Functional Dyspepsia in Clinical Practice

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PJ Pascricha, NJ Talley. NEJM 2026; 394: 166-176. Functional Dyspepsia

This is a terrific, succinct review of functional dyspepsia.

Key points:

  • “The syndrome probably comprises several different and as yet incompletely characterized disorders; local microinflammation driven by an aberrant response by type 2 helper T cells may represent an important subset of cases.”
  • “Functional dyspepsia can overlap with other gastrointestinal syndromes, particularly irritable bowel syndrome and gastroesophageal reflux disorder, and persons with such overlap have more severe symptoms.”
  • “There is no approved drug therapy; treatment is empirical and directed at symptoms, consisting of acid suppressants and low-dose tricyclic antidepressants (and other neuromodulators), along with appropriate nutritional and psychological support.”

Discussion points:

  • Epidemiology: “Worldwide, functional dyspepsia is present in 7.2% of adults (10.1% in the United States), affects women 1.6 times as often as men, and is more common in persons younger than 40 years of age.”
  • Diagnostic workup: Workup depends on clinical judgement. Careful evaluation is needed in the presence of alarm symptoms like GI bleeding, anemia, weight loss, dysphagia, personal/family history of gastrointestinal cancers.

Treatments:

  • “Acid-inhibition pharmacotherapy is considered to be first-line treatment in functional dyspepsia. However, the benefits of this approach are modest at best”
  • Neuromodulators: “Tricyclic antidepressants are considered first-line therapy in this category…Results of the Functional Dyspepsia Treatment Trial showed significant superiority of low-dose amitriptyline over placebo in achieving prespecified “adequate relief” for the last 5 weeks of the 10-week trial (53% with amitriptyline vs. 40% with placebo, P=0.05). The effect appeared to be greatest in participants with epigastric pain (relative risk, 1.34; 95% CI, 1.02 to 1.59). In contrast, the response obtained with escitalopram (a selective serotonin-reuptake inhibitor) did not differ from that obtained with placebo.39 The benefit of amitriptyline was independent of changes in depression or anxiety scores…Mirtazapine (an atypical tetracyclic antidepressant that also antagonizes histamine H1 receptors and serotonin 5-hydroxytryptamine [5-HT] type 3 receptors) also has shown efficacy in functional dyspepsia and may be best suited for patients with prominent nausea and clinically significant weight loss.41“
  • Psychology: “Recognition and treatment of uncontrolled anxiety and depression are important in all cases. In refractory functional dyspepsia, it is also important to consider psychological therapies as an adjunct for helping patients cope with their symptoms and perhaps attenuate the severity of symptoms. Studies support the use of cognitive behavioral therapy, mindfulness-based stress reduction, and hypnotherapy in functional dyspepsia, and benefits may last up to 12 months.42…the evidence from these trials is considered to be very low.”
  • Diet: “Dietary advice has not been shown to be effective in studies.”The effectiveness of simple dietary advice (i.e., small low-fat meals and avoidance of carbonated drinks to limit gastric distention), although seemingly rational, has not been borne out in a randomized trial.33 Low-FODMAP (fructans, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diets have not been shown to reduce symptoms any more than traditional dietary advice.34…” IgE-mediated (classical) food allergy is generally not mistaken for functional dyspepsia, and screening for IgG-mediated reactivity to food antigens is not recommended.25“
  • Immune-Modulating Treatment: “A randomized, controlled trial of montelukast, a cysteinyl leukotriene antagonist, in children with duodenal eosinophilia and dyspeptic symptoms showed a significant effect in reducing pain as compared with placebo (62% vs. 32%, P<0.02), and the effect appeared to be even greater (84%) in patients with more than 20 eosinophils per high-powered field.43“

My take (borrowed from the authors) “Given the limited efficacy of drugs that are recommended under national and international guidelines…, the consideration of therapies for which evidence is insufficient may be reasonable in refractory cases.”

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Tango Dancing in Buenos Aires

Should We Adopt Mass Screening for Celiac Disease?

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MG Stahl et al. Gastroenterol 2026; 170: 240-245. Open Access! Mass Screening of Celiac Disease: A Crossing Point Between Secondary and Primary Prevention?

The authors make several good arguments for mass screening for celiac disease.

Key Points:

  • “The worldwide prevalence is high, affecting an estimated 1% to 3% of the general population…One study showed that two-thirds of children remain undiagnosed.” (Dig Liver Dis. 2023; 55:608-613). Thus, screening would identify many cases that would otherwise go undiagnosed and untreated
  • ” As one of the most HLA-restricted diseases, nearly all patients carry HLA-DQ2.5, DQ2.2, or DQ8 (and very rarely DQ7.5), and their absence makes CeD extremely unlikely. Although 30% to 40% of the general population carry these alleles, only approximately 3% will go on to develop CeD”
  • “The Environmental Determinants of Diabetes in the Young (TEDDY) study showed that although there was some early anxiety reported, there was no long-term psychological harm in disclosing genetic risk to parents of children that were tested and most parents adapted over time”
  • “Children identified as highest risk at birth through HLA-DQ typing also represent an ideal cohort to test interventions such as dietary modifications or microbiome targeted therapies during the predisease phase, during the key “window of opportunity,” ideally before seroconversion (primary prevention).” There are no currently proven primary prevention interventions.
  • Some of the drawbacks to screening: 1. “Evidence on health benefits of treating asymptomatic CeD is limited.” 2. “The potential psychosocial effects of both newborn genetic testing and a strict gluten-free diet in individuals diagnosed through screening need to be considered.” 3. “HLA-DQ typing may be cost prohibitive in some regions of the world.” 4. “Most children identified to be at risk for CeD based on HLA-DQ will not develop CeD.”

My take: I am skeptical about the benefits of screening at birth and how it would work in our current health care system. We have plenty of examples in our field in which early screening is not followed up well (eg. Hepatitis C, Biliary Atresia). If more evidence emerges on the benefits of primary prevention, then more widespread screening at birth may be worthwhile. For example, there is “a clinical trial underway in Sweden, the GRAin study (NCT04593888) that aims to investigate whether eating a gluten reduced diet (<2 g of gluten per day) may reduce the risk of CeD in children with genetic risk.”

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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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More Pediatric Data Supporting GLP-1 RA Efficacy for MASLD

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AM Tou et al. J Pediatr Gastroenterol Nutr. 2026;82:146–155. Glucagon‐like peptide‐1 receptor agonists in pediatric metabolic dysfunction‐associated steatotic liver disease

Methods: Retrospective study in patients ≤18 years old with a diagnosis of MASLD, who were prescribed a GLP-1RA from January 2, 2018 and January 10, 2024 at the Children’s Hospital of Philadelphia. 42 patients met inclusion criteria (out of a cohort of 111 that had received GLP-1RA with diagnosis of MASLD). Of the GLP-1RA medications, liraglutide was most frequently prescribed (44%), followed by semaglutide (27%), dulaglutide (25%), and exenatide (4%).

Key findings:

  • ALT improved by a mean of 56 U/L at 6 months (p = 0.04), and by 37 U/L at end of treatment (p = 0.004)
  •  71% of patients had a therapeutic indication for T2DM and 29% for obesity
  • “Improvements were also observed in aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), glycated hemoglobin (HbA1C), and triglycerides. Body mass index (BMI) percentile and z-score showed no significant changes, but BMI stabilization was observed”

My take: While Semaglutide has an FDA indication for MASLD treatment, there is limited pediatric data. This study indicates that GLP1-RAs are likely to have similar efficacy in adolescents. The lack of weight loss in this study is likely related partly to use in T2DM which has a lower response and the use of GLP-1RAs known to have lower response with regard to weight loss.

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Have You Read the New “Dietary Guidelines for Americans, 2025-2030”?

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Here’s a link to the new 10-page guidelines: Dietary Guidelines for Americans

Here are critiques:

What’s Good About This Guidance:

  1. Short enough to read and understand
  2. The emphasis of reducing unprocessed foods and clear language
  3. Encouraging early introduction of potential allergens at 6 months of life. This lowers the risk of developing food allergies later.

Some of the questionable advice:

  1. Increasing the protein recommendation to 1.2-1.6 gm per day, up to double prior recommendations. The reason why this level of protein is not a good idea for everyone is noted in a prior blog post: Is a High Protein Diet Beneficial and Safe?. And from the AJC critique: “Pushing protein higher can also crowd out vegetables and fiber, which play a major role in heart health, digestion and overall wellness.”
  2. Backing away from previous advice about alcohol. The current guidance states to “consume less alcohol.” From NY Times: “It is the first time in decades that the government has omitted the daily caps on drinking that define moderate consumption. The guidelines no longer warn of risks like cancer.”
  3. Encouraged changes (more red meat, full-fat dairy) may increase saturated fat intake above stated goal of less than 10%.

The NY Times article on conflicts of interests notes that “Robert F. Kennedy Jr. had promised that his panel, which released new guidelines this week, would have no “conflicts of interest”….Some parts of the guidelines represent such a departure from previous versions that it seems like the administration “handpicked” scientists likely to support those conclusions, “versus undertaking a neutral review of the science,” said Lindsey Smith Taillie, a professor of nutrition at the U.N.C. Gillings School of Global Public Health.”

My take: Overall, the focus on reducing processed foods and decreasing added sugar are worthwhile. The brevity of the guidelines make them accessible. At the same time, the guidelines appear to continue a pattern of RFK Jr of selecting advisers, whether with diet recommendations or with vaccine policy, to support a desired outcome.

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Gastroenterology and the Rise of Private Equity Investments

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TA Brenner et al. Clin Gastroenterol Hepatol 2026: 24: 7-9. Geodemographic Trends in Private Equity Acquisitions of US Gastroenterology Practices: An Analysis of Transactions From 2013 to 2023

An excerpt:

“The combination of high-volume procedures, strong ancillary revenue streams, and opportunities for outpatient consolidation has made gastroenterology a prime target for PE-backed investment. For many gastroenterologists, this trend is no longer theoretical—it is local, visible, and shaping the landscape of everyday practice.”

“Between 2013 and 2023, PE firms acquired 114 outpatient gastroenterology practices, encompassing 1169 clinical sites nationwide…That includes 854 clinics, 266 endoscopy centers, and 49 infusion centers. Collectively, these sites employed approximately 2675 physicians and advanced practice providers. In total, around 14% of all gastroenterology clinical sites nationwide are now affiliated with PE-backed platforms.”

 (A) Trend in private equity acquisitions of gastroenterology practices (red)
and gastroenterology clinical sites (blue) by year.

“PE firms are less likely to invest in gastroenterology practices located in the poorest communities… Practices in zip codes with the lowest income levels were about 60% less likely to be acquired than those in wealthier areas (aRR, 0.37; 95% CI, 0.31–0.45; P < .001)…PE firms tend to prioritize markets with strong commercial payer mixes and higher rates of elective procedures, steering clear of areas with high Medicaid penetration or large numbers of uninsured patients.”

Key Points:

  • “First, consolidation is accelerating…Even if you are not interested in selling, you may need to compete with PE-backed groups that have more capital, better tech infrastructure, and stronger payer contracts”
  • “Second, staying independent may become more difficult. As regional consolidation increases, remaining unaffiliated could put independent practices at a disadvantage. PE-backed platforms often negotiate better rates with commercial insurers and have the scale to invest in centralized billing, marketing, and compliance.”
  • “Third…If PE firms avoid lower-income or rural areas, gastroenterology access could become more uneven and more challenging to sustain in underserved regions.”
  • “Studies in other specialties suggest that practices owned by PE firms often face changes in staffing, autonomy, and productivity expectations. Physicians may experience higher pressure to perform more procedures, see more patients, or adopt system-wide workflows they did not design.”

My take: PE acquisitions are affecting broad areas of healthcare. However, they do not seem to result in improvement in patient care or physician satisfaction.

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Updated Data on PPI Effectiveness For Eosinophilic Esophagitis

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AJ Lucendo et al. Clin Gastroenterol Hepatol 2025; 23: 2115-2127. Proton Pump Inhibitors for Inducing and Maintaining Remission in Eosinophilic Esophagitis: An Updated Systematic Review and Meta-Analysis

Background/Methods: This systematic review aimed to update the response/remission rates of PPI therapy for eosinophilic esophagitis. Compared to review in 2016, the current review covers a 10-fold increase in population (from 619 to 7304 patients), with a more balanced distribution between children (41%) and adults, and with a geographical representation from several continents.

Key findings:

  • PPI therapy led to clinical response in 65% (95% confidence interval [CI], 57.2–72.4)) and histological remission (<15 eos/hpf) in 45.4% (95% CI, 41.6%–49.3%) of patients, without differences between children and adults (41.4% vs 48%; P = .17)
  • Overall, 34.1% (95% CI, 27.9%–40.5%) achieved <5 eosinophils per high-power field
  • Maintenance half-doses led to sustained histological remission in 68.2% (95% CI, 63.7%–72.6%) of patients
  • Clinical and histological remission (<15 eos/hpf) was achieved in 45% of patients
  • Histological remission was significantly higher with double PPI doses compared with standard (51.7% vs 28.3%; P < .005)

In the discussion, it was noted that Japanese cohorts had a better response to PPI therapy with a histological remission (67.9%). This could be related to more favorable metabolism of PPI. “CYP2C19∗17 haplotype (related to ultrarapid and rapid PPI metabolizers), is the least prevalent (<3%) in patients with Asian ancestry.”

My take: This study reinforces previous data showing a 40-50% remission rate with PPI therapy for EoE. Twice a day PPI therapy is significantly more effective than once a day.

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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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