Should the Gluten Threshold Dose in Celiac Disease Change Based on Immune Activation?

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Background: Interleukin 2 (IL2) rises acutely after gluten ingestion, allowing the definition of threshold doses that trigger immune activation.

Methods: This was a randomized double-blind, placebo-controlled adaptive dose–response trial in adults with biopsy-proven celiac disease on a gluten-free diet for >2 years. Participants (n = 51; median age, 52 years; 69% were female) underwent 3 oral gluten (1–1000 mg) or placebo challenges at 4-week intervals. Eliciting dose (EDp, ie, the dose at which p% of people respond) was estimated by interval-censored survival analysis.

Key findings:

  • Gluten induced dose-dependent IL2 elevations, with ≥2-fold increases in 83% at 1000 mg, 83% at 610 mg, 36% at 90 mg, 17% at 13 mg, 27% at 8 mg, and 17% at 3 mg; none responded to 5 mg, 2 mg, 1 mg, or placebo.  
  • Estimated ED50 was 111 mg, ED10 was 2.4 mg, ED05 was 0.8 mg, and ED01 was 0.1 mg

From the editorial:

“To date, the few investigators who addressed this question defined tolerance in relation to quantifiable histologic damage (intestinal morphometry)…Bearing in mind that the typical Western diet contains 10–15 g of gluten per day, these studies found that the protracted, daily ingestion of 1000, 200, or 50 mg of gluten elicits significant damage at the mucosal level.2,3 A daily dose of 10 mg was also associated with minimal architectural changes in some patients…

In 2007, the Food and Agricultural Organization/World Health Organization Codex Alimentarius Commission4 applied these findings to establish that commercially available gluten-free food must not contain more than 20 mg/kg gluten (20 part per million [ppm]), as this would ensure that daily gluten intake does not exceed 10 mg…Not a single case of proven intolerance to 20 ppm gluten-free food has been described…in some 20-ppm countries, most labeled gluten-free products already contain much less than 20 ppm of gluten, usually <10 ppm5…

The authors concluded that the daily gluten threshold should be decreased because acute IL2 release occurred at 3 mg, which is less than is allowed by current food-labeling rules for gluten-free products…

Because symptoms did not correlate with the result of the IL2 test for gluten doses <1 g, further prolonged microchallenge studies remain the only reliable strategy to investigate the correlation between the IL2 test and the gold standard of CeD activity—histologic damage of the small intestinal mucosa.10,11“

My take: This study is intriguing that there is evidence of immune activation at lower gluten exposures; however, it does not prove that changing the gluten threshold is beneficial.

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Breaking the Silence: A Doctor’s Struggle with Mental Health

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T Khan et al. NEJM 2026; 395: 529-531. Doctor’s Dirty Little Secret — The Cost of Silence

An excerpt:

No one would suspect that for the past month I’d been plotting my death. Death felt like the only way to let go of the fear and exhaustion that was swallowing me whole…

“You know we don’t lock people up just for having suicidal thoughts anymore, right?” The on-call emergency psychiatrist’s tone, though comforting, was edged with frustration…

“Most of us have had thoughts of suicide at some time in our careers,” she said plainly. “It’s an occupational hazard — like a needlestick or missing your kid’s recital.”

With those matter-of-fact words, she named the doctor’s dirty little secret: we are human. But we believe this admission could cost us everything. That curbside consult saved my life. For the first time in a long while, I didn’t feel alone.

I’d been an emergency doctor for nearly half my life, running on a steady drip of cortisol. By my 40s, my body struggled to keep pace with the demands of the job…

I was responsible for everyone and everything all at once — crisis, illness, intoxication, and circumstance colliding, each person having been carried to me by whatever fear or fate had gripped them. I absorbed the frequent interruptions along with the urgency and blame, until the weight of it all settled as a constant heaviness in my chest…

I was deep in burnout.

And I am not alone. In the United States, female physicians die by suicide at more than 2.27 times the rate of women in the general population, and male physicians at 1.41 times the rate of men in general.1 These statistics are not abstract. They reflect the real suffering of physicians, who are also children, spouses, parents, siblings, and friends, and they reflect a story I never expected would one day become my own. The data challenge the enduring myth that doctors are somehow superhuman…

Despite copious literature on burnout, effective solutions remain scarce…many of us find deep meaning in our work, which fuels perseverance even in the face of adversity…

It took crashing into a wall for me to understand the delicate dance between grit and resilience. Grit is the pedal that drives us forward; resilience is the wheel that helps us change course. Resilience guided me to seek help — which was surprisingly difficult to find…

I kept my license, my family, and my life — for now. But many physicians aren’t as fortunate. Shame, stigma, and institutional failures may keep them silent, but silence is not strength. And asking for help is not a betrayal of the profession.

Related article: A Albert. Gastro & Endo News July 2026. Listen to Your Youngers: Why Gen Z Doctors Refuse to Die for RVUs Open Access! “I think we do better by our patients when we do better for ourselves…The younger generation isn’t “killing” medicine. They’re trying to survive it. They’re realizing that an exhausted, dehydrated doctor who hasn’t seen sunlight in three days isn’t “dedicated”—they’re a liability.”

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Practice-Changing Study on Minor Papillotomy for Treatment of Pancreas Divisum

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GA Cote et al. JAMA 2026; 335;(8):682-692. doi:10.1001/jama.2025.23988. Open Access! Minor Papillotomy for Treatment of Idiopathic Acute Pancreatitis With Pancreas Divisum: A Randomized Clinical Trial

Background:  When pancreas divisum is identified by cross-sectional imaging, many clinicians proceed to ERCP with minor papillotomy because of its suggested benefit in reducing future episodes of pancreatitis. This practice has been disputed because pancreas divisum is present in 7% to 10% of asymptomatic individuals…the primary aim of the Sphincterotomy for Acute Recurrent Pancreatitis (SHARP) trial was to determine if ERCP with minor papillotomy reduces the risk of acute pancreatitis in patients with pancreas divisum and otherwise unexplained acute recurrent pancreatitis.

Normal Pancreatic Anatomy:

Methods: This multicenter, sham-controlled, double-blind randomized clinical trial enrolled adults (n=148) with 2 or more episodes of acute pancreatitis and pancreas divisum; participants were followed up for a median of 34 months. Adults with other etiologies for acute pancreatitis or concomitant chronic calcific pancreatitis were excluded.

Key findings:

  • ERCP with minor papillotomy did not significantly reduce the rate of acute pancreatitis during follow-up (34.7% vs 43.8% for sham ERCP; adjusted hazard ratio, 0.83).
  • The adverse event of acute pancreatitis within 30 days of randomization occurred more frequently in the ERCP with minor papillotomy group (14.7%) vs the sham ERCP group (8.2%) 
  • There was no between-group difference in acute pancreatitis episode frequency and development of chronic calcific pancreatitis, diabetes, or exocrine pancreatic dysfunction.

Discussion: “The current trial showed that patients who underwent ERCP with minor papillotomy did not have a lower risk of developing another episode compared with those managed conservatively (sham ERCP). The added risk of post-ERCP pancreatitis (occurred in 13.3% of ERCP with minor papillotomy group vs 0% with sham ERCP) furthers the argument to avoid minor papillotomy for pancreas divisum alone and controverts years of teaching that had been grounded in data from cohort studies suggesting a benefit.”

My take (borrowed from authors): Among patients with unexplained acute recurrent pancreatitis and pancreas divisum, ERCP with minor papillotomy does not reduce the risk of another episode of acute pancreatitis or related sequelae.

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A Natural Experiment: Sugar Rationing and Metabolic Dysfunction-Associated Steatotic Liver Disease

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J Zheng et al. Clinical Gastroenterology Hepatology 2026; 24: 2168-2180. Open Access! Sugar Rationing in the First 1000 Days After Conception and Long-Term Risk of Metabolic Dysfunction-Associated Steatotic Liver Disease and Major Adverse Liver Outcomes: A Natural Experiment Study

A previous blog post (The Hidden Dangers of Early Sugar Exposure) reviewed the beneficial effects of sugar rationing in Britain around WWII. There were lower rates of type 2 diabetes and hypertension.

Today’s article, reviews the effects of sugar rationing on liver outcomes.

Methods:

Key findings:

  • Among 63,698 participants, early-life sugar rationing was associated with a 30% reduced risk of MASLD (hazard ratio, 0.70), 17% lower risk of metabolic dysfunction-associated steatotic liver disease with alcohol consumption, 35% for major adverse liver outcomes, and 32% for cirrhosis. 
  • The protective effect increased with longer exposure.

My take: Reducing sugar, including in the prenatal period, reduces the risk of adverse liver outcomes in addition to type 2 diabetes and hypertension.

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From AGA Today in Medicine on 8/19/26 – Ongoing Cyclospora Outbreak:

Negative Study: Nortriptyline for Functional Dyspepsia

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Yesterday’s post showed that peppermint oil/sweets were not superior to placebo for management of pediatric IBS. Today’s study, likewise, shows that nortriptyline was not superior to placebo for functional dyspepsia, another DGBI. At the same time, the trials also showed fairly high response rates along with low adverse effect rate.

Methods: This was a multicenter, RCT of patients with FD (functional dyspepsia) in primary, secondary, and tertiary care. Sixty-nine participants were randomly assigned to nortriptyline (weeks 1–2: 10 mg; weeks 3–4: 25 mg; weeks 5–12: 50 mg) vs placebo for a 12-week treatment. The primary outcome was clinical response based on a decrease in FD symptoms of at least 30% compared with baseline, in 50% of the last 10 weeks of the treatment period.

Key finding:

  • The primary outcome showed no significant difference in response for nortriptyline compared with placebo (45% vs 58%; odds ratio [OR], 0.574)
  • There was no significant difference in adverse events between the nortriptyline and placebo group
  • Nortriptyline plasma levels were significantly higher in responders compared with non-responders (13.0 μg/L vs. vs 9.0 μg/L; P = .003)
  • The belief to have received nortriptyline showed a higher response rate than the belief to have received placebo (77% vs 36%; OR, 11.439; P = .004)

The accompanying editorial makes several important points:

  • “Placebo response is intrinsic to all DGBI trials. Across pediatric and adult populations, placebo response rates of 30% to 60% are common.3–5 Symptom fluctuation, regression to the mean, expectation bias, and cognitive–affective modulation of visceral perception all contribute. In children, parental expectations and heightened suggestibility may further amplify contextual effects. Nevertheless, they also highlight that placebo effects are an integral part of the therapeutic response seen in DGBI trials and clinical practice.”
  • “Expectancy effects deserve deliberate consideration in both trial design and clinical care. The nortriptyline trial elegantly demonstrated that participants’ belief or expectation about treatment allocation was more strongly associated with response than the medication itself…In clinical practice, clear explanations, symptom validation, confident framing of the treatment rationale, and a strong clinician–patient alliance can ethically harness expectancy and placebo effects to enhance response.6“
  • “Neither study suggests that pharmacologic therapy has no role in management. The association between higher nortriptyline plasma levels and response leaves open the possibility that a subset of patients derive biological benefit. Likewise, peppermint oil was safe and well-tolerated. However, these trials caution against overinterpreting modest signals from small or uncontrolled studies and emphasize the importance of adequately powered, methodologically rigorous trials in conditions characterized by high placebo response.”

My take: Rigorous pharmacologic studies show that medications, to date, recommended for patients with DGBIs have difficulty outperforming placebo; yet, there is a high response in patients with DGBIs. In this setting, the use of medications with a low incidence of adverse effects and plausible beneficial effects continue to have a role in improving symptom control.

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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.

A Randoized Trial of Peppermint Oil for Pediatric Irritable Bowel Syndrome

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N Vermeijden et al. Clinical Gastroenterology and Hepatology, 2026; 24, 2286-2296. Peppermint Oil and Sweets in Pediatric Irritable Bowel Syndrome and Functional Abdominal Pain: A Randomized Trial

Methods: A large randomized controlled trial evaluated 228 children and adolescents aged 8 to 18 years across multiple hospitals.  The primary endpoint was treatment success, defined as a ≥30% reduction of abdominal pain intensity after 8 weeks. 

Key finding:

  • Treatment success rates—measured as a 30% or greater drop in pain intensity after 8 weeks—were similar for peppermint oil (44.0%), peppermint sweets (38.7%), and placebo (37.3%)

My take: The overall response rate for peppermint oil, peppermint sweets and placebo ranged from 37% to 44%. Given its safety, it should still be considered a useful treatment for pediatric IBS (see more on this tomorrow). It is listed as a recommended therapy in recent guidelines with low evidence of effectiveness.

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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

Prognostic Tool for Biliary Atresia after Kasai: Serum Bile Acids (2026)

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E Grimaud et al. Hepatology 2026; 84: 117-128. Serum bile acid levels predict the development of portal hypertension and high-risk esophageal varices following successful Kasai in biliary atresia

Methods: The authors examined the predictive value of serum bile acids (sBA) patients (n=57) with biliary atresia who underwent a successful Kasai Procedure (KP), defined as a total serum bilirubin level of ≤25 μmol/L within 6 months after KP.

Key findings:

  • sBA thresholds of 56 and 30 μmol/L at a median time of 6 and 11 months after KP predicted HRV within 5 years after KP with a sensitivity of 100%.
  • No patient with sBA <18 μmol/L (between 4-9 months after KP) developed portal hypertension (PH) at 3 and 5 years after Kasai, whereas sBA >41 μmol/L predicted PH with PPV of 91% and 97% at 3 and 5 years after KP, respectively

From editorial on pages 1-2: “Persistent elevation f=of sBA likely reflects ongoing intrahepatic cholestasis and bile-acid mediated hepatocellular and fibrogenic injury, even in the setting of ostensibly adequate biliary drainage.”

My take: This study is in agreement with others regarding the predictive value of sBA. It suggests the current definition of a successful KP needs modification to incorporate sBA. Those with good bilirubin parameters but with persistent elevation of sBA could be considered partially-successful KP.

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Braud Bakery in Reykjavik

Sodium Bicarbonate Locks to Prevent Central Line Infections

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K McNevin, BE Rosete et al. J Pediatr Gastroenterol Nutr. 2026;82:1303–1308. A comparison between sodium bicarbonate and ethanol for central line locks in pediatric patients with intestinal failure

Background: Since 2022, there has been growing interest in the use of sodium bicarbonate locks. This dates back to 2018, when Belcher pharmaceuticals managed to get the FDA to designate Ethanol as an orphan drug with a subsequent increase in cost (at that time) to ~$10,000 for a 10-vial pack (10-day supply) (Related post: FDA ‘Safety Initiative’ Now Means an Ounce of Ethanol Costs $30,000). As such, many (?most) children with intestinal failure (IF) no longer had access to Ethanol Lock Therapy which prevents life-threatening infections to their central lines. Sodium bicarbonate has been shown to inhibit bacterial proliferation by impeding bacterial adherence and preventing biofilm formation.15, 16 

Methods: A retrospective cohort study was conducted in pediatric patients with IF (19 children who received ethanol locks and 36 with sodium bicarbonate locks) followed by the Intestinal Rehabilitation Program at Seattle Children’s Hospital who received ethanol or sodium bicarbonate locks from 2018 to 2023.

Volume of the lock was calculated based on the documented catheter length when available and by drawing back from the line until blood return was obtained when length unavailable. Ethanol locks were withdrawn from the catheter after the dwell while SBL were flushed.

Key findings:

  • Rates of CLABSI were similar between the ethanol and sodium bicarbonate lock cohorts (2.03 per 1000 catheter days and 1.59 per 1000 catheter days; p = 0.617)
  • The sodium bicarbonate group had a lower rate of line replacement (2.21 in the EL group and 0.00 in the SBL group (p = 0.01) and trended toward a lower rate of line repair with1.94 in the EL group and 1.07 in the SBL group (p = 0.23).

Discussion:

  • “While alternatives exist and may also be effective, SBL has the added benefit of a substantially lower cost. At the time this manuscript was written, based on SCH mediation wholesaler data, the cost of 1 mL of ethanol (Ablysinol®) was $186.66 whereas 1 ml of sodium bicarbonate 8.4% was $0.18.”

My take (borrowed from the authors); Based on these data, SBL should be considered as a primary option for lock therapy in children with IF.

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Seljalandsfoss in Iceland (attribution: Jennifer Hochman)

Regulating Medication Promotion on the Internet

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N Kruger et al. NEJM 2026; 395: 319-321. When Celebrities Prescribe — Regulating Drug Promotion on the Internet

An excerpt:

Since the 1980s, direct-to-consumer advertising of prescription drugs has been prevalent in the United States — one of only two high-income countries to permit such ads…Endorsements of prescription drugs on social media can be rapidly disseminated across platforms, complicating regulatory oversight…

Under federal law, a prescription drug is considered to be misbranded if labeling or advertising for the product is false or misleading, which can include omission of material information. According to implementing regulations from the Food and Drug Administration (FDA), fair balance is required in the communication of benefits and risks…when social-media influencers and online pharmacies are the source of drug-related communication, their financial or other relationships to manufacturers or compounding pharmacies can be unclear…

Patient-facing content that now circulates pervasively on social-media platforms can blur the distinction between health-related information about prescription drugs and misleading advertising…

Stronger guardrails are needed to protect the public and to keep pace with the ways in which patients now encounter drug promotion…

The FDA could modernize fair-balance requirements for digital platforms by mandating that information about risks be presented directly alongside claims about benefits (e.g., provided in the same social-media communication, using spoken or visually prominent content), rather than being relegated to fine print or a separate website…

The Protecting Patients from Deceptive Drug Ads Act (S. 652) attempts to modernize oversight by requiring influencers to disclose compensation they receive for prescription-drug promotion to the Open Payments database. It would also authorize civil penalties for entities engaging in paid social-media communication that they know is misleading or that is recklessly false and extend FDA advertising requirements, including fair-balance obligations, to telehealth companies. Under such a regime, regulators could prioritize enforcement actions against high-reach celebrity-endorsement campaigns, since a small number of people have outsized influence and enforcement activities could deter similar behavior.

My take: Paid influencers should be held to the same standards of disclosure about their pharmaceutical endorsements as manufacturers.

Kvernufoss, Iceland.
The size of the waterfall can be gaged in part by looking at the people behind the falls.