Microbiota: a novel regulator of pain.

Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.

Painful interactions: Microbial compounds and visceral pain.

Visceral pain, characterized by abdominal discomfort, originates from organs in the abdominal cavity and is a characteristic symptom in patients suffering from irritable bowel syndrome, vulvodynia or interstitial cystitis. Most organs in which visceral pain originates are in contact with the external milieu and continuously exposed to microbes. In order to maintain homeostasis and prevent infections, the immune- and nervous system in these organs cooperate to sense and eliminate (harmful) microbes. Recognition of microbial components or products by receptors expressed on cells from the immune and nervous system can activate immune responses but may also cause pain. We review the microbial compounds and their receptors that could be involved in visceral pain development.

The role of toll-like receptor 4 and mast cell in the ameliorating effect of electroacupuncture on visceral hypersensitivity in rats.

BACKGROUND: Visceral hypersensitivity is one of the main pathogenesis of irritable bowel syndrome (IBS) and mast cell activation is closely related to visceral hypersensitivity. As a critical molecule of the innate immune system, toll-like receptor 4 (TLR4) may modulate the activation of mast cell. Alleviating effect of electroacupuncture (EA) on visceral hypersensitivity has been proved, whereas, whether the TLR4 and mast cell is involved in this process remains unclear. METHODS: Forty Sprague-Dawley rats were randomly divided into five groups: control group, model group, EA group, sham EA group, and mast cell stabilizer (MCS) group. Visceral sensitivity during colorectal distension was assessed by the measurement of visceral motor reflex (VMR). TLR4 mRNA and protein expression were assessed by real-time PCR and immunohistochemistry, respectively. Mast cell number and mast cell tryptase (MCT) expression were detected. The level of inflammatory cytokine in serum was detected with ELISA. KEY RESULTS: Visceral sensitivity was significantly higher in the model group than in the control group. EA and MCS significantly reduced VMR score at 0.8 mL and 1.2 mL distention pressures. Compared with model group, TLR4 mRNA expression, the protein expression of TLR4 and MCT, and the number of mast cells with degranulation in the colonic tissue, serum concentration of IL-1ß and IL-8 were all significantly decreased in EA and MCS group. CONCLUSIONS & INFERENCES: Electroacupuncture ameliorated visceral hypersensitivity in colon-sensitized model probably via decreasing the level of pro-inflammatory cytokines released by mast cell which were decreased when the TLR4 expression in the colonic tissue was downregulated by EA.

Psychoneuroimmunological approach to gastrointestinal related pain.

BACKGROUND AND PURPOSE (AIMS): Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. METHODS: A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. RESULTS: Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. CONCLUSIONS (BASED ON OUR FINDINGS): Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. IMPLICATIONS (OUR OPINION ON WHAT OUR FINDINGS MEAN): Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use.

Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans.

Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders.