The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages

Abstract

Bacteria and their viruses, bacteriophages (phages), are the most abundant components of the mammalian gut microbiota where these two entities coexist over time. The ecological dynamics underlying the coexistence between these two antagonistic populations in the gut are unknown. We challenged a murine synthetic bacterial community with a set of virulent phages, to study the factors allowing phages-bacteria coexistence in the gut. We found that coexistence was neither dependent on an arms race between bacteria and phages, nor on the ability of phages to extend host range.Instead, our data suggest that some phage-inaccessible sites in the mucosa of the ileum serve as a spatial refuge for bacteria, which from there disseminate in the gut lumen. Luminal phages amplify by infecting luminal bacteria maintaining phage throughout the gut. We conclude that the heterogeneous distribution of microbes in the gut contributes to the long-term coexistence of phages with phage-susceptible bacteria. This observation could explain the persistence in the human gut of intestinal phages, such as the crAssphage, as well as the low efficiency of oral phage therapy against enteric pathogens in animal models and clinical trials.

Long-term persistence of crAss-like phage crAss001 is associated with phase variation inBacteroides intestinalis

“…It remains unclear what mechanisms are responsible for the long-term persistence and high prevalence of crAss-like phages in the human gut. Several mechanisms of phage persistence are possible, including spatial heterogeneity of microbial habitats in the gut (Lourenço et al, 2020), physiological stochasticity of phage sensitivity phenotype in their host bacteria (Lourenço et al, 2018), reversible genetic switching (phase variation) of surface receptor expression (Porter et al, 2020), constant sweeps of new mutations leading to arms race co-evolution with their hosts (Scanlan, 2017), or perhaps, an unusual life cycle (carrier state infection, pseudolysogeny) of the viruses themselves. Establishing these mechanism(s) is a challenging task due to the lack of tools for genetic manipulation, and the low similarity of crAss-like phage genomes and proteins to well characterised model viruses (Dutilh et al, 2014).…”

Shining Light on Human Gut Bacteriophages

“…If kill-the-winner dynamics occur at a strain or sub-strain level, stability is maintained at the species or genus taxonomic levels over time or it is possible that these phages engage in “piggyback-the-winner” dynamics (Silveira and Rohwer, 2016 ; Breitbart et al, 2018 ). The spatial heterogeneity of the gut also provides hosts with phage-inaccessible reservoirs in microhabitats creating source-sink dynamics that reduce selective pressures and allow the coexistence of both (Lourenço et al, 2020 ). Additionally, the oscillation of bacteria between phage-permissive and non-permissive phenotypes could also have an important role in this persistence (Porter et al, 2020 ).…”

“…An example of such spatial heterogeneity was identified in a study of virulent phage-bacteria coexistence in the gut using a murine model. It was found that the examined phages were in lower abundance in the mucosa while bacterial counts were high and vice versa in the lumen, thus, creating a luminal-mucosal gradient of phages and bacteria (Lourenço et al, 2020 ). In this example, the mucosa (source) was described as a phage-inaccessible refuge for the bacteria from where they can gradually disseminate into the lumen (sink) and phage predation occurs.…”

“…As a result, when these bacteria disseminate from their refuge and come in contact with a cognate phage they remain susceptible to infection thus allowing both the bacteria and phage to be maintained. These dynamics can interplay to support the coexistence of virulent phages and susceptible hosts in the gut (Holt, 1985 ; Lourenço et al, 2020 ). Interestingly, this is consistent with the idea that populations of intestinal bacteria, particularly commensals, reside in microhabitats such as crypts ( Figure 2B ).…”

Wide distribution of alternatively coded Lak megaphages in animal microbiomes

“…1b and S5), despite the fact that Prevotella are able to degrade mucins and are equipped to colonise the mucosa 26 . Theoretically, the relative abundance of Lak phages compared to Prevotella might also be higher in the mucosa compared to the lumen, because adhesion of phages to the mucosa should increase phage-bacteria encounter rates 27,28 . The finding that this is not the case may relate to the counteracting effect of the mucosa allowing bacteria to evade phage predation 27,28 .…”