Inflammation-Modulated Metabolic Reprogramming Is Required for DUOX-Dependent Gut Immunity in Drosophila

Lee, Kyung‐Ah; Cho, Kyu-Chan; Kim, Boram; Jang, In-Hwan; Nam, Ki-Bum; Kwon, Young Eun; Kim, Myung-Jin; Hyeon, Do Young; Hwang, Daehee; Seol, Jae Hong; Lee, Won–Jae

doi:10.1016/j.chom.2018.01.011

Cited by 83 publications

(99 citation statements)

References 63 publications

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“…This is consistent with previous results showing that intestinal barrier failure after loss of a septate junction protein Snakeskin (Ssk) results in altered gut morphology, dysbiosis, and reduced Duox level (37). Duox act as an important defense mechanism in ECs against enteric infection and its expression is increased in the intestine upon infection and aging (20,55), while its expression is dampened in the tumor-bearing intestine with massive loss of ECs and impaired EC renewal capacity. A recent study demonstrated lactic acid from L. plantarum activates Nox for ROS production that promotes intestinal damage and dysplasia (21).…”

Section: Discussionsupporting

confidence: 92%

JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis

Zhou

Boutros

2020

Proc. Natl. Acad. Sci. U.S.A.

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In all animals, the intestinal epithelium forms a tight barrier to the environment. The epithelium regulates the absorption of nutrients, mounts immune responses, and prevents systemic infections. Here, we investigate the consequences of tumorigenesis on the microbiome using a Drosophila intestinal tumor model. We show that upon loss of BMP signaling, tumors lead to aberrant activation of JNK/Mmp2 signaling, followed by intestinal barrier dysfunction and commensal imbalance. In turn, the dysbiotic microbiome triggers a regenerative response and stimulates tumor growth. We find that inhibiting JNK signaling or depletion of the microbiome restores barrier function of the intestinal epithelium, leading to a reestablishment of host–microbe homeostasis, and organismic lifespan extension. Our experiments identify a JNK-dependent feedback amplification loop between intestinal tumors and the microbiome. They also highlight the importance of controlling the activity level of JNK signaling to maintain epithelial barrier function and host–microbe homeostasis.

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Section: Discussionsupporting

confidence: 92%

JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis

Zhou

Boutros

2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This is consistent with previous results showing that intestinal barrier failure after loss of a septate junction protein Snakeskin results in altered gut morphology, dysbiosis and reduced Duox level (Salazar et al, 2018). Duox act as an important defence mechanism in ECs against enteric infection and its expression is increased in the intestine during infection and ageing (Lee et al, 2018;Guo et al, 2014), suggesting that Duox expression is induced during normal intestinal regeneration under infection or ageing, while its expression is dampened in the tumor bearing intestine with massive loss of ECs and impaired EC renewal capacity. A recent study demonstrated lactic acid from L. plantarum activates Nox for ROS production that promotes intestinal damage and dysplasia (Iatsenko et al, 2018).…”

Section: Tumor Growth Causes Intestinal Dysfunction and Dysbiosissupporting

confidence: 93%

JNK-dependent intestinal barrier failure disrupts host-microbe homeostasis during tumorigenesis

Zhou

Boutros

2019

Preprint

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ABSTRACTIn all animals, the intestinal epithelium forms a tight barrier to the environment. The epithelium regulates the absorption of nutrients, mounts immune responses and prevents systemic infections. Here, we investigate the consequences of tumorigenesis on the microbiome using a Drosophila intestinal tumor model. We show that upon loss-of BMP signaling, tumors lead to aberrant activation of JNK signaling, followed by intestinal barrier dysfunction and commensal imbalance. In turn, the dysbiotic microbiome triggers a regenerative response and stimulates tumor growth. We find that inhibiting JNK signaling or depletion of the microbiome restores barrier function of the intestinal epithelium, leading to a reestablishment of host-microbe homeostasis, and organismic lifespan extension. Our experiments identify a JNK-dependent feedback amplification loop between intestinal tumors and the microbiome. They also highlight the importance of controlling the activity level of JNK signaling to maintain epithelial barrier function and host-microbe homeostasis.

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“…from mothers to offspring) (Bakula 1969; Starmer et al 1988; Spencer 1992; Ridley et al 2012; Wong et al 2015; Téfit et al 2018). Second, host immune system participates to the destruction of harmful gut bacteria and the retention of beneficial ones (Lee et al 2017; Lee et al 2018). Third, Drosophila larvae actively search and associate with beneficial yeast species ensuring they engage in symbiosis with locally adequate nutritional symbionts (Fogleman et al 1981; Fogleman et al 1982).…”

Section: Discussionmentioning

confidence: 99%

Environmental specificity and evolution in Drosophila-bacteria symbiosis

Guilhot

Rombaut

Xuéreb

et al. 2019

Preprint

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13Environmentally acquired microbial symbionts could contribute to host adaptation to local 14 adaptation like vertically transmitted symbionts do. This scenario necessitates symbionts to 15 have different effects in different environments. In Drosophila melanogaster, communities of 16 extracellular bacterial symbionts vary largely among environments, which could be due to 17 variable effects on phenotype. We investigated this idea with four bacterial strains isolated 18 from the feces of a D. melanogaster lab strain, and tested their effects in two environments: 19 the environment of origin (i.e. the laboratory medium) and a new one (i.e. fresh fruit with live 20 yeast). All bacterial effects on larval and adult traits differed among environments, ranging 21 from very beneficial to marginally deleterious. The joint analysis of larval development speed 22 and adult size further suggests bacteria would affect developmental plasticity more than 23 resource acquisition in males. The context-dependent effects of bacteria we observed, and its 24 underlying mechanisms, sheds light on how environmentally acquired symbionts may 25 contribute to host evolution. 26 27 77 from the feces of adult flies and chosen for their ease of cultivation and recognition on 78 standard microbiological medium. After inoculating bacteria-free eggs with these four 79 bacterial isolates, we recorded phenotypic fly traits at the larval and adult stages. Our results 80 show drastically different effects of symbionts on the hosts in laboratory medium and natural 81 substrate. Some differences among environments can be explained by the environment-82 specific mechanisms of bacterial benevolence. The joint analysis of larval development time 83 and adult size further suggests bacteria affect host developmental plasticity more than 84 resource acquisition. 85 86 Materials and Methods 87Drosophila strain 88 All insects were from the Oregon-R Drosophila melanogaster strain. This strain was founded 89 in 1927 and has since been maintained in the laboratory. Our sub-strain was obtained from 90 colleagues and reared on a laboratory medium comprising banana, sugar, dead yeast, agar and 91 a preservative (Table S2.1). Before and during the experiment reported here, animals were 92 maintained at 21 °C (stocks) or 23°C (experiment), with 70% humidity and a 14h 93 photoperiod. 95Microbial isolates 96 We isolated a small number of symbiotic bacterial strain from the flies. Our aim was to use 97 bacteria that were easy to culture and recognize morphologically but not to sample the whole 98 community of bacteria associated with our flies stock. An important choice was to focus on 99 aerobic bacteria that grow rapidly on standard agar plates at 25 °C, which excluded the 100 anaerobes Lactobacillus that are among the best known symbionts of D. melanogaster. 101In order to isolate bacteria present in fly feces, several groups of twenty Drosophila 102 melanogaster flies were placed in sterile glass vials for 1 h. After fly removal, vials were 103 washed w...

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Inflammation-Modulated Metabolic Reprogramming Is Required for DUOX-Dependent Gut Immunity in Drosophila

Cited by 83 publications

References 63 publications

JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis

JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis

JNK-dependent intestinal barrier failure disrupts host-microbe homeostasis during tumorigenesis

Environmental specificity and evolution in Drosophila-bacteria symbiosis

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