Microbiota and Phage Therapy: Future Challenges in Medicine

Abstract

An imbalance of bacterial quantity and quality of gut microbiota has been linked to several pathologies. New strategies of microbiota manipulation have been developed such as fecal microbiota transplantation (FMT); the use of pre/probiotics; an appropriate diet; and phage therapy. The presence of bacteriophages has been largely underestimated and their presence is a relevant component for the microbiome equilibrium. As a promising treatment, phage therapy has been extensively used in Eastern Europe to reduce pathogenic bacteria and has arisen as a new method to modulate microbiota diversity. Phages have been selected and "trained" to infect a wide spectrum of bacteria or tailored to infect specific antibiotic resistant bacteria present in patients. The new development of genetically modified phages may be an efficient tool to treat the gut microbiota dysbiosis associated with different pathologies and increased production of bacterial metabolites and subsequently decrease systemic low-grade chronic inflammation associated with chronic diseases. Microbiota quality and mitochondria dynamics can be remodulated and manipulated by phages to restore the equilibrium and homeostasis of the system. Our aim is to highlight the great interest for phages not only to eliminate and control pathogenic bacterial infection but also in the near future to modulate the microbiota by adding new functions to selected bacteria species and rebalance the dynamic among phages and bacteria. The challenge for the medicine of tomorrow is to re-think and redesign strategies differently and far from our traditional thinking.

Keywords: Phage therapy; chronic disease; microbiota; mitochondria; pathology treatment.

Figure 1

Bacteriophages modulate microbiota quality and quantity. Gut microbiota release metabolites and factors including hydrogen sulfide (H2S), reactive oxygen species (ROS), nitric oxide (NO) and short chain fatty acids (SCFAs) that can directly affect mitochondria activity, adenosine triphosphate (ATP) production, and nuclear genome. High ROS production can trigger an inflammatory response and increase cell oxidative stress. Furthermore, cell stress can trigger mitochondrial and bacterial DNA insertion in the nuclear genome leading of cellular gene expression. Nitric oxide can inhibit the tricarboxylic acid cycle (TCA) by reducing acetyl-CoA production. In addition, high production of hydrogen sulfide (H2S) by the microbiota inhibit complex IV of the electron transfer chain (ETC). SCFAs, in particular butyrate, are able to fuel the TCA cycle. In parallel, SCFAs can induce release of anti-inflammatory IL-10 cytokines and signaling hormone GLP-1 to reduce energy intake. Unbalanced microbiota displayed low bacterial diversity and potentially increased the proportion of pathogenic bacteria that favor mucosal inflammation. Manipulation of microbiota by lytic phage can be used to selectively reduce pathogenic bacteria. In addition, prophages that carry biosynthesis genes of metabolites that positively regulate mucosal inflammation can be engineered to genetically modify commensal bacteria [9,10].