Salmonella infection is a common bacterial disease affecting the intestinal tract, which usually spreads from raw or undercooked poultry, eggs, or meat, contaminated water, or contact with animals. The infection affects up to 5,000 people a year, especially infants and young children, adults over 65, and people of all ages with weakened immune systems.
Now, in a breakthrough study at the Hebrew University of Jerusalem and the Weizmann Institute of Science in Rehovot, researchers have found that stem cells in the gut actively defend the body against this dangerous bacterial infection. They identified a previously unrecognized protective mechanism in the intestine in which intestinal stem cells can actively respond to Salmonella infection and help safeguard the gut from bacterial invasion.
Intestinal stem cells are responsible for continuously renewing the intestinal lining and maintaining a barrier against pathogens. Until now, these cells were largely considered passive participants during infection, relying on surrounding immune and epithelial cells for protection.
The findings of the new study have been published in the prestigious journal Nature Immunology. The study was led by Sacha Lebon, a doctoral student at Hebrew University, under the supervision of Dr. Matan Hofree of the university’s Benin School of Computer Science and Engineering, and the Lautenberg Center for Immunology and Cancer, and Dr. Moshe Biton, an immunology and regenerative biology researcher at the Weizmann Institute.
The two scientists met while doing post-doctoral research at Harvard University. In 2019, Biton opened his Weizmann lab to explore gut tissue pathologies and homeostasis (the self-regulating process by which biological systems maintain internal stability while adjusting to changing external conditions). During his postdoctoral studies, he successfully characterized epithelial cells in the small intestine of a mouse model and discovered substantial diversity among them. He went on to discover a new cell type in the airway that is the main source of the gene that causes cystic fibrosis.
Study mapped early responses to Salmonella
In 2022, Hofree opened his own lab at Hebrew University, conducting research in computational biology, machine learning, gene expression, and systems biology. Working together, they discovered that intestinal stem cells actively defend the gut against infections like Salmonella by sensing bacteria and triggering localized immune responses.
“Our most important discovery was the active role stem cells of the gut have in responding to these pathogens,” Hofree told The Jerusalem Post. “We also see a similarity in gene expression between stem cells infected with Salmonella and stem cells in Crohn’s disease and more broadly in irritable bowel disease (IBD) in general.”
The cell dynamics of intestinal mucosal tissue can be studied to better understand why healthy tissue malfunctions. The great variety of cell types that live in the gut carry out a variety of tasks in the intestine to maintain tissue health. When its balance is disrupted, several pathologies can arise, among them IBD, allergies, and cancer.
Until recently, scientists have had a limited understanding of cell mechanics and gene expression. But advances in the field, such as single-cell RNA sequencing – a method that can identify patterns of gene expression – have made it possible for researchers to learn how different cells function and communicate, and how these cell interactions cause disease.
Using these advanced experimental techniques, the Biton and Hofree team found that stem cells in the intestine can sense Salmonella bacteria and activate an inflammasome-dependent response (a specialized, fast-acting branch of the innate immune system that acts as a sensor for cellular danger).
Following infection, the stem cells quickly differentiate into specialized Paneth cells – specialized secretory epithelial cells that are “guardians” of intestinal health – located in the base of glands in the intestine’s tiny, finger-like projections called villi that line the small intestine and absorb nutrients.
“Our findings show that intestinal stem cells are not only responsible for tissue regeneration, but they also participate directly in the early defense against bacterial infection,” Hofree said.
Using single-cell RNA sequencing and other techniques, the team mapped the early epithelial response to Salmonella infection. The single-cell layer forming the innermost lining of the small and large intestines doesn’t just passively allow invasion; it undergoes dramatic reorganization and triggers powerful defense mechanisms.
“Our results suggest that stem-cell differentiation is part of an intrinsic protective program that helps preserve intestinal function during infection,” Biton added.
Prior work has shown chronic inflammation in Crohn’s disease, a type of inflammatory bowel disease that is linked to a persistent or misguided activation of the gut’s emergency defense mechanism. This protective, Salmonella-induced signature is also found in the intestines of Crohn’s patients, even without active Salmonella infection. The epithelium is stuck in a state of chronic, active defense against an assumed infection, resulting in inflammation.
The nearly 30,000 Israeli patients suffering from Crohn’s disease show high expression of this specific infection-linked gene signature, particularly in stem cells, suggesting that the genetic or environmental susceptibility in Crohn’s mirrors cellular changes caused by bacterial infection. The inflammation may stem from a broken epithelial barrier. The researchers believe that the shared stem cell signature might be informative in identifying specific IBD subtypes.
For patients with Crohn’s or chronic gut inflammation, the findings from this collaborative study offer major implications for future diagnosis, prevention, and treatment, the researchers said. Crohn’s patients appear to express a similar “infection-like” signature even without an active Salmonella infection.
“We wanted simple explanations for such diseases. But it’s complex. Half of the risk is genetic, but no single gene has been discovered as the root cause; the rest is the environment,” Hofree noted. “In future studies, we plan to explore the influence of exposure to other kinds of bacteria and examine potential links to other chronic diseases.”
Salmonella infection symptoms include diarrhea, fever, nausea, vomiting, headache, and stomach cramps within three days of exposure. While it often passes by itself in up to a week, severe dehydration and other very unpleasant symptoms may require medical attention.
It spreads through fecal-oral transmission; inadequate washing of the hands after using the bathroom or touching animals can spread it.
Even pets such as turtles, lizards, chickens, and hedgehogs can carry the bacteria. Antibiotics may be given for severe cases or high-risk individuals.
The annual incidence in Israel – between 21 and 53 Salmonella infection cases per 100,000 people – is higher than the rates reported in the US and the EU. Most occur during the summer months when warmer temperatures promote bacterial growth.
To avoid becoming infected with the bacteria, make sure eggs are fully cooked (hard-boiled); always store eggs in the refrigerator; and refrain from eating foods containing raw or undercooked eggs, such as homemade mayonnaise and certain mousses.