The intestine, a high-turnover tissue, plays a critical role in regulating aging and health in both vertebrates and invertebrates. Maintaining the epithelial barrier function of the intestine by preserving innate immune homeostasis significantly delays aging and prevents mortality. In an effort to explore effective chemicals and materials that can improve intestinal integrity, we performed a nonbiased screen utilizing Drosophila as an animal model. We showed that long-term uptake of aspirin markedly prevented age-onset gut leakage, the over-proliferation of intestinal stem cells, and the dysbiosis of commensal microbiota in fruit flies. Mechanistically, aspirin efficiently downregulated chronic activation of intestinal immune deficiency signaling during aging. Furthermore, our in vivo and in vitro biochemical analyses indicated that aspirin is a negative modulator in control of the K63-linked ubiquitination of Imd. Our findings uncover a novel regulatory mechanism by which aspirin positively modulates intestinal homeostasis, thus delaying aging, in Drosophila .
Negative regulators of the inflammatory responses are essential for the maintenance of immune homeostasis and organismal fitness. In Drosophila, the deubiquitinase (Dub) dTrbd selectively restricts the K63-linked ubiquitination modification of dTak1, a pivotal kinase of the IMD signaling pathway, to regulate the IMD innate immune response. However, which domain and how it functions to enable dTrbd’s activity remain unexplored. Here, we provide compelling evidence showing that the NZF domain of dTrbd is essential for its association with dTak1. Meanwhile, the Linker region of dTrbd is involved in modulating its condensation, a functional state representing the Dub enzymatical activity of dTrbd. Of interest, the activated IMD signals following bacterial stimuli enhance the dTrbd/dTak1 interaction, as well as the condensate assembly and Dub enzymatical activity of dTrbd. Collectively, our studies shed light on the dual mechanisms by which the IMD signaling-mediated feedback loop of dTrbd/dTak1 precisely regulates the innate immune response in Drosophila.
BackgroundSanzi formula (SZF) is a kind of Chinese herbal compound that has a certain effect on the prevention and treatment of colorectal adenoma (CRA), which can prevent and control the process of CRA-cancer transformation. In this study, we explored the mechanism of action of SZF in anti-CRA using 16S rRNA sequencing and metabolomics technology.MethodsMice were randomly divided into three groups: Control group, Apcmin/+ model group, and SZF treatment group. Except for the Control group, which used C57BL/6 J mice, the remaining two groups used Apcmin/+ mice. The Control group and Apcmin/+ model group were treated with ultrapure water by gavage, while the SZF treatment group was treated with SZF for 12 weeks. During this period, the physical changes of mice in each group were observed. The gut microbiota was determined by high-throughput sequencing of the 16S rRNA gene, and LC-ESI-MS/MS was used for colorectal metabolomics analysis.ResultsSequencing of the 16S rRNA gut flora yielded 10,256 operational taxonomic units and metabolomic analysis obtained a total of 366 differential metabolites. The intestinal flora analysis showed that SZF could improve intestinal flora disorders in Apcmin/+ mice. For instance, beneficial bacteria such as Gastranaerophilales significantly increased and harmful bacteria such as Angelakisella, Dubosiella, Muribaculum, and Erysipelotrichaceae UCG-003 substantially decreased after the SZF intervention. In addition, metabolomic data analysis demonstrated that SZF also improved the colorectal metabolic profile of Apcmin/+ mice. In Apcmin/+ mice, metabolites such as Anserine and Ectoine were typically increased after SZF intervention; in contrast, metabolites such as Taurocholic acid, Taurochenodesoxycholic acid, Hyocholic acid, Cholic acid, and Tauro-alpha-muricholic acid showed noteworthy reductions. Metabolic flora association analysis indicated that 13 differential flora and 11 differential metabolites were associated.ConclusionSZF affects the abundance of specific intestinal flora and regulates intestinal flora disorders, improves colorectal-specific metabolites, and ameliorates intestinal metabolic disorders to prevent and treat CRA. Furthermore, the application of intestinal flora and colorectal metabolomics association analysis offers new strategies to reveal the mechanism of action of herbal medicines for the treatment of intestinal diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.