinal holo’ome in driving inflammation and tumorigenesis, and guide the development of intervention strategies. Such therapeutic or dietary interventions could be translated to the clinic aiming to treat patients against microbial and intestinal environment imbalances as a means to alleviate intestinal inflammation and CRC.

Figure 2. Recording the holo’ome longitudinally in humans.

The holo’ome can be recorded via genomics, transcriptomics and proteomics of the host and the microbiota, metabolomics and proteomics of stool samples and secreted factors (e.g. cytokines and metabolites) of blood samples. To identify detrimental synergisms within the holo’ome, its parts need to be recorded around two points in time for each human individual: a. at a disease-free state, years before the onset of subclinical disease or long after disease remission, and b. upon the onset of subclinical disease. Disease remission may be facilitated by diet- or microbiota-based treatments that change the intestinal or blood environment or the microbiota.