The adult human distal gut microbial community is typically dominated by 2 bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here, we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from Eubacterium rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the Firmicutes possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling, high-resolution proteomic analysis, and biochemical assays of microbial-microbial and microbial-host interactions. B. thetaiotaomicron adapts to E. rectale by up-regulating expression of a variety of polysaccharide utilization loci encoding numerous glycoside hydrolases, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is used by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of its major bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.human gut Firmicutes and Bacteroidetes ͉ carbohydrate metabolism ͉ gnotobiotic mice ͉ gut microbiome ͉ nutrient sharing
Painful bladder syndrome is a debilitating condition that affects 3–6% of women in the United States. Multiple lines of evidence suggest that changes in central nervous system processing are key to the development of chronic bladder pain conditions, but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distension-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distension. Additionally, pharmacological blockade or virally-mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA localized effects on responses to bladder distention are associated with changes in extracellular signal regulated kinases 1/2 phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization.
Activation of extracellular signal-regulated kinases (ERK) 1/2 in dorsal horn neurons is important for the development of somatic hypersensitivity and spinal central sensitization after peripheral inflammation. However, data regarding the roles of spinal ERK1/2 in the development of visceral hyperalgesia are sparse. Here we studied the activation of ERK1/2 in the lumbosacral spinal cord following innocuous and noxious distention of the inflamed (cyclophosphamide- treated) and non-inflamed urinary bladder in mice. We also correlated the spinal ERK1/2 activation to distention-evoked bladder nociception as quantified by the abdominal visceromotor response (VMR). Cyclophosphamide treatment (bladder inflammation) evoked increased bladder hyperalgesia and allodynia to bladder distention, as evident from an upward and leftward shift of the VMR stimulus-response curve compared to that of non-inflamed mice. Development of bladder hyperalgesia was associated with robust enhancement of ERK1/2 activation in the dorsal horn and deeper laminae bilaterally in the L6-S1 spinal cord. Functional blockade of spinal ERK1/2 activity via intrathecal administration of the upstream MEK inhibitor U0126 attenuated distention-evoked bladder nociception, and caused a significant downward shift of the VMR stimulus-response curve. In summary, we have provided functional and immunohistochemical evidence that activation of lumbosacral spinal ERK1/2 is associated with the development of primary visceral (bladder) hyperalgesia. Our results suggest that aberrant processing of visceral nociceptive information at the level of the lumbosacral spinal cord via activation of ERK1/2 signaling may contribute to chronic bladder pain in the context of inflammation.
Purpose Bladder pain is a debilitating symptom of many urologic conditions, and there is no generally effective treatment. Abnormal urothelial turnover is common to multiple disease states, but the specific components of urothelial injury and the resulting molecular signals that lead to bladder pain are unknown. We examined mouse models of bladder injury induced by uropathogenic E. coli (UPEC), protamine sulfate (PS), and bacterial lipopolysaccharide (LPS) to identify cellular and molecular correlates underlying pain sensitization in response to the stimuli. Materials and Methods C57BL/6 female mice were given intravesicular PS, LPS or UPEC, and the impact of each on nociception was determined by measuring the evoked visceromotor response to bladder distention at 24 hours post inoculation. Levels of pyuria and tissue inflammation were examined by urinary cytology and tissue histology. Quantitative PCR and gene expression analysis were used to identify injury profiles associated with nociception. Results PS treatment was significantly analgesic upon bladder distention. PS-treated bladders did not exhibit pyuria or extensive tissue damage. PS injury was associated with a global decrease in expression of inflammation-associated genes. In contrast, UPEC injury significantly increased the nociceptive response to bladder distention. LPS treatment did not affect nociception. Finally, injury-induced expression of inflammation-associated genes correlated with nociceptive responses. Conclusion PS treatment of the bladder is analgesic, tissue protective, and suppresses inflammatory cytokine expression normally associated with nociception. Additionally, the injury modalities that result in differential tissue response patterns provide an innovative method for identification of mediators of visceral pain.
Background: Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention. Results: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice. Conclusions: Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.
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