De plus en plus d’études indiquent que le microbiote intestinal pourrait jouer un rôle important sur les fonctions du système nerveux en modulant l’activité des cellules nerveuses. Il a été montré ...que les produits dérivés des bactéries peuvent influencer la perception de la douleur. De plus, des perturbations du microbiote (ou dysbiose) sont souvent associées à des pathologies intestinales ou extraintestinales comme des désordres neurodégénératifs ou des troubles développementaux. Cette revue présente les études précliniques et cliniques mettant en évidence un impact du microbiote sur la perception de la douleur dans différents contextes pathologiques. Le lien entre le microbiote et l’activation des neurones est discuté au travers de l’interaction directe hôte–microbiote qui implique l’activation des nocicepteurs par les composés ou métabolites microbiens. De nouvelles études sur l’interaction entre le microbiote et le système nerveux devraient conduire à l’identification de nouveaux ligands microbiens et de médicaments ciblant les récepteurs de l’hôte, qui pourraient à terme améliorer la gestion de la douleur chronique et le « bien-être ».
An increasing number of studies indicates the central role played by the intestinal microbiota on the peripheral and central nervous system. Indeed, it has been shown that not only bacterial-derived products can influence the perception of pain, but also perturbations in microbiota (or dysbiosis) are often associated with intestinal or extra-intestinal pathologies such as neurodegenerative or developmental disorders. In this review, we present the preclinical and clinical studies highlighting the impact of the microbiota on the perception of pain in different pathological contexts.We discuss the cellular and molecular mechanisms by which intestinal microbiota modulate “pain-sensing” sensory neurons at the periphery, and the overall impact of the brain/gut/microbiota axis in the control of aversive painful behaviors and neurological disorders. Finally, we discuss the direct host/microbiota interaction which involves the activation of nociceptors by microbeassociated molecular patterns (MAMPs). Thus, new studies on the interaction between the microbiota and the nervous system should lead to the identification of microbial ligands and drugs targeting host receptors, which could ultimately improve the management of chronic pain and “well-being”.
The objective of this study was to longitudinally quantify Escherichia coli resistant to ciprofloxacin and ceftriaxone in calves treated with enrofloxacin or tulathromycin for the control of bovine ...respiratory disease (BRD). Dairy calves 2 to 3 wk of age not presenting clinical signs of pneumonia and at high risk of developing BRD were randomly enrolled in 1 of 3 groups receiving the following treatments: (1) single label dose of enrofloxacin (ENR); (2) single label dose of tulathromycin (TUL); or (3) no antimicrobial treatment (control, CTL). Fecal samples were collected immediately before administration of treatment and at d 2, 4, 7, 14, 21, 28, 56, and 112 d after beginning treatment. Samples were used for qualification of E. coli using a selective hydrophobic grid membrane filter (HGMF) master grid. The ENR group had a significantly higher proportion of E. coli resistant to ciprofloxacin compared with CTL and TUL at time points 2, 4, and 7. At time point 28, a significantly higher proportion of E. coli resistant to ciprofloxacin was observed only compared with CTL. The TUL group had a significantly higher proportion of E. coli resistant to ciprofloxacin compared with CTL at time points 2, 4, and 7. None of the treatment groups resulted in a significantly higher proportion of E. coli isolates resistant to ceftriaxone. Our study identified that treatment of calves at high risk of developing BRB with either enrofloxacin or tulathromycin resulted in a consistently higher proportion of ciprofloxacin-resistant E. coli in fecal samples.
Nontyphoidal serovars of
are pathogenic bacteria that are common causes of food poisoning. Whereas
mechanisms of host cell invasion, inflammation, and pathogenesis are mostly well established, a new ...possible mechanism of immune evasion is being uncovered. Programmed death ligand 1 (PD-L1) is an immunosuppressive membrane protein that binds to activated T cells via their PD-1 receptor and thereby halts their activation. PD-L1 expression plays an essential role in the immunological tolerance of self-antigens but is also exploited for immune evasion by pathogen-infected cells and cancer cells. Here, we show for the first time that
infection of intestinal epithelial cells causes the induction of PD-L1. The increased expression of PD-L1 through
infection was seen in both human and rat intestinal epithelial cell lines. We determined that cellular invasion by the bacteria is necessary for PD-L1 induction, potentially indicating that
strains are delivering mediators from inside the host cell that trigger the increased PD-L1 expression. Using knockout mutants, we determined that this effect largely originates from the
pathogenicity island 2. We also show for the first time in any cell type that
combined with gamma interferon (IFN-γ) causes a synergistic induction of PD-L1. Finally, we show that
plus IFN-γ induction of PD-L1 decreased the cytokine production of activated T cells. Understanding
immune evasion strategies could generate new therapeutic targets and help to manipulate PD-L1 expression in other diseases.
The objective of this study was to evaluate the longitudinal effect of enrofloxacin or tulathromycin use in calves at high risk of bovine respiratory disease (BRD) on antimicrobial resistance genes ...and mutation in quinolone resistance-determining regions (QRDR) in fecal E. coli. Calves at high risk of developing BRD were randomly enrolled in one of three groups receiving: (1) enrofloxacin (ENR; n = 22); (2) tulathromycin (TUL; n = 24); or (3) no treatment (CTL; n = 21). Fecal samples were collected at enrollment and at 7, 28, and 56 days after beginning treatment, cultured for Escherichia coli (EC) and DNA extracted. Isolates were screened for cephalosporin, quinolone and tetracycline resistance genes using PCR. QRDR screening was conducted using Sanger sequencing. The only resistance genes detected were aac(6')Ib-cr (n = 13), bla-CTX-M (n = 51), bla-TEM (n = 117), tetA (n = 142) and tetB (n = 101). A significantly higher detection of gyrA mutated at position 248 at time points 7 (OR = 11.5; P value = 0.03) and 28 (OR = 9.0; P value = 0.05) was observed in the ENR group when compared to calves in the control group. Our findings support a better understanding of the potential impacts from the use of enrofloxacin in calves on the selection and persistence of resistance.
BackgroundAlthough evidence points to a role for histamine and serotonin in visceral hypersensitivity, activation of calcium channels such as transient receptor potential vanilloid 4 (TRPV4) also ...causes visceral hypersensitivity. We hypothesised that TRPV4 is important for the generation of hypersensitivity, mediating histamine- and serotonin-induced visceral hypersensitivity.MethodsIn response to histamine, serotonin and/or TRPV4 agonist (4αPDD), calcium signals and TRPV4 localisation studies were performed on dorsal root ganglia (DRG) neurons projecting from the colon. To evaluate visceral nociception, colorectal distension (CRD) was performed in mice treated with serotonin or histamine and with 4αPDD. Intrathecal injection of TRPV4 silencer RNA (SiRNA) or mismatch SiRNA was used to target TRPV4 expression.ResultsPre-exposure of DRG neurons projecting from the colon, to histamine or serotonin, increased Ca2+ responses induced by 4αPDD by a protein kinase C (PKC), phospholipase Cβ (PLCβ), mitogen-activated protein kinase kinase (MAPKK) and phospholipase A2 (PLA2)-dependent mechanisms. Serotonin or histamine treatments enhanced TRPV4 expression at the plasma membrane by a MAPKK mechanism. Hypersensitivity induced by serotonin or histamine were both significantly inhibited by TRPV4 SiRNA intrathecal injection. Administration of sub-nociceptive doses of serotonin or histamine potentiated 4αPDD-induced hypersensitivity in response to CRD.ConclusionsSerotonin and histamine sensitise TRPV4 response to 4αPDD both in vivo (increased visceral hypersensitivity) and in vitro, in sensory neurons, by a PKC, PLA2, PLCβ and MAPKK-dependent mechanism. Serotonin and histamine caused a MAPKK-dependent increase in TRPV4 expression in colonic sensory neurons plasma membranes. Further, histamine- or serotonin-mediated visceral hypersensitivity depend on TRPV4 expression in sensory neurons. TRPV4 appears as a common mechanism to several known mediators of visceral hypersensitivity.
Background and purpose: Changes in extracellular fluid osmolarity, which occur after tissue damage and disease, cause inflammation and maintain chronic inflammatory states by unknown mechanisms. ...Here, we investigated whether the osmosensitive channel, transient receptor potential vanilloid 4 (TRPV4), mediates inflammation to hypotonic stimuli by a neurogenic mechanism.
Experimental approach: TRPV4 was localized in dorsal root ganglia (DRG) by immunofluorescence. The effects of TRPV4 agonists on release of pro‐inflammatory neuropeptides from peripheral tissues and on inflammation were examined.
Key results: Immunoreactive TRPV4 was detected in DRG neurones innervating the mouse hindpaw, where it was co‐expressed in some neurones with CGRP and substance P, mediators of neurogenic inflammation. Hypotonic solutions and 4α‐phorbol 12,13‐didecanoate, which activate TRPV4, stimulated neuropeptide release in urinary bladder and airways, sites of neurogenic inflammation. Intraplantar injection of hypotonic solutions and 4α‐phorbol 12,13‐didecanoate caused oedema and granulocyte recruitment. These effects were inhibited by a desensitizing dose of the neurotoxin capsaicin, antagonists of CGRP and substance P receptors, and TRPV4 gene knockdown or deletion. In contrast, antagonism of neuropeptide receptors and disruption of TRPV4 did not prevent this oedema. TRPV4 gene knockdown or deletion also markedly reduced oedema and granulocyte infiltration induced by intraplantar injection of formalin.
Conclusions and implications: Activation of TRPV4 stimulates neuropeptide release from afferent nerves and induces neurogenic inflammation. This mechanism may mediate the generation and maintenance of inflammation after injury and during diseases, in which there are changes in extracellular osmolarity. Antagonism of TRPV4 may offer a therapeutic approach for inflammatory hyperalgesia and chronic inflammation.
N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be ...generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a- and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.
Highlights • Neuropathic pain is a chronic condition that represents a major health problem. • There is a need for new medications with greater efficacy and less adverse effects. • TRP channels are ...emerging targets for neuropathic pain therapeutics.
The inhibition of N-type calcium channels by opioid receptor like receptor 1 (ORL1) is a key mechanism for controlling the transmission of nociceptive signals. We recently reported that signaling ...complexes consisting of ORL1 receptors and N-type channels mediate a tonic inhibition of calcium entry. Here we show that prolonged ( approximately 30 min) exposure of ORL1 receptors to their agonist nociceptin triggers an internalization of these signaling complexes into vesicular compartments. This effect is dependent on protein kinase C activation, occurs selectively for N-type channels and cannot be observed with mu-opioid or angiotensin receptors. In expression systems and in rat dorsal root ganglion neurons, the nociceptin-mediated internalization of the channels is accompanied by a significant downregulation of calcium entry, which parallels the selective removal of N-type calcium channels from the plasma membrane. This may provide a new means for long-term regulation of calcium entry in the pain pathway.
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