Scope: Ulcerative colitis (UC) is rapidly increasing worldwide but prolong use of available corticosteroids treatment is associated with numerous adverse effects. There is the urgent need to develop novel therapeutic options. However, this requires the use of suitable disease models, but current models are generated with chemical agents mainly in rodents, which are unable to recapitulate the human occurrence. The aim of this study is to validate the occurrence of spontaneous UC in cynomolgus monkeys and explore the potential of Hericium erinaceus mycelium-derived polysaccharide in reversing UC pathologies. Methods and results: Postmortem bowel evaluation and biochemical analysis including inflammatory markers and fecal occult blood testing (FOBT) as well as nutrition status parameters, confirm the non-artificial induced spontaneous occurrence of UC in cynomolgus monkeys. Subsequently, H. erinaceus mycelium-derived polysaccharide supplementation significantly attenuates UC pathologies, improves nutritional status, reduces the incidence of diarrhea, and reduces inflammation in UC monkeys. Importantly, the polysaccharides administration enhances intestinal function and reshapes the gut microbiota. Conclusion: The study confirms the spontaneous UC monkeys can closely mimic the occurrence of UC in humans. Moreover, H. erinaceus mycelium-derived polysaccharide can effectively restore UC in monkeys, which show the prospects as precision nutritional supplement for the management of UC.