STOCKHOLM — Severe infections requiring hospital treatment were associated with amore than threefold increase in risk for inflammatory bowel disease (IBD) in a prospective cohort study that used data from the UK Biobank. In addition, the association was strongly modified by an individual’s immune-related genetics, and the risk remained elevated for up to a decade.

“Survival is not always the end of the story after severe infection,” said Lintao Dan, MD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, who presented the study here at the European Crohn’s and Colitis Organisation Congress (ECCO) 2026.

“Our results suggest that, in some individuals, infection leaves a long-lasting imprint on the immune system that may contribute to the development of IBD many years later.”

Based on the findings, the researchers proposed a “two-hit” model of pathogenesis.

“The first hit is a latent immune-related genetic susceptibility that remains clinically silent,” Dan explained. “The second hit is a severe infection that triggers widespread immune activation. Most people recover fully [from severe infection], but in genetically susceptible individuals, immune resolution fails, leading to persistent inflammation and, ultimately, IBD.”

Beyond the Acute Phase of Infection

Advances in critical care mean that more patients survive serious infections than ever before; however, growing evidence from conditions such as long COVID suggests that infections can have persistent effects on immune regulation and long-term health, Dan noted.

“Traditionally, infection has been viewed as a complication of IBD,” he added. “But accumulating data suggest the reverse may also be true, that certain infections could play a causal role in triggering disease. Experimental models suggest infection can directly trigger intestinal inflammation.”

In order to investigate the link between severe infection and long-term IBD risk, including which patients are most vulnerable, Dan and his colleagues examined whether hospital-treated infections were associated with subsequent IBD risk and if immune-related genetic variants modified that association.

Persistent Risk

The analysis included 359,636 UK Biobank participants with no prior diagnosis of IBD at baseline. Participants were followed for a mean of 12.1 years after their first recorded hospital-treated infection.

Over 900 infectious diseases were captured using inpatient and primary care data and classified by pathogen type (bacterial, viral, fungal, or parasitic) and anatomical site. Incident diagnoses of IBD, Crohn’s disease (CD), and ulcerative colitis (UC) were identified using linked health records.

Using Cox proportional hazards models adjusted for potential confounders, the investigators found that hospital-treated infection was associated with more than a threefold increase in IBD risk (adjusted hazard ratio [aHR], 3.44; 95% CI, 3.14-3.77), with a stronger association seen in CD than in UC.

“These are not trivial differences,” Dan noted. “They suggest that infection history could be an important but underrecognized risk marker.”

And, he added, “This elevated risk was not transient; it remained significantly increased for up to 10 years after infection.”

The increased risk was observed across all major pathogen categories and seven anatomical infection sites (including neurologic, heart, respiratory, genitourinary, gastrointestinal, bone, and bloodstream), suggesting that the relationship was not driven by a single organism or organ system.

“The consistency across infection types points to severe infection itself and the immune disruption it causes, rather than a specific pathogen,” said Dan.

Genetics Modify Postinfection Risk

The team then examined whether host genetics influenced susceptibility to postinfection IBD. Genetic analyses were conducted in 350,829 participants with available whole-genome sequencing data, focusing on 51 immune-related genes selected a priori.

Of these, 44 genes showed significant gene-infection interactions, modifying IBD risk following infection. These included genes previously implicated in IBD pathogenesis, such as IL12B, IRGM, MAP3K8, and CCL20, with some variants showing disease-specific effects for CD or UC.

Using these data, the researchers then generated an Infection IBD Score. The Infection IBD Score was designed to capture context-specific genetic risk, rather than baseline susceptibility alone.

“The score captures infection-activated genetic susceptibility and enables robust postinfection risk stratification,” explained Dan.

Cluster analyses based on these immune-related genes identified genetically distinct subgroups, one of which showed a significantly higher risk for IBD and UC after infection.

Among participants with a history of hospital-treated infection, the Infection IBD Score showed a clear risk gradient. Compared with individuals with low scores, those in the highest score group had a more than sixfold increased risk for IBD (aHR, 6.35; 95% CI, 4.83-8.35), while those in the low-score group had a more modest increase (aHR, 3.15; 95% CI, 2.86-3.48).

“What matters most is not just genetic risk in general, but genetic risk in the context of immune stress,” said Dan.

“In most people, immune homeostasis is restored,” he explained. “But in susceptible individuals, resolution is incomplete, leading to persistent inflammation and, eventually, IBD.”

The findings provide proof of concept but raise the possibility that infection history, combined with genetic profiling, could one day be used for risk stratification, earlier monitoring, or preventive strategies in high-risk individuals.

Is Infection Just Preclinical IBD?

“Could these infections reflect preclinical IBD rather than acting as true triggers?” asked session co-moderator Laurent Beaugerie, MD, gastroenterologist from Hôpital Saint-Antoine, Paris, France.

“That’s an important question. We examined different infection types, including bacterial and parasitic infections, and found consistent associations across categories. This suggests a shared immune-mediated mechanism rather than undiagnosed preclinical IBD alone,” replied Dan.

Beaugerie continued: “How do you envision clinical use of your genetic score?”

Dan acknowledged that the score is “not yet ready for clinical use.” It’s “based on a defined set of immune-related genes validated using proteomic data and external datasets,” he explained, adding that “it provides proof of principle that context-specific genetic risk prediction is possible.”

Commenting on the broader implications, Dan said the work adds to a growing body of evidence that environmental immune stressors play a central role in IBD development.

“Our hope is that by understanding how infections interact with host genetics, we can move toward earlier identification of people at risk — and eventually, prevention,” he said.

Dan declared having no relevant disclosures. Beaugerie disclosed receiving grants from Biogen, Takeda, Ferring, Celltrion, and Viatris, and personal fees from Takeda, Janssen, Nordic Pharma, Gilead, Bristol Myers Squibb, and Viatris.