Severe Immune-Mediated Enteropathy

Severe immune-mediated enteropathy means the small intestine is badly inflamed or injured because the immune system is attacking or mis-controlling the lining of the gut. “Severe” means the damage is strong enough to cause relentless watery diarrhea, weight loss, dehydration, and poor absorption of nutrients (malabsorption). Under the microscope, doctors often see blunting or loss of the finger-like villi that normally absorb food, plus immune cells crowding the tissue. The trigger can be a specific immune disease (for example, celiac disease or autoimmune enteropathy), inborn immune problems (like IPEX or CVID), immune-targeting medicines (immune-checkpoint inhibitors), some drugs (for example, olmesartan), or donor-immune attacks after bone-marrow transplant (gut GVHD). Correct diagnosis matters because treatments differ: some people improve with a strict gluten-free diet (celiac disease), while others need steroids or other immune-suppressing medicines, drug withdrawal (if a medicine caused it), or specialist management (for IPEX, CVID, or GVHD). PMC+4PubMed+4Lippincott Journals+4

Severe immune-mediated enteropathy means the lining of your small intestine is badly inflamed because the immune system is attacking it. The villi (tiny finger-like projections that absorb food) can become flat or damaged. This causes poor absorption of nutrients, weight loss, and ongoing watery diarrhea. It can happen in several conditions, such as celiac disease (especially refractory celiac that does not improve with a strict gluten-free diet), autoimmune enteropathy, immune-checkpoint-inhibitor colitis/enteritis (a side effect of some cancer drugs), and enteropathy linked to immune deficiencies like CVID. Doctors confirm the cause with history, blood tests, stool tests, and small-bowel biopsies. Treatment targets the trigger (like gluten) and calms the immune attack with diet, medicines, or sometimes advanced therapies. PubMed+3Lippincott Journals+3Gastrojournal+3

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Other names

• Autoimmune enteropathy (AIE) – a non-celiac autoimmune disease with villous atrophy and anti-enterocyte/goblet-cell antibodies in some patients. PMC+1

• Celiac disease (celiac sprue; gluten-sensitive enteropathy) – an immune reaction to gluten that injures the small bowel; severe cases can mimic other enteropathies. PubMed

• Refractory celiac disease (RCD type 1 or type 2) – persistent villous atrophy and symptoms despite ≥1 year of strict gluten-free diet; type 2 has abnormal clonal intraepithelial T-cells. Gi Board Review+1

• CVID-associated enteropathy – chronic gut inflammation in common variable immunodeficiency. PMC+1

• IPEX-associated enteropathy – early-onset, life-threatening diarrhea linked to FOXP3 defects (regulatory T-cell failure). NCBI+1

• Drug-induced sprue-like enteropathy – classically olmesartan-associated; looks like severe celiac but improves after stopping the drug. The Lancet+1

• Immune-checkpoint-inhibitor (ICI) enterocolitis/enteritis – inflammation triggered by anti-CTLA-4/PD-1/PD-L1 cancer drugs. Annals of Oncology+1

• Gastrointestinal graft-versus-host disease (GI-GVHD) – donor immune cells attack recipient gut after allogeneic transplant. NCBI+1

• Eosinophilic gastroenteritis (EGE) – Th2-driven, eosinophil-rich inflammation often involving small bowel; can cause malabsorption. PMC

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Types

1. Antigen-driven autoimmune type
   • Celiac disease (gluten-triggered) and its refractory forms. PubMed+1

2. Non-celiac autoimmune type (AIE)
   • Autoimmune attack on enterocytes/goblet cells; often steroid-responsive but may need other immunosuppression. PMC

3. Primary immune-dysregulation type
   • IPEX (regulatory T-cell failure, FOXP3 mutation) and CVID-enteropathy (antibody deficiency with dysregulated mucosal immunity). NCBI+1

4. Therapy-induced immune type
   • Immune-checkpoint inhibitors (CTLA-4/PD-1/PD-L1) causing enterocolitis/enteritis. Annals of Oncology

5. Drug-associated sprue-like type
   • Olmesartan-associated enteropathy (and rarely other ARBs). PubMed

6. Allogeneic immune attack type
   • GI-GVHD after hematopoietic stem-cell transplant. NCBI

7. Eosinophil-predominant allergic/immune type
   • Eosinophilic gastroenteritis affecting small bowel layers. PMC

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Causes

1. Gluten exposure in celiac disease – gluten triggers an adaptive immune response that flattens villi and causes malabsorption; strict gluten-free diet (GFD) is the cornerstone. PubMed

2. Refractory celiac disease, type 1 – persistent symptoms/villous atrophy despite ≥1 year of strict GFD; immune injury continues independently of gluten. PMC

3. Refractory celiac disease, type 2 – similar persistence plus clonal, aberrant intraepithelial T-cells; higher complication risk. Gi Board Review

4. Autoimmune enteropathy (AIE) – autoimmune attack against intestinal epithelial cells; some patients have anti-enterocyte or anti-goblet cell antibodies. PMC

5. IPEX syndrome (FOXP3 defect) – loss of regulatory T-cell control causes early, severe watery diarrhea and villous atrophy. NCBI

6. CVID-associated enteropathy – antibody deficiency with non-infectious gut inflammation that mimics celiac but is serology-negative. PMC

7. Immune-checkpoint inhibitor therapy (CTLA-4/PD-1/PD-L1) – breaks immune tolerance and can inflame small and large bowel. PMC

8. Olmesartan (ARB)–associated sprue-like enteropathy – severe diarrhea and villous atrophy that improve after stopping the drug; the strongest signal is with olmesartan. PubMed

9. Other ARBs (rare reports) – occasional similar cases reported with other ARBs, but much less frequent than olmesartan. PubMed

10. GI graft-versus-host disease – donor immune cells attack gut mucosa after transplant, leading to ulcers, denudation, and malabsorption. NCBI

11. Eosinophilic gastroenteritis – Th2-allergic pathways cause eosinophil infiltration of small bowel layers with protein-losing enteropathy. PMC

12. Combined immune dysregulation in adults – heterogeneous non-celiac immune villous atrophy patterns described in updated AIE reviews. PMC

13. Overlap autoimmune diseases (e.g., thyroiditis, type 1 diabetes) with enteropathy – clustering of autoimmunity is common in AIE and celiac cohorts. PMC

14. Post-immune therapy rebound – after tapering immunosuppression, relapses of ICI-related enteritis can occur months later. Frontiers

15. Enteropathy-associated T-cell lymphoma (complication of RCD-II) – malignant clonal T-cells damage mucosa (important to exclude in severe cases). Gi Board Review

16. Autoantibody-mediated epithelial injury – in AIE, anti-enterocyte/goblet antibodies are supportive markers and reflect epithelial autoimmunity. PMC

17. Microbiome-immune interactions (GVHD) – disrupted intestinal barrier and flora worsen immune injury in GVHD. Frontiers

18. HLA-linked susceptibility (celiac) – HLA-DQ2/DQ8 confer risk (useful to exclude celiac when absent). BSHI

19. Immune activation by infections in immunodeficiency (CVID) – infections occur, but the non-infectious immune enteropathy drives chronic injury. PubMed

20. Medication-provoked immune patterns beyond ARBs (less common) – selected agents (e.g., some immunotherapies) can provoke small-bowel-predominant injury patterns. Annals of Oncology

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Common symptoms

1. Watery diarrhea many times a day, sometimes at night; hallmark of severe disease. PMC

2. Weight loss from poor absorption and reduced intake. PMC

3. Weakness and fatigue due to dehydration and vitamin/calorie loss. PubMed

4. Bloating and gas from malabsorption. PubMed

5. Abdominal cramping or pain, often around the navel. PubMed

6. Greasy, bulky stools (steatorrhea) in villous atrophy states. PMC

7. Dehydration (thirst, dark urine, dizziness). PMC

8. Electrolyte problems (low potassium, low sodium) from stool losses—can cause cramps or palpitations. PMC

9. Anemia (iron, folate, or B12 deficiency) with pallor and shortness of breath on exertion. PubMed

10. Swelling of legs (edema) from low albumin/protein loss. PMC

11. Bone pain or fractures from low vitamin D/calcium (longstanding malabsorption). PubMed

12. Mouth ulcers and glossitis (tongue inflammation) with nutrient deficits. PubMed

13. Skin rashes (e.g., dermatitis herpetiformis in celiac; eczema-like rashes in IPEX). PubMed+1

14. Fever when inflammation is very active (especially ICI-colitis or GVHD). PMC+1

15. Growth failure in infants/children (if pediatric onset, e.g., IPEX or AIE). NCBI

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Diagnostic tests

A) Physical exam

1. General appearance and vitals – look for weight loss, muscle wasting, fever, fast heart rate; check orthostatic blood pressure for dehydration. Helps judge severity and the need for urgent fluids. PMC

2. Abdominal exam – diffuse tenderness and hyperactive bowel sounds suggest active diarrhea; marked pain or guarding prompts imaging to exclude complications. PubMed

3. Skin and oral exam – rashes (e.g., dermatitis herpetiformis) and mouth ulcers point to malabsorption or celiac disease. PubMed

4. Edema check (legs, sacrum) – protein loss from enteropathy can cause pitting edema; confirms severity and nutritional compromise. PMC

5. Growth parameters in children – weight-for-age and height-for-age track failure to thrive in pediatric immune enteropathies (e.g., IPEX, AIE). NCBI

B) “Manual” bedside tests

6. Stool occult blood test (guaiac) – quick bedside check for blood; positive results (especially with ICI-colitis or GVHD) suggest more severe mucosal injury. PMC+1

7. Bedside hydration assessment – capillary refill, skin turgor, mucous membranes; guides immediate fluid therapy in profound diarrhea. (Clinical best practice)

8. Dietary review / supervised gluten challenge (selected cases) – in uncertain celiac history, specialists sometimes plan a careful gluten challenge before repeat testing; this is structured, not casual. PubMed

C) Laboratory & pathological tests

9. Celiac serology – tTG-IgA (with total IgA) and EMA; IgG-based tests if IgA-deficient. Essential when celiac disease is suspected. PubMed

10. HLA-DQ2/DQ8 typing – excellent to rule out celiac when absent; not a stand-alone diagnostic test. BSHI+1

11. Comprehensive stool testing – pathogen PCR panel, ova/parasites, fecal calprotectin (elevated in inflammatory conditions); helps exclude infections and quantify inflammation. PubMed

12. Routine blood panels – CBC (anemia), iron/ferritin, folate, B12, albumin, electrolytes, magnesium, calcium, vitamin D—document malabsorption severity. PubMed

13. Immunology profile for CVID – serum IgG/IgA/IgM levels and vaccine antibody responses if CVID enteropathy is suspected. PMC

14. Autoantibodies in AIE – anti-enterocyte and anti-goblet-cell antibodies support AIE but are neither fully sensitive nor specific; absence does not exclude AIE. PMC+2Nature+2

15. Duodenal/small-bowel biopsies (via endoscopy) – the cornerstone: shows villous atrophy, crypt hyperplasia, and inflammatory patterns; pathologists also look for apoptosis or atypical lymphocytes to sort RCD types. PMC+1

16. Flow cytometry / T-cell receptor clonality (RCD) – distinguishes RCD type 1 vs type 2 and helps exclude enteropathy-associated T-cell lymphoma. Gi Board Review

D) Electrodiagnostic / physiologic tests

17. Electrocardiogram (ECG) – not a gut test, but crucial when diarrhea is severe to detect potassium- or sodium-related rhythm risks before giving certain therapies. (Standard medical safety practice)

18. Antroduodenal or small-bowel manometry / wireless motility capsule (selected) – physiologic assessments used by motility centers when symptoms suggest co-existing dysmotility; not diagnostic of enteropathy itself, but can explain refractory bloating or pain. (Specialist use; adjunctive)

E) Imaging & endoscopic visualization

19. Upper endoscopy with multiple duodenal biopsies – required for celiac confirmation (unless a pediatric non-biopsy pathway applies) and for AIE/RCD assessment. PubMed

20. Capsule endoscopy – surveys the entire small bowel for villous atrophy, scalloping, mosaicism, ulcers; also helpful in olmesartan-enteropathy and in complicated celiac. PubMed

21. CT enterography (CTE) or MR enterography (MRE) – evaluates bowel wall inflammation, strictures, and complications; MR avoids radiation, useful for repeated follow-up. (GI imaging practice)

22. Colonoscopy with ileoscopy – checks for concurrent colitis (common with ICI-toxicity and GVHD) and samples the terminal ileum. PMC+1

23. Targeted transplant imaging (selected GVHD cases) – cross-sectional scans help rule out mimics and complications; radiology-pathology correlation improves grading. AJR American Journal of Roentgenology

Non-pharmacological treatments

(I keep the language simple and practical. Where evidence is disease-specific, I say so.)

1. Strict gluten-free diet (GFD): You remove wheat, barley, and rye completely. Purpose: stop the gluten trigger in celiac disease. Mechanism: removing gluten switches off the autoimmune reaction and lets villi heal. In most people, symptoms improve in weeks and labs normalize within months. Needs expert dietitian support; label reading is key. Lippincott Journals+1

2. Dietitian-led “hidden gluten” audit: A trained dietitian checks all foods, meds, and kitchen tools. Purpose: find small gluten sources that keep disease active. Mechanism: reducing trace exposures calms mucosal immune activation. ScienceDirect

3. Exclusive or partial enteral nutrition (case-by-case—more evidence in Crohn’s): Special formulas can give bowel “rest” and provide calories when eating is hard. Purpose: correct malnutrition fast. Mechanism: easy-to-absorb nutrients reduce antigen load and support healing. (More established in Crohn’s; used pragmatically in severe malabsorption.)

4. Parenteral nutrition (TPN) in extreme cases: Nutrition goes into a vein. Purpose: prevent starvation while the gut heals. Mechanism: bypasses inflamed mucosa so the body gets protein, calories, and micronutrients. (Short-bowel/intestinal failure guidelines support TPN when needed.) BAPEN

5. Rehydration and electrolyte replacement: Oral rehydration solution or IV fluids restore volume and salts. Purpose: stop dizziness, kidney stress. Mechanism: replaces water, sodium, potassium lost in diarrhea.

6. Micronutrient repletion plan: Replace iron, folate, B12, vitamin D, calcium, zinc, magnesium, and sometimes copper. Purpose: fix anemia, bone loss, neuropathy, and fatigue. Mechanism: corrects deficits from villous damage and poor intake. PMC+1

7. Bone health program: weight-bearing exercise, vitamin D/calcium goals, and bone density scans when indicated. Purpose: prevent fractures from osteopenia. Mechanism: improves bone remodeling as gut heals. Celiac Disease Foundation

8. Lactose and high-fat trigger reduction (temporary): A damaged brush border can cause temporary lactose or fat malabsorption. Purpose: reduce bloating and greasy stools during healing. Mechanism: less “difficult” substrates until villi recover. (Clinical practice guidance.) Lippincott Journals

9. Low-FODMAP trial for functional overlay: In a subset with IBS-like gas/bloating after mucosa heals, a time-limited low-FODMAP trial can ease symptoms. Purpose: symptom relief. Mechanism: reduces fermentable sugars that cause gas. (Adjunct in selected patients.)

10. Probiotic trial (select cases): Some patients try a high-potency probiotic while monitoring symptoms. Purpose: improve gut flora balance; benefit varies. Mechanism: alters microbiome; strongest evidence is in pouchitis, less in celiac/AIE. (Use cautiously.)

11. Food safety and infection prevention in CVID or immunosuppressed: Purpose: reduce gut infections when immunity is low. Mechanism: lowers pathogen exposure. PubMed

12. Medication review: Avoid NSAIDs or drugs that irritate gut, check for sorbitol or lactose excipients. Purpose: remove aggravating factors. Mechanism: reduces non-immune injury and osmotic diarrhea.

13. Pelvic-floor therapy (diarrhea urgency): Purpose: improve control and reduce leakage. Mechanism: strengthens external sphincter coordination.

14. Psychological support/CBT: Chronic illness causes stress and food fear. Purpose: improve coping and adherence. Mechanism: CBT reduces anxiety and improves symptom perception.

15. Vaccinations up to date (especially if on immunosuppression or in CVID): Purpose: prevent infections that can worsen gut disease. Mechanism: vaccine-induced immunity where appropriate. PubMed

16. Sunlight and safe weight-bearing activity: Purpose: support bone and muscle. Mechanism: improves vitamin D status and strength. PMC

17. Dietary fiber re-introduction when tolerable: Purpose: normalize stool and microbiome as inflammation settles. Mechanism: feeds beneficial bacteria; go slow to avoid bloating. nutritionguide.pcrm.org

18. Elemental or semi-elemental formulas as supplements: Purpose: easier absorption when appetite is low. Mechanism: small peptides and MCTs absorb with less effort. (Used in malabsorption practice.)

19. Kitchen cross-contact controls: Separate toaster, cutting boards, pans for gluten-free food. Purpose: stop trace gluten. Mechanism: cuts daily immune triggers. ScienceDirect

20. Regular follow-up pathway (labs + diet check): Purpose: catch relapse early. Mechanism: track serology, nutrition, and symptoms on a schedule. Nature

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Drug treatments

(Doses are typical starting points or schedules used in guidelines/reviews; individual regimens must be personalized by your clinician.)

1. Budesonide (open-capsule) – locally acting steroid. Dose: often 9 mg daily (modified for delivery to proximal small bowel). Purpose: first-line for RCD-I; reduces inflammation with fewer systemic effects. Mechanism: topical glucocorticoid dampens mucosal immune activity. Side effects: less systemic than prednisone; possible edema, mood change, glucose rise. PMC

2. Prednisone – systemic corticosteroid. Dose: e.g., 0.5–1 mg/kg/day short term then taper. Purpose: rapid control in severe flares or AIE. Mechanism: broad immunosuppression. Side effects: hyperglycemia, infection risk, bone loss, mood changes. PMC

3. Azathioprine – thiopurine immunosuppressant. Dose: ~1.5–2.5 mg/kg/day after TPMT/NUDT15 testing. Purpose: steroid-sparing in AIE/RCD-I; sometimes used in RCD-II adjunctively. Mechanism: inhibits lymphocyte proliferation. Side effects: leukopenia, hepatotoxicity, infections. GastroRes

4. 6-Mercaptopurine (6-MP) – thiopurine. Dose: ~1–1.5 mg/kg/day. Purpose: alternative to azathioprine. Mechanism: purine antagonist reduces T-cell activity. Side effects: myelosuppression, liver enzyme rise. (Thiopurine class effects.)

5. Methotrexate – antimetabolite immunomodulator. Dose: e.g., 15–25 mg weekly with folic acid. Purpose: steroid-sparing in autoimmune enteropathies. Mechanism: inhibits folate-dependent pathways; anti-inflammatory at low dose. Side effects: liver toxicity, cytopenias, mucositis; avoid in pregnancy. (Autoimmune practice.)

6. Mycophenolate mofetil – antiproliferative. Dose: 1–1.5 g twice daily. Purpose: option in AIE/CVID enteropathy not controlled by steroids. Mechanism: blocks inosine monophosphate dehydrogenase in lymphocytes. Side effects: infections, GI upset, cytopenias. PubMed

7. Tacrolimus – calcineurin inhibitor. Dose: individualized to trough levels. Purpose: rescue in severe autoimmune enteropathy. Mechanism: inhibits T-cell activation via calcineurin. Side effects: nephrotoxicity, tremor, hypertension, infections. (AIE case series.) BioMed Central

8. Cyclosporine – calcineurin inhibitor. Dose: adjusted to levels. Purpose: similar rationale as tacrolimus for steroid-refractory cases. Mechanism/side effects: as above (gingival hyperplasia with cyclosporine).

9. Infliximab – anti-TNF monoclonal antibody. Dose: 5 mg/kg IV at weeks 0, 2, 6, then q8 weeks. Purpose: steroid-refractory ICI colitis/enteritis or severe immune enteropathy; sometimes tried in AIE. Mechanism: neutralizes TNF-α to reduce mucosal inflammation. Side effects: infusion reactions, infection (TB/hepatitis reactivation). PMC+1

10. Vedolizumab – anti-α4β7 integrin gut-selective biologic. Dose: 300 mg IV weeks 0, 2, 6 then q8 weeks. Purpose: steroid-refractory ICI colitis/enteritis; gut-selective option with less systemic immunosuppression. Mechanism: blocks lymphocyte gut homing. Side effects: infections; generally favorable safety. PMC+1

11. Ustekinumab – IL-12/23 blocker. Dose: weight-based IV induction then SC q8–12 weeks (off-label scenarios). Purpose: difficult immune enteropathies when anti-TNF/vedolizumab fail. Mechanism: down-regulates Th1/Th17 pathways. Side effects: infections. (Used by extrapolation in immune-mediated gut disease.)

12. Tofacitinib – JAK inhibitor. Dose: 5–10 mg PO bid (ulcerative colitis labeling; off-label in RCD-II case reports). Purpose: rescue in refractory inflammatory cases. Mechanism: blocks JAK-STAT signaling. Side effects: zoster, lipids, VTE signal at higher risks. ScienceDirect

13. Upadacitinib – JAK1-selective inhibitor. Dose: per UC labeling (off-label here). Purpose/Mechanism/AE: as above (selective JAK1). (Considered only in expert centers.)

14. Cladribine (2-CdA) – purine analog cytotoxic to lymphocytes. Dose: short IV/SC cycles per protocols. Purpose: targets aberrant IELs in RCD-II; can improve survival in responders. Mechanism: depletes abnormal T cells. Side effects: cytopenias, infection; rare reports of rapid lymphoma emergence post-therapy underline need for expert monitoring. PMC+2CGH Journal+2

15. Bile-acid binders (e.g., cholestyramine) – resin. Dose: 4 g 1–4×/day. Purpose: treat bile-acid diarrhea that can accompany small-bowel disease. Mechanism: binds bile acids. Side effects: bloating, drug interactions.

16. Antibiotics for SIBO (e.g., rifaximin): Dose: common course 550 mg tid × 14 days. Purpose: reduce bacterial overgrowth that worsens malabsorption. Mechanism: lowers small-bowel bacteria. Side effects: headache, nausea.

17. Pancreatic enzymes if secondary pancreatic insufficiency suspected. Purpose: improve fat absorption. Mechanism: replace lipase. Side effects: cramps, constipation.

18. Antidiarrheals (loperamide) for symptom control while treating the cause. Dose: per label with clinician guidance. Side effects: constipation if overused.

19. Proton-pump inhibitor if acid-related upper symptoms or to protect with steroids/NSAID avoidance; indirect support only.

20. Parenteral vitamin and mineral therapy (e.g., IV iron, IM B12) when oral fails. Purpose/Mechanism: correct deficits to support mucosal healing and whole-body recovery. PMC

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Dietary molecular supplements

1. Iron (oral or IV): replaces iron lost from malabsorption; improves energy and anemia correction. Typical oral elemental iron 45–65 mg/day; IV for severe cases. Mechanism: rebuilds hemoglobin and enzymes. Watch constipation or infusion reactions. PMC

2. Vitamin D3 + Calcium: supports bone healing during recovery; common deficits in celiac. Typical D3 1000–2000 IU/day (or tailored), calcium 1000–1200 mg/day through diet/supplement. Mechanism: improves calcium absorption and bone remodeling. Celiac Disease Foundation

3. Vitamin B12 (oral high-dose or IM): fixes neuropathy and anemia from ileal malabsorption. Typical IM monthly or high-dose oral daily. Mechanism: restores DNA synthesis and nerve health. bidmc.org

4. Folate: corrects megaloblastic anemia and supports mucosal cell turnover. Typical 1 mg/day. Mechanism: provides methyl donors for new cells. Celiac Disease Foundation

5. Zinc: low zinc is common; deficiency worsens diarrhea and skin healing. Typical 25–50 mg elemental/day short term. Mechanism: cofactor for enzymes and immunity. PMC

6. Magnesium: diarrhea depletes magnesium; low levels cause cramps and fatigue. Typical 200–400 mg/day (watch laxative forms). Mechanism: supports energy and muscle function. PMC

7. Copper (select cases): severe malabsorption can cause low copper and anemia/neutropenia. Replacement is individualized. Mechanism: enzyme cofactor. Celiac Disease Foundation

8. Niacin and other B-complex: GFD diets can be low in B vitamins; repletion supports energy and mucosal repair. Mechanism: coenzymes for metabolism. nutritionguide.pcrm.org

9. Omega-3 fatty acids: may reduce inflammatory signaling; evidence in celiac is limited but sometimes used. Typical EPA/DHA 1–2 g/day if approved. Mechanism: alters eicosanoid pathways.

10. Soluble fiber (psyllium) once inflammation calms: helps form stools and feed good bacteria. Typical 1–2 tsp in water daily, titrate. Mechanism: prebiotic effect and water binding. nutritionguide.pcrm.org

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Immunity-modulating / regenerative” therapies

1. Teduglutide (GLP-2 analog) for short-bowel/intestinal failure complicating severe enteropathy: reduces parenteral support by enhancing intestinal absorption and mucosal growth. Dose per label (0.05 mg/kg/day SC). Monitor for intestinal neoplasia risk and biliary issues. Specialist therapy only. Medscape+2PMC+2

2. Autologous hematopoietic stem-cell transplantation (auto-HSCT) in select RCD-II at expert centers: aims to reset immune system when medical therapy fails. Mechanism: high-dose chemo “reboots” immunity, then stem-cell rescue. Risks are serious; considered case-by-case. PubMed+1

3. Cladribine (2-CdA) cycles (covered above): lymphocyte-depleting therapy for RCD-II with careful surveillance. PMC

4. Biologic escalation (vedolizumab or infliximab) in ICI enteritis to spare steroids and allow cancer therapy decisions with oncology. Gut-selective vedolizumab may reduce systemic immunosuppression. PMC+1

5. JAK inhibitors (e.g., tofacitinib) in highly refractory inflammatory phenotypes at centers with experience. Emerging reports only; risks must be weighed. ScienceDirect

6. Targeted therapy for complications (e.g., lymphoma protocols if EATL develops), managed by hemato-oncology. (Rationale from RCD-II natural history.) Frontiers

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Procedures / Surgeries

1. Feeding tube (nasojejunal or PEG-J): short- or medium-term enteral feeding when oral intake is not enough. Why: prevent severe malnutrition while treating inflammation.

2. Central venous catheter for parenteral nutrition: for intestinal failure or when absorption is too poor. Why: life-saving nutrition support. BAPEN

3. Diagnostic/therapeutic endoscopy: repeat biopsies, treat bleeding/strictures, or dilate narrowed segments. Why: stage disease and relieve obstruction.

4. Segmental small-bowel resection: only for complications like perforation, bleeding, or strictures unresponsive to dilation. Why: treat emergencies, not the immune process.

5. Oncologic surgery if lymphoma develops. Why: treat malignancy that can arise in RCD-II. Frontiers

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Preventions

1. Absolute gluten avoidance in celiac spectrum. Lippincott Journals

2. Regular dietitian check-ins to keep diet truly gluten-free. ScienceDirect

3. Vaccinations (per schedule) if you’ll be on immunosuppression or have CVID. PubMed

4. Routine labs to catch nutrient gaps early. Nature

5. Bone health plan (vitamin D/calcium, weight-bearing). Celiac Disease Foundation

6. Avoid NSAIDs/smoking to protect gut lining.

7. Food safety (hand-washing, safe cooking), especially with low immunity. PubMed

8. Medication cross-check for gluten/lactose excipients when sensitive.

9. Manage stress and sleep to support immunity.

10. Early specialist referral if symptoms persist >3–6 months despite good diet.

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When to see a doctor (red flags)

See a gastroenterologist urgently if you have blood in stool, severe abdominal pain, fever, dehydration, fainting, rapid weight loss, nighttime diarrhea, swelling of legs, new jaundice, or persistent symptoms despite a verified strict GFD. People on cancer immunotherapy should call their oncology team at the first signs of new diarrhea because early treatment prevents severe ICI enteritis. PMC

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What to eat” and “what to avoid

Eat:

1. Naturally gluten-free whole foods (rice, corn, potatoes, legumes). 2) Lean proteins (fish, eggs, poultry) to rebuild muscle. 3) Lactose-free dairy or fortified plant milks early if lactose intolerant. 4) Low-fat cooking during steatorrhea, then gradually liberalize. 5) Fruits/vegetables peeled and cooked at first for comfort, then expand. 6) Gluten-free whole grains (quinoa, buckwheat, millet) for fiber and B vitamins. 7) Electrolyte drinks if diarrhea is heavy. 8) Iron-rich foods (meat, legumes) with vitamin C to boost absorption. 9) Omega-3 sources (fish, flax) for general health. 10) Plenty of water.

Avoid (or limit early):

1. All gluten (wheat, barley, rye; watch cross-contact). 2) Ultra-processed GF snacks low in fiber and vitamins. 3) High-lactose foods until brush border heals. 4) Excess alcohol. 5) Very spicy or very fatty meals during flares. 6) Sugar alcohols (sorbitol, mannitol) that can worsen diarrhea. 7) Caffeine excess if it triggers stools. 8) Raw salad bowls early if they worsen bloating—re-introduce later. 9) Unvetted supplements that may contain gluten. 10) Undercooked foods if immunity is low. ScienceDirect+1

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Frequently asked questions

1) Is severe immune-mediated enteropathy the same in everyone?
No. It is a pattern of intestinal injury caused by different immune problems (e.g., celiac, AIE, ICI enteritis, CVID). Treatment depends on the exact cause. Lippincott Journals+1

2) How long until I feel better after a strict gluten-free diet?
Many improve within weeks, and antibodies often normalize by ~6 months; complete mucosal healing may take longer in adults. MDPI

3) What if I am strict but still sick?
You need a non-responsive celiac work-up to check for hidden gluten, alternative diagnoses, or refractory celiac. Gastrojournal

4) How is RCD-I different from RCD-II?
RCD-I has no abnormal T-cell clone and often responds to budesonide/steroids. RCD-II has aberrant IELs and a higher risk of ulcerative jejunitis or lymphoma; it needs specialized therapy. CGH Journal+1

5) Can biologics help?
Yes, especially in ICI enteritis (infliximab or vedolizumab after steroids). Use in AIE/RCD is individualized. PMC+1

6) What nutrients should I check?
Iron, folate, B12, vitamin D, calcium, magnesium, zinc, and sometimes copper. Replace as needed. PMC

7) Do probiotics cure this?
Evidence is limited; they may help some symptoms but are not a cure. Use as an adjunct only.

8) What is teduglutide and do I need it?
It is a GLP-2 analog that helps people with intestinal failure and short bowel reduce IV nutrition. It is not routine for celiac/AIE without intestinal failure. Medscape

9) Can RCD-II turn into lymphoma?
Yes, risk is high without control; close monitoring is essential. Frontiers

10) Are JAK inhibitors an option?
Only in very refractory cases at expert centers; data are limited. ScienceDirect

11) What about stem-cell transplant?
Auto-HSCT has been tried in RCD-II with selected benefit but significant risk; reserved for specialized centers. PubMed

12) I’m on cancer immunotherapy—who manages my diarrhea?
Contact oncology early; they coordinate steroids and, if needed, infliximab/vedolizumab per ASCO/NCCN guidance. ASCOPubs+1

13) Will a low-FODMAP diet fix my disease?
It may ease gas/bloating after healing, but it does not treat the immune cause. Use short term with dietitian guidance.

14) Can I ever reintroduce gluten?
In celiac disease, no—gluten must be avoided lifelong. Lippincott Journals

15) How often should I follow up?
Early after diagnosis or flare, every 3–6 months to check symptoms, labs, and diet; then yearly if stable, or sooner if problems return. Nature

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The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: September 29, 2025.