Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2026
Gastric amyloid pathology and mucosal denervation in ATTRv amyloidosis: insights from patients, mice, and gut microenvironment profiles.
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Hsueh Hsueh-Wen, Yang Ping-Hao, Tseng Ping-Huei, Yeh Ti-Yen, Hsu Hao-Chia, Chen Chieh-Chang, Hsu Chia-Lang, Cheng Ya-Yin, Ting Tsai-Wei, Lin Cheng-Chen, Ke Hui-Fang, Kuo Ching-Hua, Chao Chi-Chao, Chang Koping, Hsieh Sung-Tsang
Аннотация
BACKGROUNDS: Hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) frequently presents with gastrointestinal autonomic dysfunction, but its underlying pathology remains unclear.
METHODS: We examined gastric mucosal amyloid deposition and innervation using conventional endoscopic biopsies in ATTRv-PN patients and a human TTR (hTTR A117S) knock-in mouse model. Clinical assessments, gut microbiota, metabolomics, and neurite growth assays were integrated.
RESULTS: Among 33 patients, 84.8% showed TTR(+) amyloid deposition in gastric mucosa. Gastric mucosal innervation density (GMID) was significantly reduced in all gastric regions compared with controls and was similarly decreased in hTTR(A117S) mice. Lower GMID correlated with gastroparesis and reflux symptom severity. Integrated analyses revealed positive associations between GMID, four microbial genera, and histidine levels. Both microbiota-derived principal components and histidine independently correlated with GMID. Histidine also promoted neurite growth in vitro.
CONCLUSIONS: Endoscopic biopsy enables assessment of both gastric amyloid pathology and mucosal innervation in ATTRv-PN. Reduced GMID is closely associated with gastrointestinal symptoms, microbiota alterations, and metabolomic changes, providing insights into disease mechanisms and potential biomarkers of autonomic gastrointestinal dysfunction.
METHODS: We examined gastric mucosal amyloid deposition and innervation using conventional endoscopic biopsies in ATTRv-PN patients and a human TTR (hTTR A117S) knock-in mouse model. Clinical assessments, gut microbiota, metabolomics, and neurite growth assays were integrated.
RESULTS: Among 33 patients, 84.8% showed TTR(+) amyloid deposition in gastric mucosa. Gastric mucosal innervation density (GMID) was significantly reduced in all gastric regions compared with controls and was similarly decreased in hTTR(A117S) mice. Lower GMID correlated with gastroparesis and reflux symptom severity. Integrated analyses revealed positive associations between GMID, four microbial genera, and histidine levels. Both microbiota-derived principal components and histidine independently correlated with GMID. Histidine also promoted neurite growth in vitro.
CONCLUSIONS: Endoscopic biopsy enables assessment of both gastric amyloid pathology and mucosal innervation in ATTRv-PN. Reduced GMID is closely associated with gastrointestinal symptoms, microbiota alterations, and metabolomic changes, providing insights into disease mechanisms and potential biomarkers of autonomic gastrointestinal dysfunction.