Tag Archives: Crohn’s disease

Elegant Study: Childhood Exposure to a Sibling with Crohn’s Disease and Disease Susceptibility

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R Chen et al. Gut. Epub ahead of print, August 31, 2026. doi:10.1136/
gutjnl-2026-339257. Childhood exposure to a sibling with Crohn’s disease alters gut microbiome and Crohn’s disease susceptibility

Thanks to Mike Hart for sharing this reference. This study is worth reading in its entirety due to the combination of experiments. This is a fairly long post to summarize the most important findings.

Background:

“In a study of 2756 Dutch families, gut microbiome composition and function were more alike between siblings than between parent-offspring pairs or spouses…These findings suggest that increased disease susceptibility among siblings of individuals with CD may be mediated by their shared gut microbiome.”

Methods:

  1. The authors used the prospective Genetic Environmental Microbial (GEM) Project and the nationwide South Korean database to assess the association between childhood exposure to affected siblings and CD onset (n=3126). This was validated in the South Korean dataset.
  2. A T-cell transfer model of colitis in germ-free mice was conducted to investigate the effects of stool from childhood-exposed (n=4) versus adult-exposed (n=4) siblings.
  3. An integrative risk model combining faecal calprotectin (FCP) and microbial enterotypes was trained and internally validated within the GEM cohort.

Key findings:

  • “In the GEM cohort, childhood exposure to an affected sibling was associated with a fourfold higher risk of developing CD compared with adult exposure (adjusted HR (aHR) 4.00; p=5.3×10−4), which was validated in the South Korean dataset (aHR 2.54; p=6.0×10−6).”
  • “Childhood exposure was associated with reduced abundances of Lachnospira,
    Roseburia     and Colidextribacter, reductions that mediation analysis identified as partially mediating CD risk.”
  • “In vivo, transplantation of childhood exposure-associated microbiota into germ-free recipient mice exacerbated colitis and elevated mucosal interleukin-22 expression, supporting a potential mechanistic role.”
  • This “model identified siblings with elevated FCP and Blautia-enriched or
    Prevotella-enriched enterotypes as highest risk, with a 10-year cumulative incidence of 22.5%.”
Figure 1b. Childhood exposure to CD was demonstrated to associate with increased disease susceptibility in the GEM cohort, and confirmed in an independent nationwide dataset.
Figure 1d. Among siblings with childhood exposure to CD, the authors developed and validated a risk stratification based on gut inflammation and enterotypes to identify individuals at high risk of CD onset
Figure 3a. Bar chart presenting the proportion of individuals with gut barrier dysfunction and gut inflammation among those exposed to CD during childhood (blue) or adulthood (orange).
Figure 5d. Kaplan-Meier curves showing the cumulative CD-free probability for individuals classified as having non-inflammation (blue), gut inflammation with Bact2 (green) and gut inflammation with Blau/Prev (orange) in the GEM cohort.

Discussion

  • This “study demonstrates that the timing of exposure to a sibling with CD, specifically childhood versus adult exposure, plays a critical role in disease susceptibility. Childhood exposure was associated with a fourfold higher risk of CD, potentially mediated by alterations in the gut microbiome.”
  • “Genetic predisposition has traditionally been considered the primary explanation for the elevated disease risk among siblings of persons with CD. However, genetic factors account for only about 10% of the variance in CD risk…childhood exposure to a sibling
    with CD, compared with adulthood exposure, was associated with a fourfold increased risk of disease onset, independent of the CD-PRS [CD – polygenic risk score].”
  • This study adds to “a growing body of evidence [that] implicates early-life exposures in CD pathogenesis. A recent meta-analysis reported that prenatal exposure to antibiotics and cigarette smoking increased the risk of CD, while breastfeeding was protective. Similarly, a large population-based study found that rural residence during childhood, but not adulthood, was associated with a lower risk of CD.”

Limitations:

  • Participants were from high-income countries.
  • Study did not include dietary intake.
  • These findings do not prove causation. There may be additional unrecognized genetic factors between the groups with exposure before and after 18 years of age.

My take: The increasing prevalence of Crohn’s disease, particularly over the last few decades, must be related to environmental factors; population genetics and genetic predisposition are unlikely to rapidly change. This is a very important study supporting the notion that exposure to siblings with Crohn’s disease and alteration of the gut microbiome increases the risk of Crohn’s disease. By identifying a microbiome group with a higher risk, this study may facilitate research to determine whether manipulation of the gut microbiome could reduce the likelihood of developing Crohn’s disease. If we can reduce Crohn’s disease in a high risk population, it may allow broader use of the same treatment principles to lower risk groups as well.

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The Safety and Effectiveness of Early Anti-tumor-necrosis-factor Therapy for Penetrating Crohn’s Disease in Pediatrics

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BD Constant et al. American Journal of Gastroenterology Publish Ahead of Print, July 1, 2026. | DOI: 10.14309/ajg.0000000000004104. The Safety and Effectiveness of Early Anti-tumor-necrosis-factor Therapy for Penetrating Crohn’s Disease Complications in Children

Methods: This was a multicenter retrospective study examining the safety of anti-TNF therapy in children (n=203) with Crohn’s disease (CD) who developed internally penetrating complications (IPCs; abscesses and inflammatory masses). The exposure timeframe was anti-TNF administration within 30 days of IPC diagnosis.

Key findings:

  • In Cox analyses, early anti-TNF was not linked to infectious serious adverse events (iSAE), noninfectious CD-related SAE, or surgeries, but was associated with increased combined clinical-biochemical-corticosteroid-free remission (hazard ratio 1.65).
  • Surgical risk differed by percutaneous drainage (PD) status: patients receiving early anti-TNF and PD had lower risk versus PD alone (event-free survival 58% vs 15%, log-rank P = 0.04).

My take: For many years, my practice has been to use early anti-TNF even in patients with internally penetrating complications. This study confirms that anti-TNF therapy may be beneficial in this setting.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Severe Consequences of Pediatric Perianal Crohn’s Disease

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A Strom et al. Clin Gastroenterol Hepatol 2026; 24: 1960-1969. Perianal Disease in Pediatric-Onset Crohn’s Disease: Incidence, Disease Course, and Long-Term Outcomes

Methods: In this nationwide Danish registry, a pediatric-onset CD cohort from 1980 to 2022 was identified. Outcomes for patients with and without perianal disease were examined.

Key findings:

  • There were 2356 patients with pediatric-onset CD, of whom 769 (32.6%) developed perianal CD. The cumulative incidence of perianal CD was 14.0%, 21.1%, and 28.1% after 1, 5, and 10 years.  After 30 years, the incidence rate was 45.2%.
  • A stoma was required in 308 (40.1%) and 147 (9.3%) patients with and without perianal disease, respectively (aHR, 2.8).
Probability of Major Abdominal Surgery in Patients with and without Perianal Disease
  • When comparing patients with/without perianal disease, the aHR for major abdominal surgery, cancer, and mortality were 1.5, 0.8, and 1.5 , respectively.
Probability of Mortality in Patients with and without Perianal Disease
  • When comparing patients with/without perianal disease, the aHR for mortality was 1.5. Of mortalities, 35 had perianal disease (4.6%; mortality rate, 2.2/1000 person-years) and 33 did not (2.1%; mortality rate, 1.4/1000 person-years). However, the confidence interval was 0.9-2.7) indicating the precision of this finding is low.

Discussion: “In our study, patients without perianal disease were diagnosed with CD more frequently in recent decades than patients with perianal disease. The differences in distribution of CD diagnosis over calendar years may be due to shorter follow-up among patients diagnosed with CD in recent decades, improved treatment delaying disease progression, and increased detection of milder CD phenotypes over time.”

My take: This study reinforces and quantitates the view that having perianal Crohn’s disease portends an increased risk for severe complications. With improving treatments, perhaps the outcomes will be more favorable now and in decades hence.

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Discordant Clostridiodes difficile Testing In Patients with Inflammatory Bowel Disease

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P Ramakrishan et al. Inflamm Bowel Dis 2026; 32: 1313–1320. Discordant Clostridioides difficile testing as a predictor of inflammatory bowel disease therapy escalation

Background: “In the general population, individuals with discordant tests (PCR+/TOX−) have similar outcomes to PCR− individuals, suggesting that this group represents individuals colonized with C. difficile.[14]”

Methods: In this retrospective study (n=117), outcomes assessed included CDI-directed therapy or escalation of IBD treatment.

Key findings:

  • 79% (93/117) were PCR+/TOX− and 21% (24/117) were PCR+/TOX+
  • PCR+/TOX+ patients had significantly higher CRP (98 vs 6 mg/L, P = .005)
  • PCR+/TOX− patients had more severe underlying IBD and higher rates of steroid use (48% vs 21%, P = .02) and were significantly more likely to require IBD therapy escalation (54% vs 25%, P = .004). Multivariable analysis showed PCR+/TOX− status (odds ratio [OR], 3.2) was a significant predictor of IBD treatment escalation. Antibiotic use did not significantly alter the need for escalation among PCR+/TOX−  patients.

Discussion:

  • “Most IBD patients who are PCR+/TOX−  are colonized with C. difficile, and IBD treatment could be considered rather than delaying for CDI therapy.”

My take: In patients with IBD, PCR-positivity for C diff is frequently a false positive due to high rates of colonization in this population. Patients who have their infection confirmed with an immunoassay are much more likely to respond to C diff therapy.

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Resources:

National Civil Rights Museum in Atlanta, GA. One of the powerful exhibits is a Woolworth lunch counter replica with headphones.  With your eyes closed, the exhibit challenges you to keep your hands on the counter as one receives menacing threats like ‘Boy, I’m going to kill you.’ 

Elevated Amylase is Common in Pediatric Patients with Inflammatory Bowel Disease

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F Vázquez López et al. J Pediatr Gastroenterol Nutr. 2026;83:79–86. Hyperamylasaemia in paediatric inflammatory bowel disease: Aetiology, outcomes and genetic determinants

Methods: This was a retrospective study with 334 pediatric patients, followed for ≥2 years (study duration was 7 years). Elevated amylase was considered to be above the laboratory’s reference range (102 U/L).

Key findings:

  • Hyperamylasaemia was found in 62/334 patients (18.6%), with 29% of these presenting at diagnosis
  • Hyperamylasaemia resolved in 77% of patients; in the majority (85%), spontaneously and in the remainder after medication withdrawal
  • One patient developed acute pancreatitis and one had recurrent pancreatitis

My take: It is best to avoid routinely checking an amylase if pancreatitis is not suspected; it could lead to ‘a wild goose chase.’ Most cases of elevated amylase are benign and self-limiting.

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Safety Data Up to Seven Years with Vedolizumab

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E Louis et al. Clin Gastroenterol Hepatol 2026; 24: 1654-1665. Open Access! Long-Term Safety of Vedolizumab in Patients With Ulcerative Colitis/Crohn’s Disease: A Prospective Observational Study

Methods: This was a prospective, observational, multicenter cohort study in adult patients (n=5208) with UC or CD starting treatment with vedolizumab or other biologics. The primary safety outcome was serious infections compared between cohorts using a Cox proportional hazards model adjusted by propensity score. Clinical effectiveness was a secondary outcome. Mean follow-up duration was 37.4 months. The vedolizumab group had greater age, duration of disease, and concomitant medication use at baseline, indicating more advanced disease.

Key findings:

  • In patients with UC, the incidence rate per 100 person-years of serious infections was 5.5 (vedolizumab) and 7.0 (other biologic), with an adjusted hazard ratio of 0.89 (P = .38).
  • In patients with CD, corresponding findings were 7.9 (vedolizumab) and 6.5 (other biologic) with adjusted hazard ratio of 1.15 (P = .16).
  • Rates of clinical response and clinical remission were similar in patients treated with vedolizumab compared with other biologics for both UC and CD.
Time to treatment failure in (A) biologic-naïve. Treatment failure included discontinuation of biologic treatment, IBD nonsurgical hospitalization, primary IBD surgery, and corticosteroid initiation.
Time to treatment failure in (B) biologic-experienced CD patients. 

My take: This large prospective study showed no new safety signals with mean followup of more than 3 years. There were no new trends or changes of clinical importance for infections (serious and opportunistic infections, gastrointestinal infections, respiratory tract infections, other infections), malignancies, infusion-related reactions, hepatotoxicity, and pregnancies. No cases of PML were reported. Efficacy was similar between vedolizumab and other biologics.

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How Does Remission in Crohn’s Disease Affect the Abnormal Microbiome/Gut Signature?

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T Braun et al. Gastroenterol 2026; 170: 971-984. Open Access! Perturbations of Diet and Gut Signatures Persist During Remission in Crohn’s Disease Despite Effective Immune Suppression

Methods: The authors analyzed diet, ileal transcriptomics, microbiomics, and metabolomics across patients with CD in remission, patients with active CD, and non–inflammatory bowel disease (IBD) controls as the reference for healthy signals.

Key findings:

  • Immune signals: Ileal transcriptomics revealed a significant decrease in genes and pathways associated with adaptive T cells and innate granulocytes during remission, which was even deeper than observed in non-IBD controls.
  • Antimicrobial gene expression: Patients in remission showed an increase in the expression of epithelial antimicrobial pathways and related genes, including DUOX2, along with an increase in genes associated with goblet cells and mucin glycosylation.
  • Microbiome and diet: In patients in remission, there was persistent pathogenic gut microbial composition, metabolic alterations, and less healthy dietary habits, which were characterized by a higher intake of ultraprocessed foods and lower consumption of fiber, folate, vitamin C, and vegetables
Purple = control (n=64), Yellow = CD remission (n=56), Red = CD active disease (n=24). Fecal signals persist during remission and substantially correlate with dietary exposures. (A) Boxplots of Faith’s phylogenetic alpha diversity, our previously defined health index,23 the previously defined Gevers IBD dysbiosis index21, and our IBD-specific index23 between controls, CD patients in remission, and CD with active disease.

Fecal signals persist during remission and substantially correlate with dietary exposures. (A) Boxplots of Faith’s phylogenetic alpha diversity, our previously defined health index,23 the previously defined Gevers IBD dysbiosis index21, and our IBD-specific index23 between controls, CD patients in remission, and CD with active disease.

My take (borrowed from the authors): This study shows that, during remission with advanced therapies, “disturbances in antibacterial epithelial signals, along with unhealthy dietary patterns, altered microbiome, and perturbed metabolome, continue and are partly linked to the risk of flare 6 months later.”

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NSAIDs and IBD Flares (2026)

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AS Mayer,et al. Arthritis Care Res. https://doi.org/10.1002/acr.80067. Open Access! Safety of Prescription Nonsteroidal Anti-inflammatory Drugs in Adults With Inflammatory Bowel Disease: Data From a Large Administrative Claims Cohort.

Methods:

  • “This retrospective cohort study included patients with IBD aged at least 18 years from Optum’s deidentified Clinformatics Data Mart Database (2000–2022). Patients with a new NSAID prescription fill were matched to those without an NSAID fill during the study period…Propensity score-based inverse probability of treatment-weighted Cox proportional hazards models evaluated the association between NSAID exposure and time to IBD-related hospitalization across IBD subtypes.”

Key findings:

Unweighted Kaplan-Meier curve for IBD-related hospitalization in patients
with Crohn disease (B).
Unweighted Kaplan-Meier curve for IBD-related hospitalization in patients
with ulcerative colitis (C).

Discussion:

  • “The use of IPTW [inverse probability of treatment weighting] to balance an extensive number of confounders associated with NSAID use optimizes the assessment of the association of NSAID exposure with IBD-related hospitalization and helps address recent concern of residual confounding in observational studies of NSAID risk in IBD.”
  • Besides the potential risk of an IBD flare, “NSAID use is associated with risk of hospitalization from several non-IBD–related entities such as acute kidney injury and adverse cardiac events…a large prospective multicenter observational study of more than 18,000 admitted patients in England found that NSAIDs were responsible for 29.6% of admissions related to adverse drug reactions, including gastrointestinal bleeding, stroke, and renal impairment.34“

My take: This study shows an association of increased hospitalization in patients with CD but not UC based on NSAID exposure. The absolute risk of this appears low and could be in fact related to residual confounders (despite use of IPTW) as this was not a prospective study. The risk of NSAIDs outside the GI tract are likely more significant for most patients. Nevertheless, there are limited options for pain management and NSAID benefits have to be weighed against other approaches.

Related blog post: Rethinking the Link between NSAIDs and IBD Flares

Interleukin-10 Autoantibodies and Development of IBD Plus One

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N Gharahdaghi et al. N Engl J Med 2026;394: 2212-2222. Interleukin-10 Autoantibodies and HLA-DRB1*01:03 in Inflammatory Bowel Disease

Background: “The allele HLA-DRB1*01:03 is the strongest genetic risk factor not only for susceptibility to ulcerative colitis but also for complicated phenotypes, including acute severe ulcerative colitis and an increased likelihood of surgical resection.2-5 However, the underlying pathogenic mechanism linking this HLA allele to disease remains unclear.”

“Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD)…In one child, anti–interleukin-10 titers and disease activity responded to B-cell–depleting anti-CD20 therapy.12“

Methods:

Key findings:

  • Interleukin-10–neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%) and in none of 1006 controls (P<0.001)
  • High anti–interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response
  • Anti–interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0), the U.K. IBD BioResource cohort (odds ratio, 24.7), and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5)

Discussion Points:

  • “The genetic association between HLA-DRB1*01:03 and anti–interleukin-10 autoreactivity provides mechanistic insight into one of the strongest known genetic susceptibility factors for IBD, with possible diagnostic, prognostic, and therapeutic implications.”
  • “Monogenic interleukin-10–signaling defects tend to manifest during infancy with colonic and penetrating disease, poor response to IBD therapies, high inflammatory activity with notably elevated C-reactive protein levels, and a high incidence of postoperative complications.27 It will be informative to establish the extent to which anti–interleukin-10 seropositivity associates with a similar disease pattern.”
  • “Our data highlight the need for research into therapeutic maneuvers to reduce anti–interleukin-10 titers — for example, by means of B-cell and plasma-cell depletion (e.g., anti-CD19, anti-CD20, anti-CD38, or CD19 chimeric antigen receptor [CAR] T-cell therapy),29-31 plasma exchange, or blockade of the neonatal Fc receptor.32“

My take: Historically, in younger patients (6 or younger) and those with more severe inflammatory bowel disease, it has been common to evaluate for monogenetic diseases which may require different treatment approaches. For similar reasons, assessing for neutralizing autoantibodies against interleukin-10 is likely to become part of routine care.

Related study: Q Zhang Q, Shakweh E, Sharip M et al. The Lancet Gastroenterology & Hepatology, 2026; 0. Open Access! HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype–phenotype association study Key findings:

  • Among 43,762 patients with IBD (21 839 with Crohn’s disease and 21 923 with ulcerative colitis or IBD unclassified), HLA-DRB1*01:03 carriage was observed in 2009 (4·6%) patients with IBD and associated with multiple severe outcomes …including colonic resection in patients with Crohn’s disease (odds ratio 1·35), colectomy in patients with ulcerative colitis or IBD unclassified (1·99), and perianal disease in both patients with Crohn’s disease (1·65) and patients with ulcerative colitis or IBD unclassified (1·70)

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Reassuring Study of Infants Exposed to Biologics

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L Palomino et al. Clin Gastroenterol Hepatol 2026; 24: 1688-1701. Open Access! Psychomotor Development in Infants Following Maternal Exposure to Biologics: Results From the DUMBO Registry

Methods: DUMBO (NCT03894228) is an ongoing, prospective, multicenter, observational registry study supported by Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) which includes women with IBD whose pregnancy was known to the investigator before the 28th week of gestation. Psychomotor development of infants was assessed using the Spanish version of the Ages and Stages Questionnaire 3rd edition (ASQ-3) during the first year of life. 

Key findings:

  • Exposure to biologics in utero, had no impact on ASQ-3 scores at month 12.
  • Multivariate analysis revealed that preterm birth (odds ratio, 0.3; 95% confidence interval, 0.1–0.6) and maternal ulcerative colitis (odds ratio, 0.5; 95% confidence interval, 0.3–0.9) were associated with an increased risk of abnormal ASQ-3. 

Discussion Points:

  • “Active maternal inflammation during the periconception period and pregnancy has been associated with low birth weight, preterm delivery, small size for gestational age, spontaneous abortion, and stillbirths.3,4…Active maternal inflammation during the periconception period and pregnancy has been associated with low birth weight, preterm delivery, small size for gestational age, spontaneous abortion, and stillbirths.3,4“
  • “In infants born to mothers with IBD, exposure to biologics would be expected to reduce their exposure to inflammatory cytokines in utero, which could potentially mitigate the impact of maternal inflammation on psychomotor development… our study found no negative impact of biologics exposure on the psychomotor development of infants, either from exposure in utero or during breastfeeding. Furthermore, we observed higher ASQ-3 scores in the personal-social domain at 4 months and in the gross and fine motor domains at 12 months in biologics-exposed vs nonexposed children, possibly reflecting a beneficial effect of treatment in reducing maternal inflammation.”
  • “Data from the PIANO study further supports our findings. Mahadevan et al assessed psychomotor development in 206 children exposed to biologics (both anti-TNF and non-anti-TNF) in utero, and 92 controls, finding higher ASQ-3 scores in the exposed group.”

My take: Biologic exposure does not appear to impair psychomotor development in infants. While this study provides useful information, I am not impressed wtih with the Acronym DUMBO for this registry.

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