Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice

Intestinal Disease Research Program, McMaster University, 1200 Main S West, Hamilton, Ontario, Canada.
Gut (Impact Factor: 14.66). 03/2006; 55(2):182-90. DOI: 10.1136/gut.2005.066100
Source: PubMed


Abdominal pain and discomfort are common symptoms in functional disorders and are attributed to visceral hypersensitivity. These symptoms fluctuate over time but the basis for this is unknown. Here we examine the impact of changes in gut flora and gut inflammatory cell activity on visceral sensitivity.
Visceral sensitivity to colorectal distension (CRD) was assessed at intervals in healthy mice for up to 12 weeks, and in mice before and after administration of dexamethasone or non-absorbable antibiotics with or without supplementation with Lactobacillus paracasei (NCC2461). Tissue was obtained for measurement of myeloperoxidase activity (MPO), histology, microbiota analysis, and substance P (SP) immunolabelling.
Visceral hypersensitivity developed over time in healthy mice maintained without sterile precautions. This was accompanied by a small increase in MPO activity. Dexamethasone treatment normalised MPO and CRD responses. Antibiotic treatment perturbed gut flora, increased MPO and SP immunoreactivity in the colon, and produced visceral hypersensitivity. Administration of Lactobacillus paracasei in spent culture medium normalised visceral sensitivity and SP immunolabelling, but not intestinal microbiota counts.
Perturbations in gut flora and in inflammatory cell activity alter sensory neurotransmitter content in the colon, and result in altered visceral perception. Changes in gut flora may be a basis for the variability of abdominal symptoms observed in functional gastrointestinal disorders and may be prevented by specific probiotic administration.

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Available from: Yukang K Mao, Oct 01, 2015
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    • "Since DSM decreased the firing frequency of nociceptive fibres, we wondered if the TRPV1 channel was involved since this is a major receptor involved in visceral nociception (Btesh et al.,2013). Verdu et al showed that antibiotic therapy induced visceral pain hypersensitivity which was inhibited by probiotic therapy (Verdu et al., 2006). Early life treatment of rats with vancomycin resulting in an altered gut microbiome, induced heightened visceral pain perception accompanied by a decrease in spinal cord TRPV1 expression (O'Mahony et al., 2014). "
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    ABSTRACT: Key points: Certain probiotic bacteria have been shown to reduce distension-dependent gut pain, but the mechanisms involved remain obscure. Live luminal Lactobacillus reuteri (DSM 17938) and its conditioned medium dose dependently reduced jejunal spinal nerve firing evoked by distension or capsaicin, and 80% of this response was blocked by a specific TRPV1 channel antagonist or in TRPV1 knockout mice. The specificity of DSM action on TRPV1 was further confirmed by its inhibition of capsaicin-induced intracellular calcium increases in dorsal root ganglion neurons. Another lactobacillus with ability to reduce gut pain did not modify this response. Prior feeding of rats with DSM inhibited the bradycardia induced by painful gastric distension. These results offer a system for the screening of new and improved candidate bacteria that may be useful as novel therapeutic adjuncts in gut pain. Abstract: Certain bacteria exert visceral antinociceptive activity, but the mechanisms involved are not determined. Lactobacillus reuteri DSM 17938 was examined since it may be antinociceptive in children. Since transient receptor potential vanilloid 1 (TRPV1) channel activity may mediate nociceptive signals, we hypothesized that TRPV1 current is inhibited by DSM. We tested this by examining the effect of DSM on the firing frequency of spinal nerve fibres in murine jejunal mesenteric nerve bundles following serosal application of capsaicin. We also measured the effects of DSM on capsaicin-evoked increase in intracellular Ca(2+) or ionic current in dorsal root ganglion (DRG) neurons. Furthermore, we tested the in vivo antinociceptive effects of oral DSM on gastric distension in rats. Live DSM reduced the response of capsaicin- and distension-evoked firing of spinal nerve action potentials (238 ± 27.5% vs. 129 ± 17%). DSM also reduced the capsaicin-evoked TRPV1 ionic current in DRG neuronal primary culture from 83 ± 11% to 41 ± 8% of the initial response to capsaicin only. Another lactobacillus (Lactobacillus rhamnosus JB-1) with known visceral anti-nociceptive activity did not have these effects. DSM also inhibited capsaicin-evoked Ca(2+) increase in DRG neurons; an increase in Ca(2+) fluorescence intensity ratio of 2.36 ± 0.31 evoked by capsaicin was reduced to 1.25 ± 0.04. DSM releasable products (conditioned medium) mimicked DSM inhibition of capsaicin-evoked excitability. The TRPV1 antagonist 6-iodonordihydrocapsaicin or the use of TRPV1 knock-out mice revealed that TRPV1 channels mediate about 80% of the inhibitory effect of DSM on mesenteric nerve response to high intensity gut distension. Finally, feeding with DSM inhibited perception in rats of painful gastric distension. Our results identify a specific target channel for a probiotic with potential therapeutic properties.
    The Journal of Physiology 06/2015; 593(17). DOI:10.1113/JP270229 · 5.04 Impact Factor
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    • "In this study antibiotic treatment from weaning induced significant diminution of microbial populations and taxonomic diversity in the adult mouse gut, which is consistent with previous reports using similar antibiotic regimens in adult mice (Cho et al., 2012; Reikvam et al., 2011; Verdu et al., 2006; Bercik et al., 2011; Zhang et al., 2014). Analysis of remaining gut bacteria in antibiotic-treated mice revealed a significant restructuring of the microbial community characterised by a decrease in the richness of bacterial species. "
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    ABSTRACT: There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential brain-gut axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 04/2015; 48. DOI:10.1016/j.bbi.2015.04.004 · 5.89 Impact Factor
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    • "A previous study revealed that visceral hypersensitivity involved the activation of spinal NMDA and non-NMDA receptors, meanwhile methylglyoxal could precisely induce the activation via a process which is discussed in the following passage. Another survey indicated that antibiotics could perturb intestinal microbiota, change the content of colon sensory neurotransmitter, and thus produce increased visceral sensitivity [31]. Investigation has shown that probiotics therapy prevents antibiotic-induced visceral hyperalgesia in mice [32]. "
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    ABSTRACT: Patients with irritable bowel syndrome (IBS) show a wide range of symptoms including diarrhea, abdominal pain, changes in bowel habits, nausea, vomiting, headache, anxiety, depression and cognitive impairment. Methylglyoxal has been proved to be a potential toxic metabolite produced by intestinal bacteria. The present study was aimed at investigating the correlation between methylglyoxal and irritable bowel syndrome. Rats were treated with an enema infusion of methylglyoxal. Fecal water content, visceral sensitivity, behavioral tests and serum 5-hydroxytryptamine (5-HT) were assessed after methylglyoxal exposure. Our data showed that fecal water content was significantly higher than controls after methylglyoxal exposure except that of 30 mM group. Threshold volumes on balloon distension decreased in the treatment groups. All exposed rats showed obvious head scratching and grooming behavior and a decrease in sucrose preference. The serum 5-HT values were increased in 30, 60, 90 mM groups and decreased in 150 mM group. Our findings suggested that methylglyoxal could induce diarrhea, visceral hypersensitivity, headache as well as depression-like behaviors in rats, and might be the key role in triggering systemic symptoms of IBS.
    PLoS ONE 08/2014; 9(8):e105307. DOI:10.1371/journal.pone.0105307 · 3.23 Impact Factor
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