Researchers Transform Gut Bacteria into ‘Little Pharmacists’

By Irene Yeh 

April 8, 2025 | Oral drugs are considered an ideal delivery method for medications because of their noninvasive nature, but they face the challenge of passing through the acidic environment of the upper gastrointestinal (GI) tract. Specifically, the stomach acts as a barrier to anything biological, including oral drugs with biologic content. To overcome this obstacle, a team of researchers at Virginia Tech—led by Dr. Bryan Hsu, assistant professor of biological sciences, and in collaboration with Liwu Li, professor of biological sciences—engineered microbes called bacteriophages, or phages, to infect and reprogram gut bacterial cells to produce and release a sustained flow of a protein-based drug.  

“What we're doing is using bacteriophages to convince the bacteria that's infected to produce some other stuff, such as a protein,” explains Hsu. "It’s like a little pharmacist that is doling out drugs.” 

What Are Phages? 

Phages are viruses that naturally infect bacteria. Shaped like “spider aliens,” they contain DNA or RNA and use their legs to latch onto bacteria. They then inject their genetic material into the bacteria, reprogramming the bacteria to produce and release a flood of new phages. These new phages go on to infect more bacteria, and the cycle continues.  

Phages also coexist with bacteria in the gut microbiome, and it’s estimated that there are 10 times more phages than bacteria in our guts, according to Hsu. While it’s still unknown what the significance of these phages are, the team realized that they could take advantage of the phages’ self-amplifying abilities to increase the chances of absorption in the lower GI tract.  

The team used a phage called T4, which targets non-pathogenic but common Escherichia coli, and engineered it to induce the production of superfolder green fluorescent protein (sfGFP). First, they confirmed successful production of sfGFP by injecting mice with these T4 phages. “We saw a lot of fluorescence, and it was localized along the walls of the intestinal tract,” says Hsu. “Having it close to the mucosal lining is the key area where you want proteins to interact. We got a good amount of protein there.” In other words, the proteins were being expressed along the intestinal walls where absorption occurs.  

Next, they conducted some proof-of-concept studies. In the first experiment, they used T4 phage to produce serine protease inhibitor (serpin), a protein that can inhibit the effects of ulcerative colitis (UC), a type of inflammatory bowel disease. The results showed that T4 was able to release serpin in the guts of mice and help reduce the symptoms of UC (Nature Biotechnology, DOI: https://doi.org/10.1038/s41587-025-02570-7). In a second experiment, the team engineered T4 phage containing the protein ClpB, which can mimic satiety. Mice injected with this T4 experienced weight loss and reduced food consumption. 

Furthermore, they found that the phages lingered in the gut for several weeks. This finding shows that phages can induce sustained protein production over a long period of time. This is also beneficial because it gives patients the ability to produce proteins that would not normally be administered orally. 

Delivering the Goods, but Not Receiving Them 

The team has found an efficient way to deliver the phages to the gut, but the next step is to figure out how to get the body to accept them. The lower GI tract does not absorb any and every compound that enters it. Hsu brought up probiotic supplements as an example. Probiotics are usually touted as highly beneficial for the gut microbiome. However, they need to have a good shelf life and stay active, and when ingested, they need to survive the acidity of the upper GI tract to make it to the lower GI tract. Even if they do make it to the lower GI tract, they often face colonization resistance, which is when spaces in the gut are already crowded with other bacteria. As such, the probiotics get flushed out and cannot provide the benefits they are supposed to for the gut microbiome. 

“Getting high concentrations absorbed selectively, meaning the one that you want to absorb and not other stuff in the background, is pretty difficult,” comments Hsu about the delivery of proteins. However, the propagation effect of the phages provides an advantage, and the study results gave hope for a more efficient method of increasing absorption in the gut.  

Another challenge the team is facing is getting clinical trials started, but as many of us are familiar with, trial processes can take years, even decades, to complete. “That’s also a very hard problem.” 

Hsu and his team are now looking into starting a company to make the phages commercially available. The hope is to provide patients with a single dose of some phages that could help with their gut health issues.