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.

Background Mast cells (MCs) are hemopoietic cells that mature in tissues and are involved in allergy, immunity and inflammation by secreting multiple mediators. The natural flavone luteolin (lut) has anti-inflammatory actions and inhibits human MCs. Objective To investigate the ability of lut, and its novel structural analog 3’,4’,5,7-tetramethoxyluteolin (methlut), to inhibit human MCs mediator expression and release in vitro and in vivo. Methods Human LAD2 cells and primary human umbilical cord-blood derived cultured MC (hCBMCs) were stimulated by substance P (SP) or IgE/anti-IgE with or without pre-incubation with lut, methlut or cromolyn (1–100 μM) for 2 or 24 hr following which a mediator secretion was measured. The effect of the compound on MC intracellular calcium levels and NF-κB activation was also investigated. Pretreatment with methlut was also studied in mice passively sensitized with dinotrophenol-human serum albumin (DNP-HSA) and challenged intradermally. Results Methlut is a more potent inhibitor than lut or cromolyn for beta-hexosaminidase (β-hex) and histamine secretion from LAD2 cells stimulated by either SP or IgE/anti-IgE, but only methlut and lut significantly inhibit preformed tumor necrosis factor (TNF) secretion. Methlut is also a more potent inhibitor than lut of de novo synthesized TNF from LAD2, and of chemokine (C-C motif) ligand 2 (CCL2) from hCBMCs. The mechanism of action from methlut may be due to its ability to inhibit intracellular calcium increase, as well as NF-κB induction at both the transcriptional and translational levels in LAD2 cells stimulated by SP without affecting cell viability. Treatment (ip) with methlut significantly decreases skin vascular permeability of Evans blue in mice passively sensitized to DNP-HAS and challenged intradermaly. Conclusion Methlut is a promising MC inhibitor for the treatment of allergic and inflammatory conditions.

Diabetic foot ulceration is a severe complication of diabetes that lacks effective treatment. Mast cells (MCs) contribute to wound healing, but their role in diabetes skin complications is poorly understood. Here we show that the number of degranulated MCs is increased in unwounded forearm and foot skin of patients with diabetes and in unwounded dorsal skin of diabetic mice (P < 0.05). Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in diabetic mice. Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues diabetes-associated wound-healing impairment in mice and shifts macrophages to the regenerative M2 phenotype (P < 0.05). Nevertheless, nondiabetic and diabetic mice deficient in MCs have delayed wound healing compared with their wild-type (WT) controls, implying that some MC mediator is needed for proper healing. MCs are a major source of vascular endothelial growth factor (VEGF) in mouse skin, but the level of VEGF is reduced in diabetic mouse skin, and its release from human MCs is reduced in hyperglycemic conditions. Topical treatment with the MC trigger substance P does not affect wound healing in MC-deficient mice, but improves it in WT mice. In conclusion, the presence of nondegranulated MCs in unwounded skin is required for proper wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes.

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Interleukin-33 (IL-33) belongs to the IL-1 family of cytokines.

Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting primarily women. It is clinically characterized by chronic, nonarticular pain and a heightened response to pressure along with sleep disturbances, fatigue, bowel and bladder abnormalities, and cognitive dysfunction. The diagnostic criteria have changed repeatedly, and there is neither a definitive pathogenesis nor reliable diagnostic or prognostic biomarkers. Clinical and laboratory studies have provided evidence of altered central pain pathways. Recent evidence suggests the involvement of neuroinflammation with stress peptides triggering the release of neurosenzitizing mediators. The management of FMS requires a multidimensional approach including patient education, behavioral therapy, exercise, and pain management. Here we review recent data on the pathogenesis and propose new directions for research and treatment.

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There has been an impressive, little understood increase in cases of Autism Spectrum Disorders (ASD). The lack of any distinctive pathogenetic mechanism has hampered the development of any effective treatments. Increasing evidence indicates oxidative stress, brain inflammation, gastrointestinal (GI) dysfunction and allergic symptoms may be present in ASD patients. The flavone luteolin has antioxidant, anti-flammatory, anti-allergy and neuroprotective properties. Given these findings, a dietary supplement was developed with a unique mixture of luteolin with the related flavonoids quercetin and rutin in a liposomal formulation of olive kernel oil (OKO), which increases their absorption. Results are presented for children with ASD (n=37, 4-14 years old) who had not obtained any benefit from multiple other regimens and who used this formulation for at least 4 months. GI and allergy symptoms improved in about 75% of children, eye contact and attention in 50%, social interaction in 25% and resumption of speech in about 10%. There were no adverse effects. Even though these results represent an uncontrolled open case series, they are encouraging because they suggest good tolerability and potential effectiveness.