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Cited by 15Gut microbiota and healthGastrointestinal motility and disordersNeuropeptides and Animal Physiology

Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells

Open access
Xiang, Chen, Chen, Peihua, Zhang, Qin, Li, Yinghui, Pan, Ying, Xie, Wenchun, Sun, Jianyuan, Liu, Zhihua·2021·iScience
DOI 10.1016/j.isci.2021.102849PMC PMC8333343

Published version of a preprint

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Abstract

The intestinal microbiota closely interacts with the neuroendocrine system and exerts profound effects on host physiology. Here, we report that nucleotide-binding oligomerization domain 1 (Nod1) ligand derived from intestinal bacteria modulates catecholamine storage and secretion in mouse adrenal chromaffin cells. The cytosolic peptidoglycan receptor Nod1 is involved in chromogranin A (Chga) retention in dense core granules (DCGs) in chromaffin cells. Mechanistically, upon recognizing its ligand, Nod1 localizes to DCGs, and recruits Rab2a, which is critical for Chga and epinephrine retention in DCGs. Depletion of Nod1 ligand or deficiency of Nod1 leads to a profound defect in epinephrine storage in chromaffin cells and subsequently less secretion upon stimulation. The intestine-adrenal medulla cross talk bridged by Nod1 ligand modulates adrenal medullary responses during the immobilization-induced stress response in mice. Thus, our study uncovers a mechanism by which intestinal microbes modulate epinephrine secretion in response to stress, which may provide further understanding of the gut-brain axis.

AI snapshot

Written from the paper’s full text.

TL;DR

Intestinal microbiota-derived Nod1 ligand acts on adrenal chromaffin cells to support chromogranin A and epinephrine retention in dense core granules, thereby optimizing catecholamine secretion during immobilization stress. Nod1 sensing recruits Rab2a to dense core granules, and loss of Nod1 or its ligand impairs epinephrine storage, secretion, and the stress-induced epinephrine surge.

Key findings

  • Nod1 is expressed in the adrenal medulla, not cortex, and Nod1 agonist iE-DAP boosts K+-stimulated catecholamine secretion from WT chromaffin cells in a Nod1-dependent manner; Nod1−/− cells respond poorly.
  • Nod1 deficiency increases atypical dense core granules: about 40% of vesicles in Nod1−/− chromaffin cells were atypical versus 10% in WT, with smaller dense-core diameters; Chga protein was reduced by half, and adrenal epinephrine was markedly reduced.
  • Microbe-derived Nod1 ligand is required: antibiotic treatment or Lyz1 deficiency reduced Chga and epinephrine in chromaffin cells, reduced Nod1 recruitment to Rab10+ dense core granules, and reduced Rab2a recruitment to synaptophysin+ dense core granules; oral iE-DAP partially restored epinephrine in Lyz1−/− mice.
  • Nod1 or Lyz1 deficiency impaired catecholamine secretion ex vivo, with single-cell amperometry showing fewer molecules released per fusion event; during 1 hr immobilization, the plasma epinephrine increase was blunted in Lyz1−/− and Dbh-cre;Nod1f/f mice, and blood glucose and liver glycogen responses were milder.

Methods

  • Mouse models included WT, Nod1−/−, Lyz1−/−, Nod1f/f, Dbh-cre, and Dbh-cre;Nod1f/f mice; antibiotic-treated mice received an oral antibiotic cocktail for 10 days, and some Lyz1−/− mice received oral iE-DAP.
  • Primary adrenal chromaffin cells and PC-12 cells were used for ex vivo assays; catecholamine secretion was measured with the GRABNE sensor and single-cell amperometry, and Chga/Rab2a/Nod1 localization was assessed by immunofluorescence, immunohistochemistry, immunoblotting, qPCR, and transmission electron microscopy.
  • In vivo stress responses were assessed by immobilization for 1 hr or 25 min, with plasma epinephrine measured by ELISA, blood glucose measured, and liver glycogen quantified.

Limitations

  • The paper states that ex vivo experiments simplify bacteria–SAM interactions; Lyz1−/− mice may have alterations in other bacterial ligands, and Dbh-cre;Nod1f/f mice may affect cells other than chromaffin cells, so the effect reflects one aspect of bacteria–host cross talk.
  • The paper notes unresolved questions: whether Nod1 also acts ligand-independently, how Nod1 ligand enters chromaffin cells, and what other factors downstream of Nod1 recruit Rab2a onto dense core granules.
  • Evident from the text: Dbh is expressed in some neurons and sympathetic nerves beyond adrenal chromaffin cells, and paraffin immunostaining may underestimate cytosolic Nod1, although the authors support a cell-intrinsic role from ex vivo chromaffin cell experiments.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.isci.2021.102849

Cites

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Statistics

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Claims the paper makes

0 of 82 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Loss of Nod1 markedly reduces the amount of Chga protein in isolated adrenal medullas.

    “Loss of Nod1 markedly reduced the amount of Chga protein (Figures 2E and 2F).”
    Quote in the paperSubstantial claim
  • Findingown data

    Chromaffin cells from Nod1−/− mice do not respond to K+ stimulation as robustly as cells from wild-type mice.

    “Chromaffin cells from Nod1−/− mice did not respond to K+ stimulation as robustly as cells from WT mice (the iE-Lys-treated groups in Figures 1C–1E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Chga, Chgb, Synaptotagmin I, and Carboxypeptidase E mRNA levels are comparable in isolated adrenal medullas from wild-type and Nod1−/− mice.

    “Meanwhile, Chga, Chgb, Synaptotagmin I, and Carboxypeptidase E mRNA levels were comparable in isolated adrenal medullas from WT and Nod1−/− mice (Figures S2C–S2F).”
    Quote in the paperSubstantial claim
  • Findingown data

    Chga immunofluorescence signal is markedly reduced in Nod1−/− adrenal medullas compared with wild-type medullas.

    “We probed for Chga in adrenal medulla of WT and Nod1−/− mice and found that the Chga immunofluorescence signal was markedly reduced in Nod1−/− medullas compared with WT medullas (Figures 2D and S2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    mRNA levels of genes involved in epinephrine synthesis and 5-HT recycling are similar in wild-type and Nod1−/− mice.

    “In addition, mRNA levels of genes involved in epinephrine synthesis and 5-HT recycling were similar in WT and Nod1−/− mice (Figures S2G–S2I).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 52
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In wild-type mice, Nod1 protein is expressed specifically in the adrenal medulla but not in the cortex, and Nod1 deficiency abolishes medullary staining.

    “Immunohistochemical (IHC) staining of adrenal gland from wild-type (WT) mice detected Nod1 expression specifically in the medulla, but not in the cortex region, whereas Nod1 deficiency abolished staining in the medulla region (Figure 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nod1 mRNA is highly enriched in the adrenal medulla and very low in the cortex.

    “Quantitative polymerase chain reaction in WT tissues showed that Nod1 mRNA was highly enriched in medulla but very low in the cortex (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of mice with an antibiotic cocktail significantly reduces bacterial load and diminishes Chga staining in chromaffin cells.

    “We found that treatment of mice with a cocktail of antibiotics (ABX) significantly reduced the bacterial load and diminished the Chga staining in chromaffin cells (Figures 3A, S3A, and S3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nod1 colocalizes with Rab10 in the adrenomedullary region in wild-type mice, indicating recruitment of Nod1 onto dense-core granules.

    “Nod1 colocalized with Rab10 in the adrenomedullary region in WT mice, indicating the recruitment of Nod1 onto DCGs (Figure 3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Deletion of Lyz1 results in a marked defect in K+-induced catecholamine secretion, less severe than in Nod1−/− cells.

    “Deletion of Lyz1 also resulted in a marked defect in K+-induced catecholamine secretion (Figures 5A–5C), albeit less severe than in cells from Nod1−/− mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Depletion of Nod1 ligand or deficiency of Nod1 leads to a profound defect in epinephrine storage in chromaffin cells and subsequently less secretion upon stimulation.

    “Depletion of Nod1 ligand or deficiency of Nod1 leads to a profound defect in epinephrine storage in chromaffin cells and subsequently less secretion upon stimulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    K+ induced comparable green fluorescence flux in wild-type cells treated with iE-Lys, LPS, and MDP, while a much stronger fluorescence flux was observed in wild-type cells treated with iE-DAP.

    “Notably, K+ induced comparable green fluorescence flux in WT cells treated with iE-Lys, LPS, and MDP (Figures 1C and 1D), while a much stronger fluorescence flux was observed in WT cells treated with iE-DAP (Figures 1C and 1D).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A few vesicles in wild-type cells have dense cores that appear less compact (type 2), which might represent dense-core granules undergoing maturation.

    “A few vesicles in WT cells had dense cores that appeared less compact (type 2); these might represent DCGs undergoing maturation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immobilization for one hour markedly increased circulating epinephrine in WT mice, but the increase was blunted in Lyz1−/− mice.

    “When the mice were immobilized for one hour, the level of circulating epinephrine markedly increased in WT mice, but the increase was blunted in Lyz1−/− mice (Figure 7A).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse immobilization model evaluates the adrenal medullary response during stress.

  • The quote only partly states this claim.

    Findingown data

    Peak current of amperometric spike events was significantly reduced in Nod1−/− and Lyz1−/− chromaffin cells compared with WT cells.

    “event were significantly reduced in Nod1−/− and Lyz1−/− chromaffin cells compared with WT cells (Figure 6C)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of catecholamine molecules released per fusion event was significantly decreased in Nod1- or Lyz1-deficient chromaffin cells, indicating fewer catecholamine molecules were secreted per fusion event in Nod1−/− and Lyz1−/− chromaffin cells compared with WT cells.

    “The molecule numbers were significantly decreased per event in Nod1-or Lyz1-deficient cells (Figure 6E).”
    • Also stated in: § Reduced catecholamine secretion in chromaffin cells deficient in Nod1 or Nod1 ligand · hedged
      “This indicates that fewer catecholamine molecules were secreted per fusion event in Nod1−/− and Lyz1−/− chromaffin cells compared with WT cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingreasoning

    The overall level of Nod1 mRNA in adrenal glands is relatively low, probably because the medulla is not the major part of the adrenal gland.

    “The overall level of Nod1 mRNA in adrenal glands was relatively low, probably because the medulla is not the major part of the adrenal gland.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The overall structure of adrenal gland and the relative ratio of medulla to whole adrenal gland were not changed in Dbh-cre;Nod1f/f mice.

    “while the overall structure of adrenal gland and the relative ratio of medulla to whole adrenal gland were not changed in Dbh-cre;Nod1f/f mice (Figures S5D–S5J).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immobilization resulted in a dramatic increase in circulating epinephrine in control mice, while the increase was less pronounced in Dbh-cre;Nod1f/f mice.

    “Immobilization resulted in a dramatic increase in the circulating epinephrine level in control mice, while the increase in epinephrine level was less pronounced in Dbh-cre;Nod1f/f mice (Figure 7C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse immobilization model evaluates the adrenal medullary response during stress.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The overall level of Nod1 mRNA in adrenal gland remained relatively low.

    “In comparison, the overall level of Nod1 mRNA in adrenal gland remained relatively low, consistent with online databases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immunoblotting and quantitative PCR showed comparable levels of Nod1 protein and mRNA present in medullas in WT and Lyz1−/− mice.

    “Meanwhile, our immunoblotting and quantitative PCR showed comparable levels of Nod1 protein and mRNA present in medullas in WT and Lyz1−/− mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunostaining showed Nod1 largely localized to DCGs in chromaffin cells in WT mice, and ABX treatment or Lyz1 depletion greatly reduced the staining signal of Nod1 on DCGs.

    “In this study, immunostaining showed Nod1 largely localized to DCGs in chromaffin cells in WT mice, and ABX treatment or Lyz1 depletion greatly reduced the staining signal of Nod1 on DCGs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    EM analysis revealed enlarged DCGs and less condensed DCG cores in chromaffin cells in Nod1−/− mice.

    “Our electron microscopy (EM) analysis revealed enlarged DCGs and less condensed DCG cores in chromaffin cells in in Nod1−/− mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chga mRNA levels were not affected in adrenal medullas of Nod1−/− mice, while Chga protein levels were reduced by half.

    “We found that Chga mRNA levels were not affected in adrenal medullas of Nod1−/− mice, while Chga protein levels were reduced by half.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpressing a dominant negative mutant of Rab2a reduced the level of Chga in PC-12 cells, and this phenotype was reversed by inhibiting lysosome activity.

    “Overexpressing a dominant negative mutant of Rab2a reduced the level of Chga in PC-12 cells, and this phenotype was reversed by inhibiting the activity of lysosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The overall structure and the relative ratio between medulla and whole adrenal gland are not altered in Lyz1−/− mice.

    “Of note, the overall structure and the relative ratio between medulla to whole adrenal gland was not altered in Lyz1−/− mice (Figures S3E–S3J).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Upon recognizing its ligand, Nod1 localizes to dense-core granules and recruits Rab2a, which is critical for Chga and epinephrine retention in dense-core granules.

    “Mechanistically, upon recognizing its ligand, Nod1 localizes to DCGs, and recruits Rab2a, which is critical for Chga and epinephrine retention in DCGs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rab2a localizes to the membranes of lysosome-like organelles, such as dense-core granules, melanosomes, and early endosomes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 and Nod2 play a key role in mediating microbe-host cross talk, including lymphoid tissue genesis, Paneth cell function, neutrophil priming, hematopoiesis, and 5-HT signaling.

    “Nucleotide-binding oligomerization domain 1 (Nod1), together with Nod2, as classic pattern recognition receptors, play a key role in mediating the microbe-host cross talk, including lymphoid tissue genesis (Bouskra et al., 2008), Paneth cell function in the intestine (Zhang et al., 2015), neutrophil priming (Clarke et al., 2010), hematopoiesis (Iwamura et al., 2017), and 5-hydroxytryptamine (5-HT)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bouskra et al., 2008 source

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    • cites Zhang et al., 2015 source

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    • cites Clarke et al., 2010 source

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    Premisecitation

    Innate immune receptors are one mechanism underlying the effect of microbiota on the HPA axis.

    “Innate immune receptors are one of the mechanisms underlying the effect of microbiota on the HPA axis (Liu et al., 2014; Zacharowski et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Liu et al., 2014 source

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    Premisecitation

    Absence of microbiota or depletion of microbes by antibiotics in rodents leads to exaggerated HPA axis activation with elevated adrenocorticotrophic hormone and corticosterone levels in response to stress, accompanied by reduced anxiety.

    “Absence of microbiota (germ-free [GF] status) or depletion of microbes by antibiotics in rodents leads to exaggerated activation of the HPA axis associated with elevated adrenocorticotrophic hormone and corticosterone levels in response to stress, accompanied with reduced anxiety (Sudo et al., 2004; Zheng et al., 2016; Diaz Heijtz et al., 2011; Huo et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sudo et al., 2004 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Colonization by microbiota regulates expression of critical HPA axis genes in hippocampus and modulates hippocampal serotonin concentration, which affects HPA activation.

    “Colonization by microbiota has been shown to regulate the expression of critical HPA axis genes in hippocampus and modulate hippocampal serotonin concentration, which also affects HPA activation (Luo et al., 2018; Farzi et al., 2015; Shanks et al., 1995; Clarke et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Luo et al., 2018 source

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    Premisecitation

    One previous study found that absence of gut microbial colonization selectively impaired catecholamine response to hypoglycemic stress in mice, but the molecular mechanism was not identified.

    “One previous study found that the absence of gut microbial colonization selectively impaired catecholamine response to hypoglycemic stress in mice (Giri et al., 2019); however, the molecular mechanism was not identified.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Giri et al., 2019 source

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    Premisecitation

    Chga plays a key role in the formation of dense-core granules.

    “Chga plays a key role in the formation of DCGs (Kim et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim et al., 2001 source

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    Premisecitation

    The presence of circulating Nod1 ligand depends on lysozyme in the intestinal lumen, and deficiency of Lyz1 in mice leads to reduced level of microbial Nod1 ligand in the circulation.

    “We previously reported that the presence of circulating Nod1 ligand depends on lysozyme in the intestinal lumen, and deficiency of Lyz1 in mice leads to reduced level of microbial Nod1 ligand in the circulation (Zhang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhang et al., 2019 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Nod1 ligand derived from intestinal microbes gets into the circulation and modulates a range of biological activities in a Nod1-dependent manner.

    “Nod1 ligand derived from intestinal microbes is known to get into the circulation and modulate a range of biological activities in a Nod1-dependent manner (Bouskra et al., 2008; Chan et al., 2017; Zhang et al., 2019; Hergott et al., 2016; Iwamura et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bouskra et al., 2008 source

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    Premisecitation

    Chga is critical for epinephrine condensation in dense-core granules.

    “Chga is critical for epinephrine condensation in DCGs (Pasqua et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pasqua et al., 2016 source

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    Premisecitation

    Rab2a is a Golgi-resident GTPase governing intra-Golgi trafficking.

    “Rab2a is known to be a Golgi-resident GTPase, governing intra-Golgi trafficking (Buffa et al., 2008; Ailion et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Buffa et al., 2008 source

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    Premisecitation

    In C. elegans, Rab2 null mutation impairs maturation of the dense core of dense-core granules, and dense-core granule cargos are mistargeted to early endosomes for degradation.

    “In C. elegans, Rab2 null mutation impaired the maturation of the dense core of DCGs, and DCG cargos were mistargeted to early endosomes for degradation (Sumakovic et al., 2009; Edwards et al., 2009).”
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    • cites Sumakovic et al., 2009 source

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    Premisecitation

    In cultured intestinal organoids, Rab2a knockdown leads to lysozyme being targeted for degradation in lysosomes instead of being stored in dense-core granules in Paneth cells.

    “In cultured intestinal organoids, Rab2a knockdown led to lysozyme being targeted for degradation in lysosomes instead of being stored in DCGs in Paneth cells (Zhang et al., 2015).”
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    • cites Zhang et al., 2015 source

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    Premisecitation

    Rab2a regulates cargo sorting events in neurons in C. elegans and intestinal Paneth cells.

    “Studies have shown that Rab2a regulates cargo sorting events in neurons in C. elegans and intestinal Paneth cells (Edwards et al., 2009; Sumakovic et al., 2009; Zhang et al., 2015).”
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    • cites Edwards et al., 2009 source

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    • cites Sumakovic et al., 2009 source

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    Premisecitation

    Treatment with antibiotics has been used to deplete microbial ligands in the circulation.

    “Treatment with antibiotics has been used to deplete microbial ligands in the circulation (Clarke et al., 2010; Bird, 2010; Arentsen et al., 2017; Hergott et al., 2016).”
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    • cites Clarke et al., 2010 source

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    Premisecitation

    Rab2a S20N was previously determined as a dominant negative mutant.

    “To perturb the activity of Rab2a, we created a Rab2a mutant, S20N, which was previously determined as a dominant negative mutant (Tisdale et al., 1992).”
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    • cites Tisdale et al., 1992 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Single-cell amperometry does not distinguish different kinds of catecholamines but can accurately quantify the number of molecules released and the kinetic parameters of each vesicle.

    “Single-cell amperometry does not distinguish different kinds of catecholamines, but it can accurately quantify the number of molecules released and the kinetic parameters of each vesicle (Dunevall et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dunevall et al., 2015 source

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    Premisecitation

    A GRABNE probe based on an α2 adrenergic receptor has been developed for in vivo and in vitro measurement of epinephrine or norepinephrine dynamics.

    “A G protein-coupled receptor (GPCR) activation-based NE (GRABNE) probe, based on an α2 adrenergic receptor, has been developed for in vivo and in vitro measurement of epinephrine or norepinephrine dynamics (Feng et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Feng et al., 2019 source

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    Premisecitation

    Single-cell amperometry measures the numbers of released catecholamine molecules during every individual exocytosis event.

    “Single-cell amperometry measures the numbers of released catecholamine molecules during every individual exocytosis event (Garcia et al., 2006; Wightman et al., 1991).”
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    • cites Garcia et al., 2006 source

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    Premisecitation

    Oligopeptide transporters encoded by SLC15A3 and SLC15A4 were reported to be responsible for transporting small peptidoglycan fragments into macrophages.

    “Previously, oligopeptide transporters encoded by SLC15A3 and SLC15A4 were reported to be responsible for transporting small peptidoglycan (PGN) fragments into macrophages (Nakamura et al., 2014).”
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    • cites Nakamura et al., 2014 source

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    Premisecitation

    Adrenal chromaffin cells are classic neuroendocrine cells that secrete catecholamines upon receiving stimulation from sympathetic nerves.

    “Adrenal chromaffin cells are classic neuroendocrine cells, which secrete catecholamines upon receiving stimulation from sympathetic nerves (Fenwick et al., 1982; Sala et al., 2008).”
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    • cites Fenwick et al., 1982 source

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    Study design and conductown data

    No photobleaching was apparent during the GRABNE experiments.

    “No photobleaching was apparent during our experiments (Figures S1D and S1E).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Catecholamine secretion can be monitored in a real-time manner using specific probes.

    “Catecholamine secretion can be monitored in a real-time manner using specific probes (Muller et al., 2014; Wang et al., 2018).”
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    • cites Muller et al., 2014 source

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    Interpretationown data

    Deficiency of Nod1 or Lyz1 leads to impaired catecholamine secretion from DCGs.

    “Taken together, these data indicate that deficiency of Nod1 or Lyz1 leads to impaired catecholamine secretion from DCGs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Elevated epinephrine, together with other stress hormones, induces physiological responses including increased blood sugar and liver glycogen mobilization.

    “The elevated epinephrine, together with other stress hormones, induces a range of physiological responses in preparation for the fight-or-flight response, including increased blood sugar level, glycogen mobilization in the liver, etc (Buira et al., 2004; Fernandez et al., 2000; Park et al., 2016; Kang et al., 2015).”
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    • cites Buira et al., 2004 source

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    Premisecitation

    Previous study found highly restricted expression of Nod1 in pancreatic beta cells but not in other pancreatic cells.

    “Interestingly, our previous study found a highly restricted expression of Nod1 in pancreatic beta cells but not in other pancreatic cells (Zhang et al., 2015).”
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    • cites Zhang et al., 2015 source

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    Premisecitation

    Stress can result in significant depletion of liver glycogen within 20 or 30 min of onset of immobilization.

    “Previous studies have shown that stress can result in significant depletion of liver glycogen within 20 or 30 min of the onset of immobilization (Sánchez et al., 2002; Fernández et al., 2000).”
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    • cites Sánchez et al., 2002 source

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    • cites Fernández et al., 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adrenal chromaffin cells recycle 5-HT through serotonin transporter (SERT).

    “It has been shown that adrenal chromaffin cells recycle 5-HT through serotonin transporter (SERT) (Brindley et al., 2016; Linder et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brindley et al., 2016 source

      Not checked in the free run.

    • cites Linder et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 activation reduced the SERT mRNA level in an intestinal epithelial cell line.

    “Indeed, another study found that Nod1 activation reduced the SERT mRNA level in an intestinal epithelial cell line (Layunta et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Layunta et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    5-HT can exert an inhibitory effect on epinephrine secretion from adrenal chromaffin cells.

    “It is worth noting that 5-HT can exert an inhibitory effect on epinephrine secretion from adrenal chromaffin cells (Brindley et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brindley et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HPA axis and serotonergic system were altered in mice lacking microbiota.

    “Previous studies had demonstrated that the HPA axis and serotonergic system were altered in mice lacking microbiota (Sudo et al., 2004; Clarke et al., 2013; Zheng et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sudo et al., 2004 source

      Not checked in the free run.

    • cites Clarke et al., 2013 source

      Not checked in the free run.

    • cites Zheng et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In primary cultured chromaffin cells, 5-HT treatment reduced the number of vesicles undergoing exocytosis, without affecting the quantal size and kinetics of transmitter release from individual vesicular fusion events.

    “In primary cultured chromaffin cells, 5-HT treatment reduced the number of vesicles undergoing exocytosis, without affecting the quantal size and kinetics of transmitter release from individual vesicular fusion events (Brindley et al., 2016, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brindley et al., 2016, 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Absence of gut microbial colonization selectively impaired the catecholamine response to hypoglycemic stress in mice, and the transcriptome in adrenal glands was altered.

    “Previous work found that the absence of gut microbial colonization selectively impaired the catecholamine response to hypoglycemic stress in mice, and the transcriptome in adrenal glands was altered (Giri et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Giri et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 and Nod2 undergo enhanced membrane recruitment upon ligand binding.

    “Previous findings have found that Nod1 and Nod2 undergo enhanced membrane recruitment upon ligand binding (Lu et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lu et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Previous studies showed enhanced membrane recruitment of Nod1 and Nod2 upon commensal bacterial colonization in β cells and intestinal Paneth cells, respectively.

    “Indeed, our previous studies have shown enhanced membrane recruitment of Nod1 and Nod2 upon commensal bacterial colonization in β cells and intestinal Paneth cells, respectively (Zhang et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of Rab2a in neurons in C. elegans led to specific lysosomal degradation of a neuropeptide normally located in DCGs.

    “Loss of Rab2a in neurons in C. elegans led to specific lysosomal degradation of a neuropeptide that is normally located in DCGs (Edwards et al., 2009; Sumakovic et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Edwards et al., 2009 source

      Not checked in the free run.

    • cites Sumakovic et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rab2a is involved in DCG cargo sorting.

    “The involvement of Rab2a in DCG cargo sorting has been previously reported (Edwards et al., 2009; Sugawara et al., 2014; Sumakovic et al., 2009; Zhang et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Edwards et al., 2009 source

      Not checked in the free run.

    • cites Sugawara et al., 2014 source

      Not checked in the free run.

    • cites Sumakovic et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Reduced level of Nod1 or Nod1 ligand impairs Rab2a recruitment onto DCG membranes, which may cause mistargeting of a significant proportion of Chga to lysosomes for degradation.

    “We propose a scenario where a reduced level of Nod1 or Nod1 ligand impairs Rab2a recruitment onto DCG membranes, which may cause mistargeting of a significant proportion of Chga to lysosomes for degradation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1, activated by Nod1 ligand, instructs maturation of gut-associated lymphoid tissues in mice.

    “For instance, Nod1, activated by the Nod1 ligand, instructs the maturation of gut-associated lymphoid tissues in mice (Bouskra et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bouskra et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 signaling in mesenchymal stromal cells regulates hematopoiesis.

    “Nod1 signaling in mesenchymal stromal cells regulates hematopoiesis (Iwamura et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Iwamura et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 signaling primes neutrophils for optimal bactericidal activity.

    “Nod1 signaling primes neutrophils for optimal bactericidal activity (Clarke et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Clarke et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Knockdown of Rab2a led to lysosomal degradation of lysozyme in intestinal Paneth cells.

    “Knockdown of Rab2a led to lysosomal degradation of lysozyme in intestinal Paneth cells (Zhang et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nod1 signaling contributes to metabolic inflammation during high fat diet-induced obesity.

    “Nod1 signaling contributes to metabolic inflammation during high fat diet-induced obesity (Schertzer et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schertzer et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oligopeptide transporters encoded by SLC15A3 and SLC15A4 are responsible for transporting small PGN fragments into macrophages.

    “It was previously reported that oligopeptide transporters encoded by SLC15A3 and SLC15A4 are responsible for transporting small PGN fragments into macrophages (Nakamura et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nakamura et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Nod1 ligand from intestinal microbes directly modulates the storage of Chga and epinephrine in DCGs in adrenal chromaffin cells, which optimizes epinephrine secretion under stress conditions.

    “In summary, Nod1 ligand from intestinal microbes directly modulates the storage of Chga and epinephrine in DCGs in adrenal chromaffin cells, which optimizes epinephrine secretion under stress conditions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: PGN fragments sensed by adrenal glands are derived from intestinal microbes residing in the GI tract.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Nod1 sensing regulates 5-HT signaling in intestinal epithelium and regulates insulin trafficking in islet beta cells.

    “Beyond immunity and inflammation, Nod1 sensing regulates 5-HT signaling in intestinal epithelium and regulates insulin trafficking in islet beta cells (Pusceddu et al., 2019; Zhang et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pusceddu et al., 2019 source

      Not checked in the free run.

    • cites Zhang et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    PC-12 cells were verified based on their morphology under the microscope and by their growth curve.

    “PC-12 cells were obtained from China Infrastructure of Cell Line Resources (Cat# TCR 8) and verified based on their morphology under the microscope and by their growth curve.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Plasmid sequences were confirmed by Sanger sequencing.

    “Sequences were confirmed by Sanger sequencing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Both Lyz1−/− and Dbh-cre;Nod1f/f animal models have drawbacks: other bacterial ligands could be altered in Lyz1−/− mice, while cells other than chromaffin cells could be affected in Dbh-cre;Nod1f/f mice.

    “However, both animal models have their drawbacks. Other bacterial ligands could be altered in Lyz1−/− mice, while cells other than chromaffin cells could be affected in Dbh-cre;Nod1f/f mice.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Dbh is expressed in certain neurons and sympathetic nerves in addition to adrenal chromaffin cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    At least 988 GFP+ cells (from more than 70 frames) were quantified per sample.

    “At least 988 GFP+ cells (from more than 70 frames) were quantified per sample.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Animal experiments were carried out in accordance with Tsinghua University animal protocols and approved by IACUC.

    “The animal experiments in the methods sections were carried out in accordance with Tsinghua University animal protocols (protocol number 20-LZH4), approved by Institutional Animal Care and Use Committee (IACUC).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The specificity of q-PCR was verified with melting curves for each PCR reaction.

    “The specificity of q-PCR was verified with melting curves for each PCR reaction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cell preparations with >95% viability, as determined by trypan blue staining, were used for further assays.

    “Cell viability was determined by trypan blue staining, and cell preparations with >95% viability were used for further assays.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    q-PCR reactions were performed in triplicate.

    “q-PCR reactions were performed with SYBR Premix Taq on a Rotor Gene 6000 thermal cycler in triplicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Image analysis was performed by a blinded researcher.

    “Image analysis were performed by a blinded researcher.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cells with red-channel fluorescence intensity lower than 105 AU (mislabeled cell fragments) or higher than 2∗107 AU (abnormally high deviation values) were excluded from statistical data.

    “We then excluded the data of cells that fluorescence intensity of red channel was lower than 105 AU (mislabeled cell fragments) and higher than 2∗107 AU (abnormally high deviation values) in the statistical data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    A level of 5× the RMS of noise at baseline was set as the threshold for signal detection.

    “A level of 5× the RMS of noise at baseline was set as the threshold for signal detection(Chen et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al., 2021 source

      Not checked in the free run.

78 of 78

  • The paper relies on this without support.

    The effect of intestinal microbiota on the sympatho-adrenal-medullary pathway has not been extensively investigated.

    “In comparison, the effect of intestinal microbiota on the SAM pathway has not been extensively investigated.”

  • The paper relies on this without support.

    Adrenal chromaffin cells store epinephrine and norepinephrine in dense-core granules.

    “Adrenal chromaffin cells store epinephrine (norepinephrine) in DCGs.”

  • The paper relies on this without support.

    Epinephrine is the major form of catecholamine present in adrenal chromaffin cells.

    “Epinephrine is the major form of catecholamine present in adrenal chromaffin cells.”

  • The paper relies on this without support.

    Dense-core granule morphology differs greatly between epinephrine-storing and norepinephrine-storing cells under the fixation condition used.

    “DCG morphology differs greatly between epinephrine-storing and norepinephrine-storing cells under the fixation condition we used (Figure S2A).”

  • The paper relies on this without support.

    Rab2a localizes to the membranes of lysosome-like organelles, such as dense-core granules, melanosomes, and early endosomes.

    “In addition, Rab2a localizes to the membranes of lysosome-like organelles, such as DCGs, melanosomes and early endosomes.”

  • The paper relies on this without support.

    PGN fragments sensed by adrenal glands are derived from intestinal microbes residing in the GI tract.

    “The PGN fragments sensed by adrenal glands are derived from intestinal microbes residing in the GI tract.”

  • The paper relies on this without support.

    Adrenal chromaffin cells are the primary source of epinephrine during the immobilization-induced stress response.

    “Adrenal chromaffin cells are the primary source of epinephrine during the immobilization-induced stress response.”

  • The paper relies on this without support.

    Dbh is expressed in certain neurons and sympathetic nerves in addition to adrenal chromaffin cells.

    “In addition to adrenal chromaffin cells, Dbh is also expressed in certain neurons and sympathetic nerves.”

  • The paper relies on this without support.

    The mouse immobilization model evaluates the adrenal medullary response during stress.

    “We employed a mouse immobilization model, which has been widely used to evaluate the adrenal medullary response during stress.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Nod1 ligands derived from the GM modulate catecholamine storage and secretion, so intestinal bacteria modulate the adreno-medullary response through Nod1 sensing in chromaffin cells.

    “Xiang et al. showed that nucleotide-binding oligomerization domain 1 (Nod1) ligands, derived from the GM, modulate catecholamine storage and secretion, and therefore intestinal bacteria modulate the adreno-medullary response through Nod1 sensing in chromaffin cells (521).”

    From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [521]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Amperometry statistical tests differ between methods and figure legend

    Major

    The amperometric recording methods specify a two-tailed t test, whereas the Figure 6 legend specifies one-way ANOVA with Tukey's post hoc test for the amperometry results.

  • Figure 7 gives two immobilization durations for the glycogen experiment

    Minor

    The Figure 7 legend says liver glycogen was measured after 25 minutes of immobilization, but its sample-size description labels the immobilized groups as having undergone one hour. The methods also specify 25 minutes for glycogen detection.

  • Figure 6 assigns four stars a different p-value threshold

    Minor

    The Figure 6 legend defines four stars as p < 0.001, while the paper's statistical-analysis section defines four stars as p ≤ 0.0001.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Fernandez, 2000, Immobilization stress induces c-Fos accumulation in liver, Cell Stress Chaperones, 5, 306, 10.1379/1466-1268(2000)005 · DOI

Cited by

Sorted by citations

Related

Authors
Xiang, C., Chen, P., Zhang, Q., Li, Y., Pan, Y., Xie, W., Sun, J., & Liu, Z.
Affiliations
Chinese Academy of Sciences (CN)
Corresponding author
  • Sun, Jianyuan
  • Liu, Zhihua
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2021-08
Volume
24
Issue
8
Pages
102849
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2021.102849
PMC
PMC8333343
OpenAlex
W3183677115
Semantic Scholar
fb666e5320a65154c95a83e0c8b8993876a45d4f
Cited by
15
References
100
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 3
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key Research and Development Program of China (2017YFA0503403, 2018YFE0207300)
  • National Natural Science Foundation of China (2019DP173024, 31527802, 31730028, 81670482, YJKYYQ20180028)
  • Chinese Academy of Sciences
  • Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017130)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
gut microbiota, NOD1, chromaffin cells, adrenal medulla, epinephrine secretion, catecholamine storage, chromogranin A, dense core granules, RAB2A, gut-brain axis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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