Philadelphia, September 3, 2026 – Practically since its discovery, the highly contagious bacterium Clostridioides difficile (C. difficile or C. diff) has been reported to not cause symptoms in infants and thus assumed that colonization was not a serious health issue. In a new study, researchers at Children's Hospital of Philadelphia (CHOP) are challenging that long-held assumption, with new findings suggesting that the bacterium can reshape the developing infant gut and may have long-term consequences. The findings were published today in the journal Science.
C. difficile is a serious bacterial pathogen that causes infection with symptoms ranging from diarrhea to deadly colonic inflammation caused by the production of toxins. It spreads quickly via its hard-to-kill spores and commonly infects vulnerable populations, including the elderly, those taking antibiotics, and often, patients in hospitals or nursing homes. Around half a million patients are infected in the US annually, resulting in approximately 30,000 fatal cases.
However, one surprising population always seemed to be resistant to the damaging effects of the bacterium: infants. An estimated 40–90% of infants in industrialized countries are colonized with C. diff without the bacterium producing obvious symptoms. "For decades, C. diff colonization in infants has been assumed to be harmless. But we asked: does asymptomatic really mean inconsequential? Could a toxin-producing pathogen actually be reshaping the developing gut without causing obvious symptoms?" said senior study author Joseph Zackular, PhD , a researcher in the Department of Pathology and Laboratory Medicine and Co-Director of the Center for Microbial Medicine at CHOP."
In this study, researchers used a combination of preclinical models, human infant intestinal biopsies, and lab grown organoids – lab-grown mini-intestines made from human tissue that can be studied outside of the body – to study the effects of C. diff colonization early in life.
The study found that the presence of C. diff in an otherwise healthy preclinical neonatal model led to a remodeling of the developing epithelium – the important layer of cells lining the gut – and a reshaping of the mucosal immune system. These effects were observed long into adulthood and increased the risk of some viral infections, suggesting that a C. diff colonization in infants may have a potential long-term effect on health. The impact of C. diff on the developing epithelial layer was also observed in human infants colonized with C. diff. This means that an early life exposure to C. diff, although seemingly benign, could have profound effects on healthy development of the gut.
"The infant gut epithelium is still building itself, so C. diff doesn't just injure it; it can alter the developmental trajectory of the tissue in ways that may last into adulthood," said study co-author Kathryn Hamilton, PhD , a researcher in the Department of Pediatrics and Co-Director of the Gastrointestinal Epithelium Modeling (GEM) Program at CHOP.
While these findings suggest C. diff can have a lasting impact on development, the long-term consequences of these effects need to be studied in more detail. With these findings challenging long-held assumptions, there is enthusiasm to explore whether this exposure can increase the risk of developing metabolic or autoimmune disorders. The study also points to a clear path forward. Much like maternal vaccines already in clinical use to protect newborns against RSV and pertussis, immunizing mothers with a vaccine targeting C. diff shielded neonates from toxin-mediated effects on the developing gut. This shows that a maternal vaccination strategy could be a precise and feasible intervention to protect infants from C. diff during this critical developmental window.
"Our findings challenge a long-held assumption in pediatric medicine: that C. diff colonization in infants is benign," Zackular said. "We show that even without overt disease, exposure to this toxin-producing pathogen leaves a lasting biological imprint on the developing gut and immune system, and that a maternal vaccine can protect against it."
This study was supported by the Center for Microbial Medicine at Children's Hospital of Philadelphia, the National Institutes of Health grants R35GM138369, 5T32AI141393, R01DK107565, R37AI095755, R01DK133453, CHOP Gastrointestinal Epithelium Modeling (GEM) Program and Core (RRID:SCR_026402), H-MARC Core for the Center for Molecular Studies in Digestive and Liver Diseases grant P30DK050306, Penn Center for Nutritional Science and Medicine, PennCHOP Microbiome Program, PennCHOP Microbiome Chappel Culpeper Fellowship, Howard Hughes Medical Institute Hanna H. Gray finalist award, Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award 1356736, Burroughs Wellcome Fund PDEP Award 1463880, CHOP SPAR Fellowship, CHOP Bridge to Faculty Program, Chappell Culpeper Family Foundation Fellowship, Abramson Cancer Center Support Grant (NIH P30 CA016520), NIH Shared Instrumentation Grant (S10 OD023465-01A1), Penn Center for Molecular Studies in Digestive and Liver Diseases (NIH P30 DK050306), Penn Vet IIZD Core pilot grant opportunity 2022, Donation from the American Beverage Foundation for a Healthy America to the Children's Hospital of Philadelphia to support the Healthy Weight Program, and a NIH National Center for Research Resources Clinical and Translational Science Program (UL1TR001878).
Semon and Manzer et al, "Early-life colonization with Clostridioides difficile remodels the developing gut." Science. Online September 3, 2026. DOI: 10.1126/science.ady2886.
About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network , which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania, New Jersey, and Delaware. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare
