Category Archives: Gastroenterology

PREdiCCt Trial: Lower Calprotectin Targets in Crohn’s Disease and Ulcerative Colitis

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Constantine-Cooke N, Gros B, Plevris N, et al Gut 2026. doi: 10.1136/gutjnl-2025-337846. (Open Access!) Associations between demographic, clinical and dietary factors and flares in inflammatory bowel disease: the PRognostic effect of Environmental factors in Crohn’s and Colitis (PREdiCCt) prospective cohort study

Methods: Multicentre, prospective cohort study conducted across 47 UK centres. Patients with Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBDU) in self-reported remission were prospectively followed up. 2629 participants (1370 CD; 1259 UC/IBDU) – followed up for a median of 4.1 years.

Key findings:

  • Baseline FC was strongly associated with patient-reported flares (FC ≥250 µg/g: adjusted HR (aHR) 2.22; FC 50–250 µg/g: aHR 1.52 (reference <50 µg/g)).
  • Baseline FC was also strongly associated with objective flares (FC ≥250 µg/g: aHR 3.25; FC 50–250 µg/g: aHR 1.98). Objective flares were “clinical flare plus C-reactive protein >5 mg/L and/or faecal calprotectin (FC) >250 µg/g with treatment escalation.” In ulcerative colitis, the probability of an objective flare within two years rose from 11% in those with baseline calprotectin below 50 µg/g to 34% in those above 250.
  • At 24 months, cumulative patient-reported and objective flare rates were 28% and 12% in CD, and 33% and 15% in UC/IBDU, respectively. Overall, patient-reported flares were more common (31%), while objective flares were less frequent (14%).
  • In UC, higher total meat intake was associated with increased risk of objective flares (highest versus lowest quartile: aHR 1.95, 95% CI 1.07 to 3.56). The absolute two-year risk rose from 12% in the lowest quartile of meat intake to 26% in the highest.
  • No consistent associations were observed for ultraprocessed foods, fiber or polyunsaturated fatty acids and flare.
Flares by faecal calprotectin (FC) stratified into FC < 50, 50 ≤ FC ≤ 250, and FC >250 μg/g. (A) Patient-reported flare in Crohn’s disease; (B) objective flare in Crohn’s disease; (C) patient-reported flare in ulcerative colitis/inflammatory bowel disease unclassified; (D) objective flare in ulcerative colitis/inflammatory bowel disease unclassified. aHR, adjusted hazard ratio.

My take: Lower calprotectin values, even in remission, are associated with better outcomes. Risk was meaningfully increased even in the 50–250 µg/g range, compared with levels below 50. Higher meat intake may increase the risk of flares for UC.

Summary of study information from Charlie Lees: The PREdiCCt Study: Can We Predict IBD Flares?

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Preliminary Work: A Vaccine to Prevent Colon Cancer and A Blood Test to Detect Colon Cancer

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D’Alise, A.M., Willis, J., Duzagac, F. et al. Nat Med (2026). https://doi.org/10.1038/s41591-025-04182-9. Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial. (Open Access!)

Background: “Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy” against these FSPS. These are “the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45).”

Key findings:

  • Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity
  • The immune response was durable and detectable at 1 year in 85% of participants
  • Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs
  • Peptide–human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro
Colorectal neoplasia burden observed at end-of-study colonoscopy inversely correlates with breadth of immune response. a, Number of participants who underwent screening colonoscopy at baseline and end of study (EoS; n = 43) who had no adenomas (adenomas absent), at least one adenoma (adenomas present) and advanced adenomas (advanced adenomas present) detected.
b, Number of adenomas per trial participant at baseline and end of study; comparison of baseline versus EoS was performed using a two-tailed Mann–Whitney U-test; NS, not significant. c, Number of reactive pools measured at 6 months (n = 34 evaluable subjects) between the participants with and without adenomas. Data are shown as the mean ± s.e.m.

My take (borrowed in part from authors): “Overall, this clinical trial provides important proof-of-concept data of the safety and the robustness of induced immunogenicity of
Nous-209 in LS carriers…and supporting its clinical development as a valuable intervention for cancer immune interception.” Vaccines have a long history in reducing cancer (for Hepatitis B, Cervical Cancer (due to HPV), Anal Cancer, Leukemia (by boosting immunity) and Others). Until recently, this has been by preventing viral infections that increase the risk of cancer. This is a new approach.

Related article: Blood test for colorectal cancer: A Mannucci et al. Gastroenterol 2026; 170: 330-343. An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study Methods: A panel of 6 cell-free and exosome-based circulating biomarkers were identified through small RNA sequencing from a biomarker discovery cohort (blood test). Key finding: “This study developed and independently tested a blood-based test with 97.3% sensitivity for screening-relevant CRC stages I–III and 61.5% for the noninvasive detection of high-grade dysplasia.”

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#5000: Simple Rule for Deciding When pH Impedance Testing Should Be Done While on Therapy

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Editor’s note: This is the 5000th post on this blog! The first post was on December 7th, 2011.

Iguazu Falls

CP Gyawali et al. Clin Gastroenterol Hepatol 2025; 23: 2459-2467. Open Access! pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but Not in Unproven GERD

Methods: Prospective 2-center study enrolled adult patients (n=79) with typical reflux symptoms with incomplete PPI response; they were studied both off PPI (wireless pH monitoring) and on PPI (pH-impedance monitoring)

Key findings:

  •  In 60 patients with proven GERD off-PPI, 56.7% had no ongoing GERD on PPI (despite reflux symptoms)
  • In unproven GERD, pH-impedance monitoring on acid suppressive therapy is unable to differentiate non-GERD symptoms from controlled GERD in the majority of patients, or identify patients who could benefit from discontinuation of acid suppression

Discussion points:

  • “Only a small proportion of PPI nonresponders have true GERD, and most have either no GERD or overlap between inconclusive GERD and a non-GERD process such as an esophageal disorder of gut-brain interaction (E-DGBI).10,11“
  • “On-therapy pH-impedance monitoring can identify refractory GERD in patients with previously proven GERD.”
  • “Definitive GERD evidence and persisting symptoms despite optimized PPI therapy is an indication for escalation of management.20… potassium competitive acid blockers provide better healing of advanced grade esophagitis21 as well as faster symptom response in nonerosive reflux disease,22,23 and could be an option”

My take:

  1. Simple rule: Only perform on-therapy pH-impedance monitoring in patients with proven GERD
  2. Many patients with GERD symptoms do not have GERD (see posts below)
  3. In patients with documented GERD, on therapy pH monitoring can be helpful in proving refractory GERD which may benefit from alternative treatments

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Nahuel Huapi Lake (near Bariloche, Argentina)

Etrasimod for Ulcerative Colitis (2026)

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AJ Yarur et al. Clinical Gastroenterology and Hepatology 2026; 24: 210 – 220. Open Access! Efficacy of Etrasimod in Ulcerative Colitis: Analysis of ELEVATE UC 52 and ELEVATE UC 12 by Baseline Endoscopic Severity.

Methods: Efficacy end points were evaluated at Weeks 12 (pooled population) and 52 (ELEVATE UC 52)

Key findings:

  • Clinical remission in the moderate group compared to placebo: Week 12: 38.3% vs 17.9%; Week 52: 36.5% vs 14.3%
  • Clinical remission in the severe group compared to placebo: Week 12: 18.2% vs 6.1%; Week 52: 29.4% vs 3.4%
  • “Our findings were consistent with those for other UC treatments…with efficacy improvements generally being greater among patients who were naive rather than experienced with biologics and/or JAKi.12–17“

My take: Etrasimod demonstrated significant induction and maintenance efficacy over placebo in both moderate and severe endoscopic disease. Its role remains limited as there are other treatments with improved likelihood of response, especially in those with prior advanced therapies. However, it is notable that recent AGA guidelines promote etrasimod as one of the higher efficacy agents in patients naive to advanced therapies.

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Calprotectin Correlates with Disease Extent and Mucosal Healing in Ulcerative Colitis

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O Steinsbo et al. Am J Gastrolenterol 2025. 120: 2623-2631. Open Access! Fecal Calprotectin Correlates With Disease Extent but Remains a Reliable Marker of Mucosal Healing in Ulcerative Colitis. Thanks to Ben Gold for this reference.

This single-center observational study (n=254) examined the correlation between fecal calprotectin (FC) levels with both disease extent and mucosal healing in ulcerative colitis. Mucosal healing was rated by the Mayo Endoscopic Score (MES).

Key findings:

  • Disease extent: FC levels were significantly lower in proctitis (440 mg/kg) as compared with left-sided colitis (840 mg/kg) or pancolitis (1,690 mg/kg)
  • Mucosal healing: In MES ≤1, FC levels were significantly lower in proctitis (24) compared to left-sided colitis (40) or pancolitis (85)

My take: Fecal calprotectin levels are clearly affected by the extent of disease involvement. However, the increase in calprotectin values associated with disease activity was significantly larger than the differences attributed to disease extent.

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Early Infliximab Levels Correlates with Outcomes in Acute Severe Ulcerative Colitis

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CFD Li Wai Suen et al.Gastroenterology, Volume 170, Issue 1, 118 – 131. Early Infliximab Levels and Clearance Predict Outcomes After Infliximab Rescue in Acute Severe Ulcerative Colitis: Results From PREDICT-UC

Methods: Data, including serum and stool testing, was extracted from from 135 patients (ages 24-42) enrolled in the PREDICT-UC prospective, randomized controlled trial

Key findings:

  • Lower day 3 serum infliximab levels predicted infliximab failure on day 14 and colectomy by 3 months; a threshold of ≤57.9 μg/mL had 83% sensitivity, 67% specificity, 24% positive predictive value, and 97% negative predictive value for colectomy
  • In patients with high clearance who did not respond to the first infliximab dose, day 14 response rate was higher with a second 10 mg/kg vs 5 mg/kg dose (38% vs 11%; risk ratio, 3.43)
  • Day 3 fecal infliximab levels correlated with endoscopic severity and was associated with day 7 nonresponse (P = .016)

Discussion points:

“Early infliximab levels and clearance predict outcomes in ASUC. Additionally, we are the first to demonstrate that a high early infliximab clearance can be overcome by additional dosing. These results demonstrate the potential of early infliximab TDM [therapeutic drug monitoring] to guide decision-making in ASUC and for the first time provide an evidence base for intensified infliximab dosing in clinical practice.”

My take: While the authors suggest TDM as a potential strategy to overcome low levels, an alternative approach would be using higher dosing and more frequent dosing, especially as infliximab levels may not be quickly available. Higher dosing is particularly important in the pediatric age group where studies have shown that “standard” dosing of 5 mg/kg result in insufficient levels of infliximab in ~80%.

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    How FODMAPS Contribute to Irritable Bowel Symptoms

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    J Gao et al. Gastroenterology. 206; 170:132 – 147. Open Access! Low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols Diet Improves Colonic Barrier Function and Mast Cell Activation in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Mechanistic Trial

    Background: “Mechanisms by which fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) drive pathophysiology of irritable bowel syndrome (IBS) are not well understood.”

    Methods: 42 patients with “Rome IV diarrhea-predominant IBS (IBS-D) underwent barrier function evaluation pre- and post-LFD along with assessment of mast cell number and activation profile. Finally, fecal supernatants (FS) were administered intracolonically to wild-type mice with and without pharmacologic inhibition, toll-like receptor 4 (tlr4)–/– mice, and mast cell-deficient mice with/without mast cell reconstitution.”

    Key findings:

    This is a highly technical study and would recommend reviewing the findings directly (open access article).

    To summarize:

    • “Patients with IBS-D had significant improvement in colonic barrier structure and function, mast cell number, and levels of mast cell mediators post-LFD (low FODMAP diet). The magnitude of physiological changes did not correlate with the magnitude of clinical response.”
    • “This study showed the complex interplay among food, microbiome, local immune activation, and epithelial physiology in IBS by demonstrating that FODMAPs increase fecal lipopolysaccharide levels, which activates colonic mast cells to causes barrier dysfunction in diarrhea-predominant IBS.”

      My take: By understanding the GI effects of a low FODMAP diet in patients with IBS-D more precisely, it may improve dietary approaches as well as other treatments like mast cell stabilizers.

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      Detecting Preclinical Crohn’s Disease in First-Degree Relatives with Biomarker Screening

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      D Turner et al. . Gut 2025;0:1–7. doi:10.1136/gutjnl-2025-336368. Preclinical stages of Crohn’s disease defined by faecal calprotectin in asymptomatic first-degree relatives: screening framework for prevention trial

      Methods: “Faecal calprotectin was measured in asymptomatic FDRs aged 6–38 years; those with persistent elevation, defined as >70 µg/g in at least two separate tests, were offered panenteric video capsule endoscopy or ileocolonoscopy”

      Population: 331 (35%) first-degree relatives (FDRs) (from a group of 950) agreed to be screened: 63 (19%) had persistently elevated calprotectin, of whom 42 underwent further evaluation

      Key findings:

      • From the initial screened cohort of 331 patients, nine (2.7%) had endoscopic appearance compatible with presymptomatic CD, and 22 (6.6%) had non-specific macroscopic mucosal changes
      • Median calprotectin was significantly higher in those with presymptomatic CD (772µg/g (IQR 279–1685)) compared with others (31µg/g (IQR 30–61), p<0.0001)
      • Calprotectin >225 µg/g predicted presymptomatic CD (area under the receiver operating
        characteristic curve 0.97 (95% CI 0.94 to 1.0; p<0.001; sensitivity 89%, specificity 94%)

      Discussion Points:

      • “There is no universally accepted definition for preclinical stages of CD, and
        the distinction between these stages remains partly subjective.”
      • “The lack of longitudinal follow-up is also a limitation, but this will be completed as part of the PIONIR trial.”

      My take (borrowed in part from the authors):

      1. Identification of pre-symptomatic CD “can facilitate designing targeted interventions and defining inclusion criteria for prevention trials.” The disease may be more modifiable in the early stages of disease.
      2. This trial suggests the calprotectin threshold of >70 is too low to target screening. For specificity, the study showed that persistent elevation above 225 merits investigation; though, it has been our practice to use a threshold of >150 for children older than 5 years.
      3. Approximately 5% of asymptomatic FDRs of CD patients have evidence of pre-symptomatic CD and approximately 10% more have non-specific mucosal changes when evaluated

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      Clostridioides difficile Treatment in 2026

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      P Feuerstadt et al. AJG 2025; 120: 2468-2470. Treatment of Clostridioides difficile: The Times They Are Changing

      This article summarizes the recent changes in the treatment options for Clostridioides difficile (C diff).

      Key points:

      • Fidaxomicin targets C diff with limited collateral microbiome disruption. This leads to significantly lower recurrence rates compared to vancomycin. Thus, it is preferred 1st line therapy for initial and recurrent C diff. In “the coming years, fidaxomicin is expected to come off patents” which will improve access and affordability.
      • Bexlotoxumab which lowered recurrence rate is no longer being produced
      • FMT via Openbiome is no longer available. In those in which FMT was used, options include the following:
      1. live-jslm (REBYOTA), a broad consortium enema-based formulation
      2. live-brpk (VOWST), a narrow consortium of Firmicutes in an encapsulated form. This treatment in adults: four capsules daily for three days
      3. Both treatments are not recommended for patients who are severely immunocompromised. In these patients, prolonged vancomycin course with taper or using every other day therapy with fidaxomicin for days 7-25 could be considered

      My take: I have been seeing less C diff cases recently. This may be due to better antibiotic stewardship, changes in C diff strains, or improved testing approaches.. My observation is supported by recent reports:

      AY Guh et al. Infect Dis Clin North Am. 2025. 39:567-580. Changes in the Epidemiology of Clostridioides difficile Infection

      Annual number of hospitalized community-onset and hospital-onset CDI events reported to the National Healthcare Safety Network, 2015 to 2023. (From CDC’s Antibiotic Resistance & Patient Safety Portal (Available at https://arpsp.cdc.gov/profile/nhsn/cdi).)

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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.

      The Risks and Absolute Risks of GLP-1 RAs and Gastrointestinal Adverse Events

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      C-H Chiang et al. Gastroenterol 2025; 169: 1268-1281. Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis

      With the widespread adoption of GLP-1 RAs, there have been increasing reports of adverse effects. This systematic review/meta-analysis (with 55 randomized controlled trials involving 106,395 participants) more fully describes the likelihood of GI adverse events.

      Key findings:

      • GLP-1RAs increased the risk of cholelithiasis (risk ratio [RR], 1.46; 95% CI, 1.09–1.97; 2 more cases per 1000) and probably increased the risk of GERD (RR, 2.19; 95% CI, 1.48–3.25; 4 more cases per 1000) compared with placebo
      • GLP-1RAs probably have little or no effect on the risk of other gastrointestinal or biliary events

      Figures 2 & 3 use a Forest plot to look at a large number of potential adverse gastrointestinal/biliary events. For example, cholecystitis and cholangitis had increased RR at 1.17 and 1.54 respectively. However neither reached statistical significance.

      My take: GLP-1 RAs definitely cause adverse gastrointestinal effects, especially nausea, vomiting, diarrhea, bloating and reduced appetite. More severe adverse effects are quite uncommon and are unlikely to influence the decision to use these medications.

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