Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches

José E Belizário, Mauro Napolitano, José E Belizário, Mauro Napolitano

Abstract

The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.

Keywords: CRISPR/Cas system; metagenomics; microbiome; phage therapy; pharmacomicrobiomics; quorum sensing.

Figures

FIGURE 1
FIGURE 1
Taxonomic distribution, prevalence and abundance of microbial taxa that inhabit healthy human body sites as defined in the human microbiome projects (HMP). The colored rectangles denote phylum/class and genera. Clinical studies of the microbiome will help to elucidate the link between microbes and the promotion of a large number of diseases and pathological conditions as shown in the figure. The images were adapted from NIH HMP (http://www.hmpdacc.org/) and National Human Genome Research Institute (https://www.genome.gov/). TORCH, Toxoplasmosis, Oher infections (coxsackievirus, HIV, syphilis, etc), Rubella, Cytomegalovirus, Herpes simplex.
FIGURE 2
FIGURE 2
Possible future therapeutic approaches to control dysbiosis. Disturbances in the ecological community of commensal, symbiotic, and pathogenic microorganisms may favor dysbiosis. This leads to increased bacterial translocation and/or release of microorganism-associated molecular patterns (MAMPs), which activate Toll-like receptors (TLRs) in several cell types. Local and body-wide immune system activities promote inflammation, which ultimately leads to chronic diseases. Novel therapeutic approaches like phage therapy, disruption of Quorum Sensing and the use of the biotechnological tool CRISPR/Cas9 to edit microbial genomes have the potential to target specific bacterial taxa thus helping to re-establish homeostasis and microbiome balance.
FIGURE 3
FIGURE 3
Actions and molecular approaches aiming to protect the environmental and human microbial ecosystems. The measurements of ecological, phylometagenomic, and microbial metabolic variations in the microbiomes require a specialized and complex set of knowledge. Collaboration between universities, research entities, non-governmental organizations (NGO), and the pharmaceutical industry professionals are key for evaluating both biological and pharmaceutical impacts in the ecosystems and elucidating the mechanism-of-action of new compounds in the host and its microbiomes. The utility of metagenomic functional reconstruction for direct association of community functions with habitat and host phenotype will be critical for proper study designs and production of greener pharmaceutical products for future personalized medicine.

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