Role of bacteriophages in shaping gut microbial community

Abstract

Phages are the most diversified and dominant members of the gut virobiota. They play a crucial role in shaping the structure and function of the gut microbial community and consequently the health of humans and animals. Phages are found mainly in the mucus, from where they can translocate to the intestinal organs and act as a modulator of gut microbiota. Understanding the vital role of phages in regulating the composition of intestinal microbiota and influencing human and animal health is an emerging area of research. The relevance of phages in the gut ecosystem is supported by substantial evidence, but the importance of phages in shaping the gut microbiota remains unclear. Although information regarding general phage ecology and development has accumulated, detailed knowledge on phage-gut microbe and phage-human interactions is lacking, and the information on the effects of phage therapy in humans remains ambiguous. In this review, we systematically assess the existing data on the structure and ecology of phages in the human and animal gut environments, their development, possible interaction, and subsequent impact on the gut ecosystem dynamics. We discuss the potential mechanisms of prophage activation and the subsequent modulation of gut bacteria. We also review the link between phages and the immune system to collect evidence on the effect of phages on shaping the gut microbial composition. Our review will improve understanding on the influence of phages in regulating the gut microbiota and the immune system and facilitate the development of phage-based therapies for maintaining a healthy and balanced gut microbiota.

Keywords: Bacteriophage; antimicrobials; gut microbiota modulation; gut virobiota; modulation of gut metabolites; phage and human immune system; phage therapy; prophage activation.

Figure 1.

Prophage induction and diffusion of induced active phage. Several factors that can spontaneously trigger the prophage induction and diffuse the multiple cellular signals are presented. (a) The signal-triggering prophage activation, RecA protein, plays an important role in induction of the canonical pathway by binding to single-stranded DNA. Several signals, such as external factors from the environment or drugs, initiate the final expression of SOS genes after LexA and Cl act in self-cleavage. LexA or Cl-like phage repressors are then automatically cleaved by the nucleoprotein filament. The SOS genes are expressed when LexA repression is reduced, which starts the DNA repair and cell growth inhibition. Meanwhile, various genetic patterns are present in the lytic states and lysogeny. The master transcription repressor CI, which suppresses the lytic genes, maintains lysogeny. Upon DNA damage, the key sensor RecA is activated and leads to the CI self-cleavage, triggering the genetic switch to the lytic pattern. (b) Intestinal spread of the activated phage after induction of the SOS system in lysogenic bacteria. The process known as “auto-transduction” allows for phage release from a subpopulation of lysogenic bacteria to collect DNA from rival (from host) cells and transfer it to the remaining population. The two types of transduction—specialized transduction, in which neighboring bacterial DNA from prophages is excised and packaged into the capsid, and generalized transduction, in which random bacterial or plasmid DNA fragments are unintentionally packaged in the capsid—occur rather infrequently. The induced active phages can reproduce in a short lytic lifetime. (c) After the diffusion of the activated phage, it may attach itself to the bacterial cell to form communities in a biofilm environment. The mucus layer plays a more vital role in the phage enrichment than the surrounding tissues or cells. Illustration created in BioRender.com based on information from hu et al. Henrot and Petit 2022.^,

Figure 2.

Role of phages in human-microbe interactions. (a) The influence of phages in shaping immune health; (i) bacteriophage adherence to mucus (BAM): pathogenic bacteria are killed by the mucosa-adhered phages; (ii) immune tolerance: human immunity tolerates phages by producing a low number of antibodies against phages due to the adaptive immunity development against phages in the early life. (b) Microbial dysbiosis due to phages can result in several diseases, such as (i) inflammatory bowel disease (IBD) and (ii) autoimmunity leading to type 1 diabetes. (c) Phages help maintain a homeostatic eubiosis inside the gut. (d) Phages provide several unique traits, for example: (i) lysogenization by phages provides immunity to the human host against superinfection. (ii) phages can provide virulence traits to pathogens when eliminating bacterial competitors; (iii) phages impart toxin-producing ability to microbes via horizontal gene transfer; (iv) phages alter normal gene expression; (v) lysogens (prophage-containing bacteria) possess increased antibiotic resistance. Illustration created with BioRender.com based on Chatterjee & Duerkop, (2018).

Figure 3.

Link between phages and the human immune system in the gut. After crossing the epithelial barrier, phages can induce both the innate and adaptive responses. (a) Innate response: the phages are recognized by the innate immune cells, which subsequently stimulate a signaling cascade, producing type I interferon and other inflammatory cytokines, thus providing the human host with the innate protective immunity. (b) Adaptive response: the phages can also trigger a humoral immune response by inducing the production of anti-phage antibodies by plasma B cells. Figure is based on the cited references^,,, and created with BioRender. PAMPs, pathogen-associated molecular patterns; PRR, pattern-recognition receptor; APC, antigen-presenting cell, MHC II, major histocompatibility complex class II; TCR, T-cell receptor; type I IFN, type I interferon.