Cellular Stress Upregulates Indole Signaling Metabolites in Escherichia coli

Kim, Chung Sub; Li, Jhe‐Hao; Barco, Brenden; Park, Hyun Bong; Gatsios, Alexandra; Damania, Ashiti; Wang, Rurun; Wyche, Thomas P.; Piizzi, Grazia; Clay, Nicole K.; Crawford, Jason M.

doi:10.1016/j.chembiol.2020.03.003

Cited by 15 publications

(10 citation statements)

References 66 publications

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“…Although microbiota metabolites affect the composition and function of the intestinal microbiota and regulate host immunity, most of them still lack identification and have unknown functions. Another recent study focused on a family of indole-functionalized bacterial metabolites termed indolokines, and the authors found that such substances are widely present in different bacteria and mouse feces and elicit immune responses in both plants and humans, which indicates that relatively conservative defense strategies exist in the biology ( Kim et al, 2020 ).…”

Section: The Effects Of Indole and Its Derivativesmentioning

confidence: 99%

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

Zhang

et al. 2021

Front. Pharmacol.

103

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The interaction between host and microorganism widely affects the immune and metabolic status. Indole and its derivatives are metabolites produced by the metabolism of tryptophan catalyzed by intestinal microorganisms. By activating nuclear receptors, regulating intestinal hormones, and affecting the biological effects of bacteria as signaling molecules, indole and its derivatives maintain intestinal homeostasis and impact liver metabolism and the immune response, which shows good therapeutic prospects. We reviewed recent studies on indole and its derivatives, including related metabolism, the influence of diets and intestinal commensal bacteria, and the targets and mechanisms in pathological conditions, especially progress in therapeutic strategies. New research insights into indoles will facilitate a better understanding of their druggability and application in intestinal and liver diseases.

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Section: The Effects Of Indole and Its Derivativesmentioning

confidence: 99%

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

Zhang

et al. 2021

Front. Pharmacol.

103

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“… 32 Except the specific physiological activities, indoles compounds also regulated the host immune and inflammatory responses. 33 Aryl hydrocarbon receptor (AhR), a cytoplasmic receptor and transcription factor, plays an important role in regulating adaptive immunity, barrier function, intestinal balance and intestinal inflammation. A study documented that the dysregulation of AhR signals exacerbated IBD conditions in mice.…”

Section: Resultsmentioning

confidence: 99%

Impact of purple sweet potato (Ipomoea batatas L.) polysaccharides on the fecal metabolome in a murine colitis model

et al. 2022

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“…48 While the colipterins are stimulated by the folate stress-inducer sulfamethoxazole, their production here is reduced by erythromycin (Figure S13). The indolokines on the other hand are stimulated by erythromycin (Figure S13), but to a far lesser extent than when treated with paraquat, 48 an agent that causes oxidative stress. Collectively, E. coli produces several bioactive aspC/tyrB-dependent metabolites that respond to different forms of cellular stress (Figure 4F).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our work here builds on prior studies examining AspC-associated metabolites in E. coli , including the colipterins and the indolokines. , The colipterns are antioxidants that induce IL-10 production in macrophages and improve colitis symptoms in a colitis mouse model, and the indolokines are human aryl hydrocarbon receptor (AhR) ligands that also serve as defense signals in bacteria, plants, and mammals . While the colipterins are stimulated by the folate stress-inducer sulfamethoxazole, their production here is reduced by erythromycin (Figure S13).…”

Section: Resultsmentioning

confidence: 99%

“…16,48 The colipterns are antioxidants that induce IL-10 production in macrophages and improve colitis symptoms in a colitis mouse model, 16 and the indolokines are human aryl hydrocarbon receptor (AhR) ligands that also serve as defense signals in bacteria, plants, and mammals. 48 While the colipterins are stimulated by the folate stress-inducer sulfamethoxazole, their production here is reduced by erythromycin (Figure S13). The indolokines on the other hand are stimulated by erythromycin (Figure S13), but to a far lesser extent than when treated with paraquat, 48 an agent that causes oxidative stress.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Cellular Stress-Induced Metabolites in Escherichia coli

et al. 2022

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Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli’s small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from “abortive” tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the “missing” tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (1) rather than a pyrazinone. Furthermore, erythromycin induced two naphthoquinone-functionalized metabolites (MK-hCys, 2; and MK-Cys, 3) and four lumazines (7–10). Using genetic and metabolite analyses coupled with biomimetic synthesis, we provide support that the naphthoquinones are derived from 4-dihydroxy-2-naphthoic acid (DHNA), an intermediate in the menaquinone biosynthetic pathway, and the amino acids homocysteine and cysteine. In contrast, the lumazines are dependent on a flavin intermediate and α-ketoacids from the aminotransferases AspC and TyrB. We show that one of the lumazine members (9), an indole-functionalized analogue, possesses antioxidant properties, modulates the anti-inflammatory fate of isolated TH17 cells, and serves as an aryl-hydrocarbon receptor (AhR) agonist. These three systems described here serve to illustrate that new metabolic branches could be more commonly derived from well-established primary metabolic pathways.

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Cellular Stress Upregulates Indole Signaling Metabolites in Escherichia coli

Cited by 15 publications

References 66 publications

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

Impact of purple sweet potato (Ipomoea batatas L.) polysaccharides on the fecal metabolome in a murine colitis model

Cellular Stress-Induced Metabolites in Escherichia coli

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