Lycopene regulates intestinal dysmotility and behavioral disorders by regulating enteric neurons and the cholinergic system

Gut dysmotility is a prevalent gastrointestinal disorder characterized by disrupted defecation and often accompanied by depression and anxiety. Lycopene (LYC) is a type of carotenoid with strong antioxidant and anti-inflammatory properties. However, the effects of LYC on gut dysmotility and related behavioral disorders remain elusive. Herein, we found that 100 mg kg^-1 d^-1 LYC notably improved the gut transit time and intestinal transit rate as well as concurrently alleviated depression- and anxiety-like behaviors in a diphenoxylate (Dip, 5 mg kg^-1 d^-1)-induced constipated mouse model. LYC pretreatment enhanced gut barrier integrity and short-chain fatty acid (SCFA) production as well as rebalanced gut microbiota homeostasis by enriching beneficial bacteria, including <i>Bifidobacterium</i> and <i>Akkermansia</i>. Furthermore, LYC restored enteric neuronal function, as evidenced by increased HuC/D and Tuj1 expression as well as balanced neurotransmitter levels. Brain transcriptomics results suggest that LYC regulates the cholinergic synapse pathway and increases acetylcholine (Ach) content in the brain, which is associated with the alleviation of neuroinflammation. In summary, this study offers insights into functional dietary component-based nutritional strategies that target gut dysmotility comorbid behavioral dysfunction.