Toll-Like Receptor 4 Regulates Chronic Stress-Induced Visceral Pain in Mice

Tramullas, Mónica; Finger, Beate C.; Moloney, Rachel D.; Golubeva, Anna V.; Moloney, Gerard; Dinan, Timothy G.; Cryan, John F.

doi:10.1016/j.biopsych.2013.11.004

Cited by 67 publications

(71 citation statements)

References 57 publications

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“…47,48 In the present study, although changes in TLRs expression were relatively minor, we observed correlations between TLR expression (in particular TLR-7) and nociceptive markers (CB2, MOR and TRPV1/3). Although these correlations have to be interpreted with caution, this further supports the possibility that TLRs act as transducers of microbial-generated signals generating local changes in neuroimmune systems and leading to a modulation of viscerosensitivity.…”

Section: Discussionsupporting

confidence: 49%

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

2015

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Abbreviations: AMP, antimicrobial peptide; CB1/2, cannabinoid receptor type 1 or 2; FGD, functional gastrointestinal disorder; FISH, fluorescent in situ hybridization; GCM, gut commensal microbiota; GI, gastrointestinal; IBS, irritable bowel syndrome; iNOS, inducible nitric oxide synthase; MOR, mu-opioid receptor; NGF, nerve growth factor; PPR, pattern recognition receptor; Reg3g, regenerating islet-derived protein 3 gamma; RELMb, resistin-like molecule-b; RT-qPCR, reverse transcription quantitative polymerase chain reaction; SFB, segmented filamentous bacteria; sIgA, secretory IgA; TLR, toll-like receptor; TPH 1/2, tryptophan hydroxylase isoforms 1 or 2; TRPV1/3, transient receptor potential vanilloid types 1 or 3Alterations in the composition of the commensal microbiota (dysbiosis) seem to be a pathogenic component of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and might participate in the secretomotor and sensory alterations observed in these patients.We determined if a state antibiotics-induced intestinal dysbiosis is able to modify colonic pain-related and motor responses and characterized the neuro-immune mechanisms implicated in mice. A 2-week antibiotics treatment induced a colonic dysbiosis (increments in Bacteroides spp, Clostridium coccoides and Lactobacillus spp and reduction in Bifidobacterium spp). Bacterial adherence was not affected. Dysbiosis was associated with increased levels of secretory-IgA, up-regulation of the antimicrobial lectin RegIIIg, and toll-like receptors (TLR) 4 and 7 and down-regulation of the antimicrobial-peptide Resistin-Like Molecule-b and TLR5. Dysbiotic mice showed less goblet cells, without changes in the thickness of the mucus layer. Neither macroscopical nor microscopical signs of inflammation were observed. In dysbiotic mice, expression of the cannabinoid receptor 2 was up-regulated, while the cannabinoid 1 and the mu-opioid receptors were down-regulated. In antibiotic-treated mice, visceral painrelated responses elicited by intraperitoneal acetic acid or intracolonic capsaicin were significantly attenuated. Colonic contractility was enhanced during dysbiosis. Intestinal dysbiosis induce changes in the innate intestinal immune system and modulate the expression of pain-related sensory systems, an effect associated with a reduction in visceral painrelated responses. Commensal microbiota modulates gut neuro-immune sensory systems, leading to functional changes, at least as it relates to viscerosensitivity. Similar mechanisms might explain the beneficial effects of antibiotics or certain probiotics in the treatment of IBS.

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Section: Discussionsupporting

confidence: 49%

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

2015

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“…The translational relevance of these findings is bolstered by knowledge that in IBS, there is evidence of lowgrade immune activation that is associated with gut microbiota alterations ) and increased kynurenine pathway metabolism (Clarke et al, 2009a;Clarke et al, 2012b;Fitzgerald et al, 2008). Interestingly, TLRs are also expressed in the CNS (Kigerl et al, 2014) where they play a role, for example, in visceral pain following chronic stress (Tramullas et al, 2014) and the TLR3 ligand poly(I:C) induces the expression of IDO in human astrocytes (Suh et al, 2007).…”

Section: The Immune System the Gut Microbiota And Implications For Kmentioning

confidence: 99%

Kynurenine pathway metabolism and the microbiota-gut-brain axis

et al. 2017

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“…51,52 Intravenous, intracerebroventricular, and also the intraprefrontal cortex administration of TAK-242, which is a specific antagonist of TLR4, remarkably suppressed VH induced by chronic stress. 53 …”

Section: Pharmacological Aspects Of Visceral Hypersensitivity and Irrmentioning

confidence: 99%

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

Farzaei

Bahramsoltani

Abdollahi

et al. 2016

J Neurogastroenterol Motil

139

116

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Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH. (J Neurogastroenterol Motil 2016;22:558-574)

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Toll-Like Receptor 4 Regulates Chronic Stress-Induced Visceral Pain in Mice

Abstract: Our results reveal a novel role for TLR4 within the PFC in the modulation of visceral nociception and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity.

Cited by 67 publications

References 57 publications

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice

Kynurenine pathway metabolism and the microbiota-gut-brain axis

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

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