Dataset Information

Aspirin Positively Contributes to Drosophila Intestinal Homeostasis and Delays Aging through Targeting Imd.

ABSTRACT: 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.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC8460307 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Aspirin Positively Contributes to <i>Drosophila</i> Intestinal Homeostasis and Delays Aging through Targeting Imd.

Zhu Yangyang Y Cai Qingshuang Q Zheng Xianrui X Liu Lei L Hua Yongzhi Y Du Beibei B Zhao Guomin G Yu Jiangliu J Zhuo Zhao Z Xie Zhongwen Z Ji Shanming S

Aging and disease 20211001 7

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 <i>Drosophila</i> as an animal model. We showed that long-term uptake of aspir ...[more]

PMID: 34631223

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Project description:Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene nubbin (nub) encodes two transcription factor isoforms, Nub-PB and Nub-PD, which antagonistically regulate immune gene expression in Drosophila. Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-κB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co-overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte-specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15. Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host-microbe interactions mediated by antagonistic transcription factor isoforms.

Dataset Information

Aspirin Positively Contributes to Drosophila Intestinal Homeostasis and Delays Aging through Targeting Imd.

Publications

Aspirin Positively Contributes to <i>Drosophila</i> Intestinal Homeostasis and Delays Aging through Targeting Imd.

Similar Datasets

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