Seed grants to support microbiome research

A feature on our efforts to support research through pilot grants

When you look in the mirror, your gaze takes in a human form. Yet the human body is comprised of 10 times more microbial cells than human ones. These single-celled organisms inhabit our skin, mucous membranes, and gut, and while they can often promote health, they can also lead to disease.

To probe the sometimes-harmonious, sometimes-detrimental relationship between microbes and their human and animal hosts, in 2013, the School of Veterinary Medicine launched the Center for Host-Microbial Interactions (CHMI). The Center, headed by Christopher Hunter and Dan Beiting, offers training as well as logistical and financial support to faculty and students planning to use cutting-edge genomics to address pressing microbiological questions.

In December, the Center announced the latest round of pilot research projects, supported by a donation from Robert and Hope Sheft. These three studies, selected from a robust pool of 19 applications, will entail collaborative, creative research in the emerging world of “big data” in which whole genomes can be sequenced for just a few thousand dollars.

Dieter Schifferli, a professor of microbiology at Penn Vet, plans to use his grant funding to embark on a study of Salmonella—specifically the strains that can lead to potentially fatal sepsis.

“For many years, I have been a ‘wet lab’ type of researcher,” says Schifferli, “but the biological field is moving in the direction of genomics.”

Schifferli’s study will make use of the Vet School’s bank of roughly 50,000 strains of Salmonella. By fully sequencing strains selected from this collection, he will look at how differences in certain genes may explain why, for example, one strain is better at colonizing the intestine than another.

“Some strains of Salmonella can make a person sick for a few days, while others can lead to septicemic shock and death,” Schifferli says. “With this grant, we’re hoping to better understand what makes certain strains of Salmonella more aggressive.”

Narayan Avadhani, the Harriet Ellison Woodward Professor of Biochemistry at Penn Vet, is using the CHMI support to understand how the microbiome—the population of microbes living in a human or animal—influences alcoholic liver disease.

“In the U.S. and many other countries,” Avadhani says, “most liver disease arises from alcohol or drug-induced toxicity. Consequently, many labs, including ours, have focused on studying alcohol metabolism in the liver.”

Yet research by Avadhani and colleagues has suggested that the problem may begin in the intestines, before alcohol even reaches the liver. Gut bacteria break down a considerable amount of ingested alcohol into aldehyde, a reactive compound that is a major contributor to liver disease and cancer. Aldehyde damages the layer of cells that line the intestine, allowing bacterial signaling molecules and other inflammatory molecules to enter the bloodstream, inducing liver toxicity.

Avadhani’s lab will use a mouse model to study how the microbiome affects the degree to which alcohol promotes gut permeability and liver toxicity. He hopes the findings will translate to humans, explaining why some individuals are more prone to alcohol-induced toxicity and liver disease.

Thomas Schaer and Dipti Pitta, both researchers at Penn Vet’s New Bolton Center, co-lead the third CHMI pilot. Their work builds off scientific investigations that have pointed to associations between infections in the gums and infections in prosthetic joints, despite the connection between the two remaining unclear.

“We know that certain human patients have bacteria that are normally associated with gum disease in their knee cartilage,” Schaer says. “I started to become curious: Do we have something similar in other animal species?”

Schaer and Pitta will investigate the oral microbiomes of miniature pigs, which naturally develop gum disease much like humans do. They plan to characterize the “normal” oral microbiome and see what happens when this healthy flora goes awry by transferring bacteria from pigs with gum disease to the gums of young, healthy animals. They’ll also be looking to see if some of these oral pathogens crop up in the animals’ knee cartilage.

“We have to be cautious in how we interpret our data,” says Schaer, “but ultimately we’d like to try to find out if periodontal disease influences the course of cartilage degeneration, such as in osteoarthritis, following an injury.”

Beiting says one goal for these pilot projects is to help researchers leverage their findings into additional grant support. That’s precisely what happened for Penn Vet’s Tracy Bale, who recently won a significant NIH award to study the connection between a mother’s vaginal microbiome and her offspring’s brain development.

“The CHMI pilot award allowed us to fund the initial studies that produced key preliminary data for our NIH grant application,” says Bale. “And the CHMI as an entity was just as instrumental in [the NIH] being extremely excited about our proposal. They could easily see the serious investment that the school had made in this area, and that bolsters their confidence in the collaborative expertise we bring together for this work.”

© 2021. Dan Beiting. All rights reserved.