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Background: Evidence has accumulated to support the involvement of gastrointestinal (GI) dysfunction, possibly via gut microbial dysbiosis and alterations in the enteric nervous system, in the pathophysiology of different neurodegenerative diseases. However, whether patients with GI dysfunction have altered risk of amyotrophic lateral sclerosis (ALS) remains unknown. Methods: Based on a historical nationwide cohort study—ESPRESSO—in Sweden, we compared the risk of ALS among individuals with a previous GI biopsy finding of normal mucosa or non-specific inflammation, as two conditions of GI dysfunction, to that of individuals without any GI biopsy. We identified all individuals with a GI biopsy result of either normal mucosa (n = 483,442) or non-specific inflammation (n = 566,663) during 1965–2016 in Sweden as the exposed groups. For each exposed individual, we randomly selected up to five controls from the general Swedish population after individual matching by age and sex. Both the exposed and unexposed individuals were followed from date of biopsy (exposed individuals) or date of selection (unexposed individuals) until ALS diagnosis, emigration out of Sweden, death, or 31 December 2016, whichever came first. Stratified Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). Results: Compared to individuals without GI biopsy, individuals with a GI biopsy result of normal mucosa had an increased risk of ALS (HR = 1.22; 95%CI: 1.04–1.42) after excluding the first 2 years of follow-up to alleviate concern of surveillance bias. This increased risk was noted among male (HR = 1.20; 95%CI: 0.94–1.51) and female (HR = 1.23; 95%CI: 1.01–1.50), as well as among younger (<60 years; HR = 1.17; 95%CI: 0.94–1.44) and older (≥60 years; HR = 1.24; 95%CI: 0.99–1.56) individuals. In contrast, no association was observed for a GI biopsy result of non-specific inflammation (HR = 1.00; 95%CI: 0.88–1.15). Neither of the GI biopsy results was related to the mortality risk after ALS diagnosis. Conclusions: Individuals with a GI biopsy result of normal mucosa—representing potentially a distinct type of GI dysfunction—had a higher future risk of ALS. No association was however noted for a GI biopsy result of non-specific inflammation. Further studies are needed to validate this finding and to understand the underlying reasons for the contrasting result pattern. [ABSTRACT FROM AUTHOR]