ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens

Proietti, Michele; Perruzza, Lisa; Scribano, Daniela; Pellegrini, Giovanni; D’Antuono, Rocco; Strati, Francesco; Raffaelli, Marco; González, Santiago F.; Thelen, Marcus; Hardt, Wolf‐Dietrich; Slack, Emma; Nicoletti, Mauro; Grassi, Fabio

doi:10.1038/s41467-018-08156-z

Cited by 78 publications

(93 citation statements)

References 39 publications

(50 reference statements)

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“…Selective binding of IgA to some commensals could also inhibit bacterial cell growth, which could play a role in IgA modulation of microbial composition . Furthermore, and to add an additional level of complexity, IgA production can be directly modulated by the intestinal microbiota through generation of ATP through a mechanism which includes P2X7‐mediated signaling of T follicular helper cells …”

Section: Microbiota‐driven or Maintained Memory Antibody Responsesmentioning

confidence: 99%

“…8 Furthermore, and to add an additional level of complexity, IgA production can be directly modulated by the intestinal microbiota through generation of ATP through a mechanism which includes P2X7-mediated signaling of T follicular helper cells. 9,10 Bacterial species differ in their IgA-inducing properties and antibody coating. Homeostatic microbial IgA coating primarily occurs in the small intestine.…”

Section: Microbiota-driven or Maintained Memory Antibody Responses Mumentioning

confidence: 99%

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The microbiome and immune memory formation

2019

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The microbiota plays an important role in regulating both the innate and adaptive immune systems. Many studies have focused on the ability of microbes to shape the immune system by stimulating B‐cell and antibody responses and the differentiation of T helper cell function. However, an important feature of the immune system is its ability to generate memory responses, which provide increased survival for the host. This review will highlight the role of the microbiota in the induction of immune memory with a focus on both adaptive and innate memory as well as vaccine efficacy.

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Section: Microbiota‐driven or Maintained Memory Antibody Responsesmentioning

confidence: 99%

Section: Microbiota-driven or Maintained Memory Antibody Responses Mumentioning

confidence: 99%

The microbiome and immune memory formation

2019

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“…Several bacterial species are also known to secrete eATP [46][47][48][49]. Notably, eATP from gut commensal bacteria is biologically active and is well documented to modulate the host immune response [19,20,50]. Interestingly, levels of eATP released by clinical isolates of C. albicans were highly variable.…”

Section: Discussionmentioning

confidence: 99%

“…In this model, extracellular ATP (eATP) released from keratinocytes was suggested as the source. Notably, eATP is released by E. coli in the intestine as well as some other bacteria species and functions to modulate the development of local immune responses [19,20]. This raises the possibility that pathogen-derived eATP could trigger neuronal recognition of pathogens in skin.…”

Section: Introductionmentioning

confidence: 99%

Extracellular ATP released fromCandida albicansactivates non-peptidergic neurons to augment host defense

Edwards

Zhang

Liu

et al. 2020

Preprint

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DHK) ¶ Authors provided equal contributionKeywords: Candida albicans, ATP, peripheral nervous system, sensory neuron, nonpeptidergic neuron. Bullet points ATP released from heat killed C. albicans activates non-peptidergic sensory neurons  Live C. albicans clinical isolates release variable amounts of ATP  Elevated levels of ATP released by C. albicans correlates with reduced infectivity in vivo  MRGPRD-expressing cutaneous neurons are required for defense against ATP-secreting C. albicans Abstract (<300 words)Intestinal microbes release ATP to modulate local immune responses. Herein we demonstrates that Candida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion from C. albicans varied between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by nonpeptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca 2+ when exposed to supernatant from heat-killed C. albicans (HKCA), and these nonpeptidergic fibers are the dominant subset that respond to HKCA. Ca 2+ flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase.To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for those C. albicans strains with high ATP secretion. Taken together, our findings indicate that C. albicans releases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses. Author SummaryBacterial release of ATP has been shown to modulate immune responses. Candida albicans displays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates. C. albicans strains with high ATP secretion show lower fungal burden following epicutaneous infection.Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killed C. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection ...

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“…In our multi-omics integration analysis, we focused on ATP and pipecolic acid, in addition to butyrate, since there is evidence supporting their role in CNS and they can be microbially derived (12,(48)(49)(50)(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

An integrated metagenomics and metabolomics approach implicates the microbiome-gut-brain-axis in the pathogenesis of Huntington’s disease transgenic mice

Kong¹,

Ellul²,

Narayana³

et al. 2020

Preprint

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Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder with onset and severity of symptoms influenced by various environmental factors. Recent discoveries have highlighted the importance of the gastrointestinal microbiome in mediating the bidirectional communication between the central and enteric nervous system via circulating factors. Using shotgun sequencing, we investigated the gut microbiome composition in the R6/1 transgenic mouse model of HD from 4 to 12 weeks of age (early adolescent through to adult stages). Targeted metabolomics was also performed on the blood plasma of these mice (n=9 per group) at 12 weeks of age to investigate potential effects of gut dysbiosis on the plasma metabolome profile. The short-chain fatty acid (SCFA) concentrations in the plasma were validated using LCMS. Results: Beta diversity differed between HD mice compared to their WT littermates at 12 weeks of age, suggesting that gut dysbiosis occurs prior to overt motor symptoms. Modelled time profiles of each species, KEGG Orthologs and bacterial genes, revealed heightened volatility in the HD mice, indicating potential early effects of HD mutation in the gut prior to significant cognitive and motor dysfunction. In addition to gut dysbiosis at 12 weeks of age, we also found functional differences between the WT and HD mice. The butanoate metabolism pathway, which leads to the production of the protective short-chain fatty acid, butyrate, was increased in the gut. However, the plasma concentration of butyrate and propionate were both decreased in the HD mice, as determined by the SCFA validation. The concentrations of ATP were increased by over 4-fold in the HD plasma, which was contrary to expectations. The statistical integration of the metagenomics and metabolomics unraveled several Bacteroides species that were positively correlated with butyrate levels, and negatively correlated with ATP and pipecolic acid in the plasma. Blautia producta and Prevotella scopos were found to be negatively correlated with the butyrate and ATP respectively. Conclusions: Our study has revealed a previously unknown relationship between the gut bacteria and plasma metabolome, suggesting the potential role of gut in modulating the pathogenesis of HD via specific altered plasma metabolites which mediate gut-brain signalling.

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ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens

Cited by 78 publications

References 39 publications

The microbiome and immune memory formation

The microbiome and immune memory formation

Extracellular ATP released fromCandida albicansactivates non-peptidergic neurons to augment host defense

An integrated metagenomics and metabolomics approach implicates the microbiome-gut-brain-axis in the pathogenesis of Huntington’s disease transgenic mice

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