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    The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Lee Kevin,Vuong Helen E,Nusbaum David J,Hsiao Elaine Y,Evans Christopher J,Taylor Anna M W Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut-brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence. 10.1038/s41386-018-0211-9
    Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Xu Dabo,Gao Jun,Gillilland Merritt,Wu Xiaoyin,Song Il,Kao John Y,Owyang Chung Gastroenterology BACKGROUND & AIMS:Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. METHODS:We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. RESULTS:Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. CONCLUSIONS:Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress. 10.1053/j.gastro.2013.10.026
    Gut microbiota is critical for the induction of chemotherapy-induced pain. Shen Shiqian,Lim Grewo,You Zerong,Ding Weihua,Huang Peigen,Ran Chongzhao,Doheny Jason,Caravan Peter,Tate Samuel,Hu Kun,Kim Hyangin,McCabe Michael,Huang Bo,Xie Zhongcong,Kwon Douglas,Chen Lucy,Mao Jianren Nature neuroscience Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages. 10.1038/nn.4606