Abnormal distribution, modification and aggregation of transactivation response DNA‐binding protein 43 (TDP‐43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) and amyotrophic lateral sclerosis (ALS). Transgenic mouse lines overexpressing wild‐type or mutant TDP‐43 exhibit ALS‐like symptom, motor abnormalities and early paralysis followed by death. Reports on lifespan and phenotypic behaviour in Prp‐TDP‐43 (A315T) vary, and these animals are not fully characterized. Although it has been proposed that the approximate 20% loss of motor neurons at end stage is responsible for the severe weakness and death in TDP‐43 mice, this degree of neurologic damage appears insufficient to cause death. Hence we studied these mice to further characterize and determine the reason for the death. Our characterization of TDP‐43 transgenic mice showed that these mice develop ALS‐like symptoms that later become compounded by gastrointestinal (GI) complications that resulted in death. This is the first report of a set of pathological evidence in the GI track that is strong indicator for the cause of death of Prp‐hTDP‐43 (A315T) transgenic mice.