Purpose-Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. Here we reviewed the bidirectional relationship between the gut microbiota and the brain, termed microbiota-gut-brain (MGB) axis, and we discuss how it contributes to the pathogenesis of certain disorders, that may involve brain inflammation.Methods-Articles were chosen from Medline since 1980 using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, stress.Findings-Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, essential metabolites, all convey information about the intestinal state to the CNS. Conversely, the HPA axis, the CNS regulatory areas of satiety and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient No. 6,624,148; 6,689,748; 6,984,667, and EPO 1365777, which cover methods and compositions of mast cell blockers, including flavonoids, as well as US patents No 7,906,153 and 8,268,365 for treatment of brain inflammation. Conflicts of interestsThe authors declare no conflicts. availability. Such interactions appear to influence the pathogenesis of a number of disorders in which inflammation is implicated such as mood disorder, autism-spectrum disorders (ASDs), attention-deficit hypersensitivity disorder (ADHD), multiple sclerosis (MS) and obesity. HHS Public AccessImplications-Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation and flavonoids are discussed.

Brain “fog” is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain “fog” characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as “minimal cognitive impairment,” an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain “fog” may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain “fog” in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain “fog.”

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain affecting more women than men. Even though clinical studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or reliable objective markers has hampered development of effective treatments. Here we report that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) were significantly (P 5 0.026, P , 0.0001, and P 5 0.002, respectively) elevated (0.82 6 0.57 ng/ml, 0.39 6 0.18 ng/ml, and 7.98 6 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 6 0.26 ng/ml, 0.12 6 0.1 ng/ml, and 5.71 6 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r 5 0.45, P 5 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P 5 0.029 and P 5 0.006, respectively) higher (2.97 6 2.35 pg/ml and 0.92 6 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 6 0.62 pg/ml and 0.69 6 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P 5 0.0001 and P 5 0.044, respectively) in the FMS patients (849.5 6 1005 pg/ml and 923.2 6 1284 pg/ml, respectively) in comparison with healthy controls (1281 6 806.4 pg/ml and 3149 6 4073 pg/ml, respectively). FMS serum levels of neurotensin were not different from controls. We had previously shown that CRH and SP stimulate IL-6 and TNF release from mast cells (MCs). Our current results indicate that neuropeptides could stimulate MCs to secrete inflammatory cytokines that contribute importantly to the symptoms of FMS. Treatment directed at preventing the secretion or antagonizing these elevated neuroimmune markers, both centrally and peripherally, may prove to be useful in the management of FMS.