Sex-based gene differences emerge in Crohn’s recurrence

Male patients with Crohn’s disease have much larger changes in gene activity than female patients when the disease returns after surgery, according to the results of a transcriptomic analysis published in Gastroenterology.

Investigators examined ileal biopsy samples collected during routine postoperative colonoscopy to better understand why recurrence remains common despite biologic therapy. Crohn’s disease recurs in more than 70% of patients after ileal resection.

“A major challenge in Crohn’s treatment presently is the therapeutic ceiling, whereby initially effective agents frequently lose their response over time,” said study author Kyle Gettler, PhD, in an interview with GI & Hepatology News.

"Institution of new therapies with distinct mechanisms of action are often less effective than initially attempted mechanisms. Defining roles for multiple nuclear hormone pathways via bulk transcriptomics defines novel pathways for Crohn’s therapeutic targeting beyond pro-inflammatory cytokine blockade and JAK-level (i.e. immediately downstream of cytokine receptors) inhibition could lead to development of novel treatment that takes patient sex into account," said Dr. Gettler, of the Department of Pathology, Molecular, and Cell Based Medicine at Icahn School of Medicine at Mount Sinai, New York.

To compare patients with and without endoscopic recurrence defined by Rutgeerts scores, the researchers used RNA sequencing to analyze 339 neoterminal ileal biopsy samples from 267 patients. The cohort included 166 samples from female patients and 173 from male patients, with a median age of 33 years. Recurrence occurred in 25% of samples from female patients and 32% from male patients. About 40% of patients were receiving tumor necrosis factor inhibitors at the time of biopsy.

Serial sampling in 70 patients allowed researchers to track changes over time after surgery, similar to how patients are monitored in routine care.

Larger molecular shifts in male patients

Recurrence was linked to widespread changes in gene activity, with 4,171 genes showing higher activity and 3,579 showing lower activity compared with samples without recurrence.

Although the same general pathways were involved in both male and female patients, the degree of change was much greater in male patients. Specifically, 7037 genes showed changes in male patients compared with 545 in female patients.

“The strong impact of patient sex on the degree to which gene expression differed between recurrent and non-recurrent samples was surprising,” Dr. Gettler said. “Several prior studies had identified patient sex as a potential risk factor for recurrence, but the observed impact after stratifying by sex was striking.”

At the same time, similar gene patterns in male and female patients suggest that the same biomarkers could be used in both groups. A model based on genes from male patients was able to identify recurrence in female patients, supporting the potential clinical use of these markers.

Beyond inflammation: Hormonal pathways

Consistent with current practice, inflammatory pathways such as tumor necrosis factor and interferon gamma were activated in recurrence.

The analysis also found that hormone-related pathways were active, including those linked to estrogen and androgens, while progesterone-related signaling was reduced. According to the authors, these findings raise the possibility that some patients may not respond fully to cytokine-targeted therapies alone, and that future treatments could incorporate pathways related to hormone signaling or epithelial biology.

Implications for treatment response

Anti–tumor necrosis factor therapy had limited impact on overall gene expression patterns after accounting for recurrence status, although specific genes differed. For physicians, this reinforces a common clinical challenge: biologic therapy may not fully prevent recurrence, even when inflammation is targeted. The findings support ongoing reliance on postoperative endoscopic surveillance rather than assuming disease control based on treatment alone.

Tissue remodeling and ‘rectalization’

The investigators identified a shift in gene expression and RNA splicing patterns in recurrent disease toward those typically seen in rectal tissue, described as “rectalization.” This shift involved pathways related to lipid metabolism, membrane trafficking, and extracellular matrix remodeling.

These findings suggest that recurrence involves structural and epithelial changes in addition to inflammation. This may help explain why some patients develop strictures or complications despite therapy and highlights the need for early detection, noted the authors.

Genetic and risk stratification insights

Genetic analyses identified 829 variants influencing gene expression, with many showing opposite effects in male versus female patients. However, polygenic risk scores for Crohn’s disease were not associated with recurrence. This distinction is relevant for practice: tools that predict who develops Crohn’s disease may not predict who develops recurrence after surgery. Instead, analyzing tissue at follow-up exams may provide more useful information for guiding care.

The sex-related findings were replicated in an independent cohort and in pediatric patients with inflamed disease vs controls, indicating that the observed differences are consistent across populations.

The authors noted limitations of their analysis, including the use of bulk RNA sequencing, which limits cell-specific resolution, and the fact that most samples were collected after recurrence had already occurred.

Takeaway for practice

For clinicians, the results support continued vigilance with postoperative surveillance, highlight potential differences in disease biology between male and female patients, and point toward future use of molecular biomarkers to guide individualized management.

“This work identifies a striking difference in expression change related to sex,” Dr. Gettler said. “This both establishes an important role for nuclear hormone pathways in recurrence, but also suggests that patient sex will be an important covariate in future studies of IBD.”

This work was supported by computational resources at the Icahn School of Medicine at Mount Sinai and by grants from the National Institutes of Health, including the National Center for Advancing Translational Sciences and the Office of Research Infrastructure. The authors reported having no disclosures.