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Novel phage alters transcriptome of a common human gut microbe

September 16, 2020
By: Alisa King

The human gut is home to a dense and diverse microbial community that represents a vital component of human health, development, and disease states. Within those communities, phage-bacterial host interactions also shape the community and contribute to the constantly fluctuating landscape. However, phage-bacterial host interactions in the human gut have been largely underexplored. 

 Danielle Campbell
PhD student Danielle Campbell of the Whitaker Lab  

A new study led by PhD student Danielle Campbell and supervised by professor of microbiology Rachel Whitaker (IGOH leader/BCXT) reveals how a temperate phage — named BV01 — of the prominent human gut symbiont Bacteroides vulgatus (B. vulgatus) broadly alters its host’s transcriptome. Additionally, BV01 and its relatives were shown to represent a novel family of phages that are ubiquitous in human gut metagenomes, infecting a broad range of Bacteroides hosts. The study also included professor of animal sciences Jason Ridlon (MME), PhD student Lindsey Ly, professor of microbiology & plant pathology Ansel Hsiao (UC Riverside), and professor of microbiology & plant pathology Patrick Degnan (UC Riverside). Their findings were reported in Cell Reports

B. vulgatus is super common and abundant in the human gut and so that was really the motivation for trying to figure out how B. vulgatus maintains the dominance in so many humans on a molecular and genetic level,” said Campbell. “Once we found that this very common strain carries this integrated virus, we started to ask if this virus plays a role in how Bacteroides lives inside a human.”

Researchers were able to predict and annotate Bacteroides phage BV01 using computational tools and comparative genomics against the host genome. In a gnotobiotic mouse model where the microbial community was defined, BV01 was capable of infection, but existed in a largely repressed state in vitro. This led the researchers to hypothesize that lysogeny with BV01 could alter properties of the B. vulgatus host.  

Zoomed out view of B. vulgatus
Zoomed out view of B. vulgatus

“We've done a pretty good job in the last couple of decades of dissecting the microbiome but sampling the phages and other viruses from the gut is a little more difficult and includes a lot more biological dark matter,” said Campbell. “We know that viruses change the way their microbial hosts live in all sorts of systems and so we suspect that those sorts of things are also occurring in the gut.”

By employing a combination of genetics, transcriptomic analyses, and analytical chemistry, BV01 was shown to alter bile acid metabolism in B. vulgatus by decreasing its ability to deconjugate bile acids. Since microbially-modified bile acids are important signals for the mammalian host, this represents a mechanism by which phages may influence mammalian phenotypes.

“We don't know the full effects of B. vulgatus on the bile acid pool, but on a cellular level, we know that the epithelial cells that line the gut are constantly sensing bile acids,” said Campbell. “The bile acids are used as signals for metabolic function, nutrient transport across the epithelial barrier, and immune responses. Disentangling exactly how BV01 and B. vulgatus impact the bile acid pool in a natural gut environment would be difficult because there are thousands of bacteria altering bile acids, but in a simplified system containing one microbe and one virus, there is a very clear result.”

Construction of genomic trees from all identified Bacteroides-associated prophages led to the proposed novel viral family Salyersviridae, which was shown to be active in human-associated communities. In naming the phage, Campbell decided to honor the late Abigail Salyers, a former Arends Professor of Microbiology and pioneer of mobile genetic elements and antibiotic resistance in the human gut microbiome.

“A lot of people in phage and virus taxonomy name them after previous researchers who really built the space of knowledge that we all work upon,” said Campbell. “Abigail was really instrumental in not just Bacteroides research, but also mobile genetic elements. I just wanted to honor her even though she didn't work on phages, but in my eyes, phages are just another mobile genetic element.”

September 16, 2020
By: Alisa King
Photos By: Danielle Campbell

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