Department of Nutrition, Texas A&M University, College Station, TX 77843, USA.
Integrated Metabolomics Analysis Core, Texas A&M University, College Station, TX 77843, USA.
Exp Biol Med (Maywood). 2022 Sep;247(17):1558-1569. doi: 10.1177/15353702221110647. Epub 2022 Jul 14.
A major component of aging is chronic, low-grade inflammation, attributable in part by impaired gut barrier function. We previously reported that deletion of ghrelin, a peptidergic hormone released mainly from the gut, exacerbates experimental muscle atrophy in aged mice. In addition, ghrelin has been shown to ameliorate colitis in experimental models of inflammatory bowel disease (IBD), although the role of endogenous ghrelin in host-microbe interactions is less clear. Here, we showed that 22-month-old global ghrelin knockout () mice exhibited significantly increased depressive-like behaviors, while anxiety levels and working memory were similar to littermate wild-type (WT) mice. Furthermore, old mice showed significantly increased intestinal permeability to fluorescein isothiocyanate (FITC)-dextran, significantly higher colonic interleukin (IL-1β) levels, and trends for higher colonic IL-6 and tumor necrosis factor-α (TNF-α) compared to WT mice. Interestingly, young and WT mice showed comparable depressive-like behavior and gut permeability, suggesting age-dependent exacerbation in gut barrier dysfunction in mice. While fecal short-chain fatty acids levels were comparable between old and WT mice, serum metabolome revealed alterations in metabolic cascades including tryptophan metabolism. Specifically, tryptophan and its microbial derivatives indole-3-acetic acid and indole-3-lactic acid were significantly reduced in old mice. Furthermore, in an experimental model of dextran sulfate sodium (DSS)-induced colitis, mice showed exacerbated disease symptoms, and higher levels of chemoattractant and pro-inflammatory cytokines in the colon. Overall, these data demonstrated that ghrelin deficiency is associated with gut barrier dysfunction, alterations in microbially derived tryptophan metabolites, and increased susceptibility to colitis. These data suggested that endogenous ghrelin contributes to maintaining a healthy host-microbe environment, ultimately impacting on brain function.
衰老是一个主要组成部分是慢性低度炎症，部分归因于肠道屏障功能受损。我们之前报道过，胃饥饿素（一种主要从肠道释放的肽类激素）的缺失会加剧老年小鼠的实验性肌肉萎缩。此外，胃饥饿素已被证明可改善实验性炎症性肠病（IBD）模型中的结肠炎，尽管内源性胃饥饿素在宿主-微生物相互作用中的作用尚不清楚。在这里，我们发现 22 个月大的全身性胃饥饿素敲除（）小鼠表现出明显增加的抑郁样行为，而焦虑水平和工作记忆与同窝野生型（WT）小鼠相似。此外，年老的 小鼠表现出明显增加的肠道对荧光素异硫氰酸酯（FITC）-葡聚糖的通透性，结肠白细胞介素（IL-1β）水平显著升高，且结肠白细胞介素（IL-6）和肿瘤坏死因子-α（TNF-α）水平有升高的趋势，与 WT 小鼠相比。有趣的是，年轻的 和 WT 小鼠表现出相似的抑郁样行为和肠道通透性，这表明 小鼠的肠道屏障功能障碍在年龄增长时加剧。虽然年老的 和 WT 小鼠的粪便短链脂肪酸水平相当，但血清代谢组学揭示了代谢级联反应的改变，包括色氨酸代谢。具体而言，色氨酸及其微生物衍生物吲哚-3-乙酸和吲哚-3-乳酸在年老的小鼠中显著减少。此外，在葡聚糖硫酸钠（DSS）诱导的结肠炎实验模型中， 小鼠表现出更严重的疾病症状，结肠中趋化因子和促炎细胞因子的水平更高。总体而言，这些数据表明胃饥饿素缺乏与肠道屏障功能障碍、微生物衍生的色氨酸代谢物改变以及对结肠炎的易感性增加有关。这些数据表明，内源性胃饥饿素有助于维持健康的宿主-微生物环境，最终影响大脑功能。
