Phages can have a profound impact on the dynamics of the gut microbiome, not only affecting certain species directly but also having a cascading effect on others, according to new mouse data published in Cell & Host Metabolism.
The findings, from a team of researchers at Brigham and Women's Hospital and the Wyss Institute, reveal that phages may impact their human host by modulating metabolites, including chemical substances found in the brain.
"One of the major interests in my lab is understanding the changes in the dynamics of the gut microbiome. Bacteriophage are a huge component of the microbiome but haven't been studied much yet," said co-corresponding senior author Georg Gerber, MD, PhD, MPH, co-director of the Massachusetts Host-Microbiome Center and chief of the Division of Computational Pathology in the Department of Pathology at the Brigham.
"Some people are exploring phage therapy, using phage to kill off microbes, but phage are also found naturally in the gut, co-existing with the rest of the ecosystem,” he noted. “We wanted to find out what they are doing in there."
In the new work, Gerber and colleagues colonised the guts of mice with a defined set of human bacterial species and then added phages, tracking the growth of each microbe.
Using high-throughput sequencing and computational analyses, they found that the phage caused slow destruction of the species they preyed upon as expected – but also reported a rippling effect on the rest of the ecosystem including blooms of non-targeted species.
Further, as well as looking at the effects on microbes the team also looked for effects on the metabolome - chemical substances that can come from both the host and the bacteria present.
“Phage predation not only directly impacts susceptible bacteria but also leads to cascading effects on other bacterial species via interbacterial interactions,” said the team. “Metabolomic profiling revealed that shifts in the microbiome caused by phage predation have a direct consequence on the gut metabolome.”
Gerber and colleagues reported that when they altered the microbiome with phage, targeted changes in the metabolome, including changes in neurotransmitter levels and bile acids, were seen.
"This finding fascinates me for follow-up and raises significant questions: Could we use phage to modulate these activities? Could this be an intervention for conditions, such as depression, where you'd want to change neurotransmitter levels?" said the researcher.
"Even if they aren't used as a direct therapeutic, our study suggests that phage may be a good tool for understanding the potential effects of other therapeutics that alter the microbiome."
New research: Knockout potential?
The team noted that although phage predation has classically been viewed through a lens of species- or strain-specific impact on bacteria, the new results highlight the importance of considering interbacterial interactions within bacterial communities and potential cascading effects.
“Our findings are consistent with the emerging understanding of how the gastrointestinal environment (e.g., dense colonization, niche competition and nutrient limitations) promotes intense competition and cooperation among species,” commented the authors.
“While clearly important, interbacterial interactions are challenging to experimentally identify and confirm in vivo given the limited tools currently available,” they said. “By analogy, in molecular biology, a general strategy to confirm the putative role of a gene is to verify loss-of-function using a genetic knockout and then verify gain-of-function by reintroducing the gene to the knockout.”
“Our results suggest that phages can provide similar information for the microbiome, although in a graded rather than absolute manner.”
“Our study reveals a highly interactive and dynamic community where lytic phage coexist and knockdown targeted bacteria, with an effect that propagates through the other members of the microbiota to ultimately modulate the gut metabolome,” said the researchers.
Given the profound effects on the metabolome and microbiome that malnutrition can have, Gerber and the team said they especially interested in exploring the intersection of phage and malnutrition in the developing world.
"We hope that our work will provide a framework to guide future investigations to elucidate the interplay between phage, the microbiota, and host health and disease," Gerber commented.
Source: Cell & Host Microbiome
Volume 25, Issue 6, Pages 803-814.E5, June 12 2019, doi: 10.1016/j.chom.2019.05.001
“Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model”
Authors: Bryan B. Hsu, et al