Исследование показало, что заселение кишечника младенцев бактерией C. difficile вызывает необратимые изменения в развитии организма

A new study from researchers at Children’s Hospital of Philadelphia (CHOP) is challenging the assumption that Clostridioides difficile ( C difficile ) poses no health risk to infants after colonization. Its findings suggest that the bacterium can reshape the developing infant gut and may have long-term consequences, the authors reported in a study published in Science. “For decades, C difficile colonization in infants has been assumed to be harmless,” said senior study author Joseph Zackular, PhD, a researcher in the Department of Pathology and Laboratory Medicine and codirector of the Center for Microbial Medicine at CHOP. “But we asked: does asymptomatic really mean inconsequential? Could a toxin-producing pathogen actually be reshaping the developing gut without causing obvious symptoms?” C difficile is known to cause severe gastrointestinal disease in adults, infecting 500,000 US adults annually and resulting in approximately 30,000 deaths. Infants, however, have been thought to be resistant to serious infection. In previous studies, C difficile was found to colonize between 40% and 70% of infants without symptoms, according to the study authors. The consequences of early-life colonization have remained unknown and assumed to be benign.  Using various preclinical models, infant intestinal biopsies, lab-grown intestines made from human tissue, and analytical methods, the researchers investigated whether early-life exposure to C difficile impacts neonatal gut development and leaves lasting consequences into adulthood.  Study Methods Among infants born in Philadelphia, C difficile has been shown to colonize 28.2% of human infants within their first month of life and nearly 75% by age 2 years. Although these infants remain asymptomatic, genomic analysis showed their strains carry active toxin genes identical to those that cause severe adult infections.  A geographic comparative analysis showed that C difficile is significantly more prevalent in infants from industrialized communities and areas. The researchers noted that this may suggest the pathogen is underacknowledged as an environmental factor associated with industrialization, which can permanently alter early-life gut development. To mimic human infant colonization of the pathogen and its potential long-term consequences, the researchers established an antibiotic-free neonatal mouse model. Mice were orally inoculated with C difficile spores at 100 times the lethal dose for an adult mouse. To evaluate cellular and genetic mechanisms, the researchers then isolated intestinal epithelial cells (IECs) and extracted them from infected neonates at postnatal day 14 for bulk RNA sequencing. The researchers also isolated intestinal stem cells (ISCs) to evaluate colonic organoid-forming efficiency (OFE) and growth behavior. Additionally, a maternal vaccination strategy was developed and tested to assess whether passive immunization could protect the neonatal gut microbiota from potential pathogen-mediated damage. “Our findings challenge a long-held assumption in pediatric medicine: that C difficile colonization in infants is benign,” Dr 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.” The Results Despite the high inoculation dose, the neonatal mice remained fully protected against morbidity and mortality. The researchers found that genetically altered neonates completely lacking B and T cells remained fully protected from C difficile -associated death. They also determined that inoculating neonatal mice with C difficile does not significantly change the natural composition or succession of their developing early-life gut microbiota. However, when the toxin was injected directly into the mouse neonates’ bloodstream, it resulted in 100% mortality, indicating that resistance is tied to mechanisms restricted to the gut. In the absence of visible disease symptoms or tissue destruction, C difficile colonization triggered an inflammatory and tissue repair response in neonatal IECs, the researchers found. This response actively alters stem cell behavior, forcing the gut to permanently favor the creation of secretory cells. In turn, this leads to a lifelong expansion of mucus-producing goblet cells and a reduction in innate lymphoid cells that persist into adulthood after the bacteria have cleared. Consequently, adult mice colonized as infants suffered from a significantly higher viral burden when later exposed to an enteric virus. We demonstrate that even in the absence of clinical disease, colonization with toxigenic C difficile reshapes ISC function in neonatal mice and human infants, resulting in persistent alterations to the intestinal epithelium and immune system. After administering a multivalent mRNA-lipid nanoparticle vaccine to maternal mice,  protective antibodies were successfully transferred to the neonates through stomach contents and stools. Although bacterial load did not change, the vaccine reduced fecal toxin titers, protecting cell viability and allowing for normal stem cell development. Through isolated human tissue testing, the researchers confirmed that human infant intestinal cells are highly sensitive to C difficile toxins. Furthermore, ISC organoids derived from colonized human infants mirrored the cellular changes seen in the mouse models.  Reframing the Narrative The study results reframe how clinicians should view C difficile colonization in infants. “We demonstrate that even in the absence of clinical disease, colonization with toxigenic C difficile reshapes ISC function in neonatal mice and human infants, resulting in persistent alterations to the intestinal epithelium and immune system,” the authors wrote.  C difficile colonization was also more prevalent among infants from industrialized communities, the authors emphasized, “raising the possibility that exposure to this pathogen represents an underappreciated environmental factor influencing host development.”  “Finally, the extent to which the timing of colonization, its duration, and strain-level variation in toxin production modulate these effects also remains to be determined,” the authors wrote. References: Semon A, Manzer HS, Keenan O, et al. Early-life colonization with Clostridioides difficile remodels the developing gut. Science. 2026;386(6812):1045-1052. doi:10.1126/science.ady2886 Children’s Hospital of Philadelphia researchers find C. difficile colonization in infants reshapes gut development. EurekAlert!. Published September 3, 2026. Accessed September 4, 2026. https://www.eurekalert.org/news-releases/1141818