| Phenotype | Proximal existing mechanism node | Key proposed intermediate node(s) | Evidence grade | Main caveat/alternative |
|---|---|---|---|---|
| Chronic Diarrhea | Intestinal Epithelial Damage | **New:** generalized malabsorption; osmotic load; fat/bile-acid spillover; electrolyte secretion | **SUPPORTED** | Multiple mechanisms coexist; phenotype-specific human causal partitioning is limited. (pqac-00000022, pqac-00000023) |
| Abdominal Pain | Intestinal Epithelial Damage | **New:** mucosal nociception; luminal distension; dysmotility | **PROPOSED** | IBS, lactose/FODMAP intolerance, and other disorders may independently cause pain. (pqac-00000022) |
| Bloating | Intestinal Epithelial Damage | **New:** brush-border enzyme loss; carbohydrate malabsorption; microbial fermentation and gas | **PROPOSED** | Direct celiac-specific human evidence for this complete chain is sparse. (pqac-00000022, pqac-00000023) |
| Constipation | Microbiome Dysbiosis / Intestinal Epithelial Damage | **New:** altered intestinal transit or defecatory function | **NOT_ESTABLISHED** | Mechanism is unknown; functional constipation, diet, thyroid disease, and medication effects are alternatives. (pqac-00000022) |
| Villous Atrophy | Intestinal Epithelial Damage | None; this is the histologic expression of the curated epithelial-damage node | **ESTABLISHED** | Patchiness and sampling orientation can affect histologic ascertainment. (pqac-00000022) |
| Weight Loss | Intestinal Epithelial Damage | **New:** macronutrient malabsorption; steatorrhea; negative energy balance | **SUPPORTED** | Reduced intake, inflammation, and fluid shifts may contribute; obesity does not exclude celiac disease. (pqac-00000007, pqac-00000022, pqac-00000023) |
| Iron Deficiency Anemia | Intestinal Epithelial Damage | **New:** proximal-duodenal iron malabsorption; depleted iron stores; impaired erythropoiesis; sometimes inflammation/hepcidin | **ESTABLISHED** | Menstrual or occult blood loss and persistent enterocyte defects can coexist. (pqac-00000002) |
| Fatigue | Intestinal Epithelial Damage / Mixed Th1/Th17/IL-21 Mucosal Cytokine Response | **New:** anemia, micronutrient deficits, pain/depression, or inflammatory sickness signaling | **NOT_ESTABLISHED** | Fatigue improves on a gluten-free diet but may persist and was not associated with nutritional deficiency or disease activity in a 2023 cohort. (pqac-00000002) |
| Growth Failure in Children | Intestinal Epithelial Damage | **New:** energy/protein and micronutrient malabsorption; reduced weight gain; disrupted GH–IGF-1 axis | **SUPPORTED** | Endocrine disease, genetics, delayed diagnosis, and socioeconomic nutrition remain alternatives. (pqac-00000002, pqac-00000007) |
| Dermatitis Herpetiformis | Autoantibody Production | **New:** TG2→TG3 epitope spreading; anti-TG3 IgA; dermal IgA–TG3 deposition; complement/neutrophil injury | **ESTABLISHED** | TG3 deposits are highly characteristic, but their precise lesion-initiating role remains incompletely resolved. (pqac-00000008, pqac-00000010) |
| Reduced Bone Mineral Density | Intestinal Epithelial Damage | **New:** calcium/vitamin-D malabsorption; secondary hyperparathyroidism; increased resorption; inflammatory RANKL/OPG imbalance | **ESTABLISHED** | Hypogonadism, low weight, immobility, menopause, and persistent inflammation also contribute. (pqac-00000000, pqac-00000001, pqac-00000003) |
| Dental Enamel Defects | Intestinal Epithelial Damage / Autoantibody Production | **New:** calcium/vitamin-D deficiency during amelogenesis; possible anti-gliadin/ameloblast cross-reactivity | **PROPOSED** | Established enamel damage is irreversible; nutritional and immune branches have not been causally separated. (pqac-00000002) |
| Recurrent Aphthous Stomatitis | Intestinal Epithelial Damage / Mixed Th1/Th17/IL-21 Mucosal Cytokine Response | **New:** oral mucosal immune dysregulation or iron/folate/B12 deficiency | **NOT_ESTABLISHED** | Association is reproducible, but trauma, infection, hematinic deficiency, and other immune diseases remain competing causes. (pqac-00000002) |
| Peripheral Neuropathy | Autoantibody Production / Mixed Th1/Th17/IL-21 Mucosal Cytokine Response | **New:** peripheral axonopathy; anti-neural/TG6 antibodies and/or perivascular T-cell injury | **NOT_ESTABLISHED** | Humoral versus T-cell causation is unresolved; B12 deficiency, diabetes, and coincident autoimmunity must be excluded. (pqac-00000009, pqac-00000013) |
| Cerebellar Ataxia | Autoantibody Production | **New:** anti-TG6/anti-Purkinje reactivity; cerebellar immune deposition; Purkinje-cell loss and gliosis | **PROPOSED** | TG6 is a biomarker/candidate antigen, not a conclusively proven human effector; non-celiac gluten sensitivity and other ataxias complicate attribution. (pqac-00000009, pqac-00000013) |
| Elevated Hepatic Transaminases | Barrier Dysfunction | **New:** portal delivery of microbial products/antigens; hepatic innate immune injury (“celiac hepatitis”) | **SUPPORTED** | Autoimmune hepatitis, MASLD, drugs, and viral liver disease are alternatives; mechanism is inferred chiefly from permeability and dietary reversal. (pqac-00000011) |
| Vitamin D Deficiency | Intestinal Epithelial Damage | **New:** fat-soluble-vitamin malabsorption; steatorrhea; reduced vitamin-D uptake | **SUPPORTED** | Low intake and sunlight exposure can contribute, and deficiency may persist on a gluten-free diet. (pqac-00000002, pqac-00000003) |
| Small intestinal lymphoma | Intestinal Epithelial Damage | **New:** persistent IL-15/JAK-STAT selection; aberrant clonal IEL expansion (RCDII); JAK1/STAT3 and NF-κB lesions; EATL transformation | **ESTABLISHED** | EATL can arise without recognized RCDII; gluten-free-diet protection is observational and not absolute. (pqac-00000014, pqac-00000015, pqac-00000016, pqac-00000018) |
| Osteoporosis | Intestinal Epithelial Damage | **New:** calcium/vitamin-D malabsorption; secondary hyperparathyroidism; osteoclastogenesis; chronic cytokine/RANKL–OPG imbalance | **ESTABLISHED** | Bone density may not fully normalize; age, sex hormones, low BMI, and primary osteoporosis modify risk. (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000004) |
| Arthritis | Mixed Th1/Th17/IL-21 Mucosal Cytokine Response / Microbiome Dysbiosis | **New:** systemic immune activation or gut–joint trafficking causing synovitis | **NOT_ESTABLISHED** | Shared genetics, rheumatoid/JIA comorbidity, and ascertainment may explain association; diet alone often does not control arthritis. (pqac-00000011) |
| Short stature | Intestinal Epithelial Damage | **New:** chronic nutrient/energy deficit; impaired GH–IGF-1 signaling; reduced linear growth | **SUPPORTED** | Genetic short stature, endocrine deficiency, and failure of catch-up growth despite mucosal treatment require separate evaluation. (pqac-00000002, pqac-00000007) |
| Female infertility | Intestinal Epithelial Damage / Autoantibody Production | **New:** zinc/folate/iron deficiency and hypothalamic–gonadal disruption; proposed anti-TG2 effects on endometrium/trophoblast/angiogenesis | **NOT_ESTABLISHED** | Human causal evidence is inadequate; shared autoimmunity, thyroid disease, HLA background, and referral bias are major alternatives. (pqac-00000012) |


*Table: Compact mapping of all curated phenotypes to proximal mechanisms, proposed intermediate nodes, conservative evidence grades, and major causal alternatives. Citations identify the gathered evidence supporting each assessment.*