What to think about when a small-bowel biopsy shows enteropathy and celiac has already been excluded on a gluten-containing diet. Walks the non-celiac differential mechanistically: wheat-related symptom syndromes, autoimmune enteropathy, Whipple disease, drug-induced enteropathies, checkpoint inhibitor enteritis, bacterial overgrowth, and tropical sprue. The histology, the medication list, and the exposure history read in parallel resolve the fork. Topics covered Non-celiac gluten sensitivity and FODMAPs IgE-mediated wheat allergy Autoimmune enteropathy and IPEX Whipple disease Drug-induced enteropathy (olmesartan, NSAID) Checkpoint inhibitor enteritis Small intestinal bacterial overgrowth Tropical sprue Key decisions Celiac must be excluded on a gluten-containing diet first; a gluten-free patient needs a gluten challenge or HLA testing, where a negative haplotype excludes celiac. Villous atrophy with depleted goblet and Paneth cells plus deep crypt apoptosis in a celiac-negative diet-failure points to autoimmune enteropathy; test anti-enterocyte antibodies and treat with open-capsule budesonide. Whipple is diagnosed on distal duodenal/jejunal biopsy showing foamy PAS-positive macrophages that are acid-fast-negative; treat with IV ceftriaxone then a year of oral trimethoprim-sulfamethoxazole for CNS coverage. Older patient on olmesartan with severe diarrhea, weight loss, negative celiac serology, and villous atrophy: stop the drug, not start a gluten-free diet or steroids. Checkpoint inhibitor enteritis: hold the drug, rule out infection including C. diff and CMV, start steroids ~1 mg/kg, escalate to infliximab or vedolizumab if refractory within a few days. SIBO gives low B12 with high folate; diagnose by breath testing (rise of at least 20 ppm within 90 minutes) and treat with rifaximin plus correcting the cause; tropical sprue gives combined low folate AND B12 and is treated with tetracycline plus folate. For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - When celiac is excluded (01:03) - The wheat-related trio (03:06) - The FODMAP framework (04:08) - Autoimmune enteropathy (07:13) - Whipple disease (10:20) - Drug-induced enteropathy (12:30) - Checkpoint enteritis and SIBO (15:23) - Tropical sprue and synthesis

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