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    Role of Neurochemicals in the Interaction between the Microbiota and the Immune and the Nervous System of the Host Organism. Oleskin Alexander V,Shenderov Boris A,Rogovsky Vladimir S Probiotics and antimicrobial proteins This work is concerned with the role of evolutionary conserved substances, neurotransmitters, and neurohormones, within the complex framework of the microbial consortium-immune system-nervous system axis in the human or animal organism. Although the operation of each of these systems per se is relatively well understood, their combined effects on the host organism still await further research. Drawing on recent research on host-produced and microbial low-molecular-weight neurochemicals such as biogenic amines, amino acids, and short-chain fatty acids (SCFAs), we suggest that these mediators form a part of a universal neurochemical "language." It mediates the whole gamut of harmonious and disharmonious interactions between (a) the intestinal microbial consortium, (b) local and systemic immune cells, and (c) the central and peripheral nervous system. Importantly, the ongoing microbiota-host interactivity is bidirectional. We present evidence that a large number of microbially produced low-molecular-weight compounds are identical or homologous to mediators that are synthesized by immune or nervous cells and, therefore, can bind to the corresponding host receptors. In addition, microbial cells specifically respond to host-produced neuromediators/neurohormones because they have adapted to them during the course of many millions of years of microbiota-host coevolution. We emphasize that the terms "microbiota" and "microbial consortium" are to be used in the broadest sense, so as to include, apart from bacteria, also eukaryotic microorganisms. These are exemplified by the mycobiota whose role in the microbial consortium-immune system-nervous system axis researchers are only beginning to elucidate. In light of the above, it is imperative to reform the current strategies of using probiotic microorganisms and their metabolites for treating and preventing dysbiosis-related diseases. The review demonstrates, in the example of novel probiotics (psychobiotics), that many target-oriented probiotic preparations produce important side effects on a wide variety of processes in the host organism. In particular, we should take into account probiotics' capacity to produce mediators that can considerably modify the operation of the microecological, immune, and nervous system of the human organism. 10.1007/s12602-017-9262-1
    Role of Keap1-Nrf2 Signaling in Anhedonia Symptoms in a Rat Model of Chronic Neuropathic Pain: Improvement With Sulforaphane. Li Shan,Yang Chun,Fang Xi,Zhan Gaofeng,Huang Niannian,Gao Jie,Xu Hui,Hashimoto Kenji,Luo Ailin Frontiers in pharmacology Patients with chronic neuropathic pain frequently suffer from symptoms of anhedonia (loss of pleasure), which is a core clinical manifestation of depression. Accumulating studies have shown the beneficial effects of the natural compound sulforaphane (SFN), an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), on depression-like phenotype through a potent anti-inflammatory effect. However, it is unknown whether SFN confers beneficial effects in neuropathic pain-associated anhedonia. Spared nerve injury (SNI) is classical rodent model of chronic neuropathic pain. We here used a rat model of SNI. Hierarchical cluster analysis of sucrose preference test (SPT) results was used to classify the SNI rats with or without an anhedonia phenotype. Nrf2 protein expression was significantly decreased in the medial prefrontal cortex (mPFC), hippocampus, spinal cord, and skeletal muscle, but not in the nucleus accumbens, in anhedonia-susceptible rats compared with sham or anhedonia-resistant rats. The expression of Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1), a partner of Nrf2, in mPFC, hippocampus, and muscle of anhedonia-susceptible rats was also significantly lower than that in sham or anhedonia-resilient rats. Subsequent SFN administration after SNI surgery exerted therapeutic effects on reduced mechanical withdrawal threshold (MWT) scores, but not on sucrose preference, through the normalization of Keap1-Nrf2 signaling in the spinal cords of anhedonia-susceptible rats. Interestingly, treatment with SFN 30 min prior to SNI surgery significantly attenuated reduced MWT scores and sucrose preference, and restored tissue Keap1 and Nrf2 levels. In conclusion, this study suggests that decreased Keap1-Nrf2 signaling in mPFC, hippocampus, and muscle may contribute to anhedonia susceptibility post-SNI surgery, and that SFN exerts beneficial effects in SNI rats by normalization of decreased Keap1-Nrf2 signaling. 10.3389/fphar.2018.00887
    Key role of gut microbiota in anhedonia-like phenotype in rodents with neuropathic pain. Yang Chun,Fang Xi,Zhan Gaofeng,Huang Niannian,Li Shan,Bi Jiangjiang,Jiang Riyue,Yang Ling,Miao Liying,Zhu Bin,Luo Ailin,Hashimoto Kenji Translational psychiatry Patients with chronic neuropathic pain frequently suffer from symptoms of anhedonia, which is a core symptom of depression. Accumulating studies suggest that gut microbiota may play a role in depression via gut-microbiota-brain axis. However, it is unknown whether gut microbiota plays a role in neuropathic pain-associated anhedonia. Here, we used a rat model of spared nerve injury (SNI). Hierarchical cluster analysis of sucrose preference test (SPT) results was used to classify the SNI rats with or without anhedonia-like phenotype. The 16S ribosomal RNA sequencing analysis showed abnormal composition of gut microbiota in the anhedonia susceptible compared to sham-operated rats and resilient rats. Furthermore, antibiotics-treated mice showed pain as well as depression-like and anhedonia-like phenotypes, suggesting a role of gut microbiota in these abnormal behaviors. Transplantation of fecal microbiota from anhedonia susceptible rats into antibiotics-treated pseudo-germ-free mice significantly exaggerated pain and depression-like phenotypes, including anhedonia. In contrast, transplantation of fecal microbiota from resilient rats into antibiotics-treated pseudo-germ-free mice significantly improved pain and depression-like phenotypes, including anhedonia. In conclusion, this study suggests that abnormal composition of gut microbiota may contribute to anhedonia susceptibility post SNI surgery, and that gut microbiota also plays a role in the pain as well as depression-like phenotypes. Interestingly, fecal microbiota transplantation from SNI rats with or without anhedonia can alter pain, depression-like and anhedonia-like phenotypes in the pseudo-germ-free mice. Therefore, it is likely that gut microbiota plays a key role in the pain as well as depression-like phenotypes including anhedonia in rodents with neuropathic pain. 10.1038/s41398-019-0379-8
    Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Guo Ran,Chen Li-Hua,Xing Chungen,Liu Tong British journal of anaesthesia The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain. 10.1016/j.bja.2019.07.026
    Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy. Lin Binbin,Wang Yuting,Zhang Piao,Yuan Yanyan,Zhang Ying,Chen Gang The journal of headache and pain Neuropathic pain (NP) is a sustained and nonreversible condition characterized by long-term devastating physical and psychological damage. Therefore, it is urgent to identify an effective treatment for NP. Unfortunately, the precise pathogenesis of NP has not been elucidated. Currently, the microbiota-gut-brain axis has drawn increasing attention, and the emerging role of gut microbiota is investigated in numerous diseases including NP. Gut microbiota is considered as a pivotal regulator in immune, neural, endocrine, and metabolic signaling pathways, which participates in forming a complex network to affect the development of NP directly or indirectly. In this review, we conclude the current understanding of preclinical and clinical findings regarding the role of gut microbiota in NP and provide a novel therapeutic method for pain relief by medication and dietary interventions. 10.1186/s10194-020-01170-x