"Gut health" is central to maintaining overall health, but intestinal cells are susceptible to attack by oxidative stress, leading to functional disorders. However, the precise molecular mechanism behind this damage has long been like an unopened door, hindering the development of effective prevention and treatment strategies.
Recently, a study led by Professor Huansheng Yang's team from Hunan Normal University, published in SCIENCE CHINA Life Sciences , has unlocked a crucial latch on this door. The research team discovered that a lipid molecule named arachidonic acid (AA) is the core effector mediating oxidative stress damage to the intestinal epithelium. The study, titled "Oxidative stress affects intestinal health by inhibiting the differentiation of porcine intestinal epithelial cells through producing arachidonic acid", systematically elucidates a clear molecular chain from oxidative stress to intestinal dysfunction.
The research first sought clues in live animals. By feeding piglets oxidized soybean oil (OSO), the team successfully constructed an oxidative stress model mimicking real production conditions, observing typical growth inhibition, diarrhea, and a global downregulation of intestinal functional gene expression.
To probe the mechanisms at the cellular level, researchers simultaneously constructed intestinal organoid models that highly simulate the in vivo environment. Through integrated analysis of transcriptome data from piglet intestinal tissue and organoids, a common key signaling pathway emerged: the arachidonic acid (AA) metabolic pathway was significantly enriched in both models. Further biochemical detection confirmed that oxidative stress indeed led to abnormally elevated AA levels in the piglets' intestines.
Was AA merely a "bystander" or the "executor"? To verify its function, the research team directly treated healthy intestinal organoids with AA. The results clearly showed that AA could directly inhibit organoid activity and stem cell differentiation capacity, leading to a significant reduction in the proportion of goblet cells and endocrine cells responsible for mucus and hormone secretion. More importantly, AA treatment specifically downregulated a series of key genes responsible for nutrient digestion, absorption, and transport, which was entirely consistent with the observations in piglets.
While the "forward" experiment established AA's damaging role, "reverse" experiments aimed to validate the effectiveness of intervention. Researchers used a specific inhibitor (pyrrophenone) to block PLA2, a key enzyme for AA production, and found this could effectively improve the vitality and differentiation capacity of oxidatively stressed organoids. Even more compellingly, intestinal organoids from Pla2g2a gene-knockout mice showed significantly enhanced resistance to oxidative stress; in live mouse experiments, gene knockout also effectively mitigated symptoms of chemically induced intestinal damage.
This evidence from both forward and reverse perspectives collectively confirms the central role of AA in oxidative stress-induced intestinal injury and points to targeted inhibition of AA release as a potential new intervention pathway.
Professor Huansheng Yang stated: "This study not only maps the specific molecular landscape of how oxidative stress damages the intestine but, more importantly, the discovery of AA provides us with a precise target for developing novel nutritional intervention strategies or feed additives to protect intestinal health. In the future, we will further explore how regulating this mediator can enhance the resilience of animal and even human intestines when facing oxidative pressure."
Science China Life Sciences
Experimental study