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Yingzi Cong, PhD, the Stanley Gradowski Professor of Gastroenterology and a professor of Microbiology-Immunology and of Pathology, was senior and co-corresponding author of the study.

The researchers say the results support the idea that beneficial compounds made by gut microbes can effectively “train” the intestinal lining, helping it preserve immune tolerance over time.

“Our laboratory has long been interested in how the gut microbiota regulates immune responses at intestinal mucosal surfaces,” said first and co-corresponding author of the study Tianming Yu, PhD, research assistant professor of Medicine in the Division of Gastroenterology and Hepatology. “Short-chain fatty acids (SCFAs), which are produced by gut bacteria during the fermentation of dietary fiber, are known to have anti-inflammatory effects in the intestine.”

How Butyrate May Influence Gut Immunity

One major question, however, has remained unresolved, Yu said.

“A large proportion of butyrate in the gut is rapidly absorbed and metabolized by intestinal epithelial cells (IECs), which limits the amount of free butyrate that can directly reach underlying immune cells,” Yu said. “This led us to ask whether butyrate might act through IECs to regulate intestinal immunity.”

To investigate, the researchers supplied mice with butyrate in their drinking water for a set period and then ended the treatment. Two weeks after the butyrate had been withdrawn, CD4+ T-cells were still producing elevated levels of IL-10, an important anti-inflammatory cytokine that helps control intestinal inflammation.

The treated mice were also more resistant to chemically induced colitis. Compared with untreated animals, they lost less weight, had lower levels of inflammatory markers, and developed less severe tissue damage. According to the study, this protection depended on IL-10 signaling.

The researchers also determined that the lasting effect did not result from changes to the gut microbiome itself. In experiments involving germ-free mice, which lack all microbes, butyrate still created a persistent immune-regulating environment.

“We found that oral butyrate treatment induces a sustained immunoregulatory response in the intestine, characterized by increased IL-10 production in CD4+ T-cells and protection from intestinal inflammation even after butyrate treatment is stopped,” Yu said. “This effect was also observed in germ-free mice, suggesting that butyrate can establish a lasting intestinal environment that does not depend on continuous microbial stimulation.”

Intestinal Cells May Store a Lasting Biological Signal

Yu and his colleagues next focused on intestinal epithelial cells (IECs), which form the physical boundary between the body and the microbiome. In laboratory experiments, epithelial cells exposed to butyrate caused a strong increase in IL-10 production in both mouse and human T-cells.

“We further found that conditioned medium from butyrate-treated IECs strongly induced IL-10-producing CD4+ T-cells in both mouse and human T-cell culture systems,” Yu said. “These findings suggest that IECs secrete some immunoregulatory factors after butyrate treatment, and these factors can act on T-cells.”

The team then used metabolomic analysis to search for molecules that might be carrying this signal. One likely candidate was N1-acetylspermidine. The compound increased IL-10 production in T-cells and appeared to account for part of the immune-regulating activity generated by epithelial cells exposed to butyrate, Yu said.

“Mechanistically, we found that butyrate acts on IECs and induces sustained transcriptional and epigenetic activation of Sat1, an acetylpolyamine biosynthetic enzyme,” Yu said. “This promotes production of the metabolite N1-acetylspermidine, which contributes to the ability of butyrate-treated IEC-conditioned medium to induce IL-10 production in CD4⁺ T-cells.”

The results challenge the traditional idea that intestinal epithelial cells are primarily temporary responders whose main role is to serve as a barrier. Instead, the findings suggest that these cells may retain a longer-lasting molecular record of beneficial signals from the microbiome.

“The significance of this work is that it identifies a mechanism by which a microbiota-derived metabolite can create durable epithelial T-cell crosstalk,” Yu said. “The intestinal epithelium is often viewed as a short-lived barrier that responds rapidly to luminal stimuli. Our findings suggest that it can also retain a lasting imprint of a microbial metabolite signal. The study also introduces the idea that beneficial microbial metabolites may ‘train’ the IECs to maintain immune tolerance over time.”

Potential Implications for Inflammatory Bowel Disease

More research will be necessary to confirm the findings and determine whether the same mechanism operates in people, but Yu said the work could eventually have implications for inflammatory bowel disease.

“One important next step is to determine how this epithelial metabolic pathway operates in human intestinal disease, especially in patients with inflammatory bowel disease,” Yu said. “We are interested in testing whether the butyrate-Sat1-N1-acetylspermidine pathway is altered in human IECs and whether it correlates with immune regulation or disease activity.”

The researchers also intend to investigate other metabolites that may contribute to the effect. N1-acetylspermidine by itself did not fully account for all of the immune-regulating activity observed in the experiments.

Over the longer term, Yu said the findings may expand scientists’ understanding of the relationship among diet, metabolites produced by gut microbes and the intestinal lining.

“Many studies have focused on how inflammation can leave harmful memory in epithelial cells, but our findings suggest that beneficial microbial metabolites may also establish protective epithelial programs,” he said. “Understanding how diet, microbiota-derived metabolites and inflammation shape intestinal epithelial memory could open new directions for restoring intestinal immune tolerance in inflammatory bowel disease.”

Wenjing Yang, MD, PhD, research assistant professor of Medicine in the Division of Gastroenterology and Hepatology, was co-first author of the study.

Additional Feinberg co-authors include Suxia Yao, MD, research associate professor of Medicine in the Division of Gastroenterology and Hepatology; and Parambir Dulai, MD, associate professor of Medicine in the Division of Gastroenterology and Hepatology.

Cong, Yu, Yang, Yao, and Dulai are members of the Center for Human Immunobiology.

The study was supported by National Institutes of Health grants DK135193, DK124132 and DK145439.

Researchers at the University of Chicago have now developed a new approach that could help overcome this problem. In a study published in Science Advances, the team used BifidoSumIL-2, an engineered strain of Bifidobacterium longum, a probiotic bacterium naturally found in the gut, to carry an immune-stimulating treatment directly into tumors.

In animal models, the therapy slowed the growth of pancreatic tumors by selectively activating T cells that fight cancer. Its effects became even stronger when researchers combined it with chemotherapy, radiotherapy or immunotherapy. The findings suggest that BifidoSumIL-2 could eventually provide a new way to improve how pancreatic tumors respond to treatment.

Using Bacteria to Deliver Cancer Therapy

“A big unmet medical need has been pancreatic cancer, and so that was going to be our mountain to climb,” said Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at the University of Chicago.

BifidoSumIL-2 was created to release a modified version of interleukin-2 (IL-2) once it reaches a tumor. IL-2 is a potent immune signaling molecule that activates T cells involved in attacking cancer. Conventional IL-2 treatment, however, can produce serious side effects and can also stimulate immune cells that actually weaken the antitumor response.

The researchers sought to avoid these problems by using SumIL-2, a modified form of IL-2 engineered to more precisely activate cancer-fighting T cells while reducing stimulation of regulatory T cells. They then placed SumIL-2 inside Bifidobacterium longum so that the therapeutic molecule could be concentrated within tumors instead of throughout the body.

Developing the treatment required scientists from several disciplines to work together, including specialists in microbiology, synthetic biology, oncology, and immunology.

“This was a highly interdisciplinary effort,” said Mark Mimee, PhD, Assistant Professor of Microbiology at the University of Chicago. “We had to bring together people who understand bacteria, people who understand tumors, and people who understand the immune system to make something like this possible.”

Why Bifidobacterium Can Target Tumors

Bifidobacterium offered the researchers an unusual advantage as a delivery system. The bacterium grows in anaerobic environments, meaning places with very little oxygen. Low oxygen levels are common inside many solid tumors, including pancreatic tumors, while healthy tissues generally contain more oxygen and are therefore less suitable for the bacteria.

“Bifidobacterium is an obligate anaerobe, so it doesn’t grow in the presence of oxygen,” Mimee said. When the bacteria are injected systemically, they are cleared from healthy tissues with abundant oxygen. Inside the low-oxygen regions of tumors, however, they can become active.

That preference allows the engineered bacteria to function as microscopic drug factories inside tumors. Once there, they produce SumIL-2 where the treatment is needed rather than broadly throughout the body. Researchers also noted that Bifidobacterium has shown a favorable safety profile in preclinical models and is already well known as a probiotic organism. It is commonly present in yogurt and is generally recognized as a safe, off-the-shelf probiotic.

Engineering the organism was not simple.

“Bifidobacterium is not the easiest organism to work with,” Mimee said. “It’s anaerobic, it grows slowly, and the genetic tools for manipulating it are much more limited compared to model bacteria like E. coli. A lot of the work was just figuring out how to reliably engineer it.”

Stronger Results With Combination Treatments

Tests in animal models showed that BifidoSumIL-2 preferentially gathered inside tumors, stimulated immune activity, and slowed the growth of pancreatic cancer. It also changed the tumor microenvironment in a potentially beneficial way by increasing the activity of cancer-fighting CD8+ T cells.

The results improved further when BifidoSumIL-2 was paired with established cancer treatments. Combining the bacterial therapy with chemotherapy, radiation therapy, or anti-PD-L1 immunotherapy led to better tumor control and longer survival than the individual treatments achieved on their own.

“This combination potential is one of the study’s most important findings; BifidoSumIL-2 not only works by itself — it works with radiotherapy, chemotherapy, and immunotherapy,” Weichselbaum said.

Despite the encouraging findings, BifidoSumIL-2 has not been tested in humans. Future research will need to examine its long-term safety, the possibility of effects outside the intended tumor, how long the immune response lasts, and whether the bacteria might eventually be given orally instead of through injection. The researchers also want to investigate whether the strategy can be combined with newer pancreatic cancer treatments, including KRAS inhibitors.

The Growing “Bugs as Drugs” Approach

The research adds to growing interest in a strategy known as “bugs as drugs.” By engineering probiotic bacteria to seek out tumors and produce therapies directly inside them, scientists may be able to concentrate powerful immune treatments where they are most useful while reducing unwanted effects elsewhere in the body.

The study, “Engineered probiotic Bifidobacterium for tumor-targeted pancreatic cancer therapy” was supported by funds from the Ludwig Foundation and the National Institutes of Health.

Additional authors include Jaehyun Lee, Kaiting Yang, Christina Nowicki, Wei Liu, Emile Naccasha, and Hua Liang from the University of Chicago; Zhichen Sun from the University of Texas Southwestern, Dallas; and Yang-Xin Fu from Tsinghua University, Beijing, China.

UChicago Medicine and the Biological Sciences Division continue to be at the forefront of cancer care and research. In April 2027, UChicago Medicine will open the AbbVie Foundation Cancer Pavilion, Chicago’s first freestanding cancer pavilion, to bring advanced diagnostics, innovative treatments, translational discoveries, and comprehensive support to patients and the community.