Julia M. Stewart

Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation

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. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS Articles were identified with a search of Medline (starting in 1980) by 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, and 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, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS 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,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin

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 Alzheimers 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.”

Spectrum of mast cell activation disorders

Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term ‘spectrum’ and highlight the main symptoms, useful diagnostic tests and treatment approaches.

Fibromyalgia Syndrome in Need of Effective Treatments

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.

Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells.

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 = 0.026, P < 0.0001, and P = 0.002, respectively) elevated (0.82 ± 0.57 ng/ml, 0.39 ± 0.18 ng/ml, and 7.98 ± 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 ± 0.26 ng/ml, 0.12 ± 0.1 ng/ml, and 5.71 ± 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r = 0.45, P = 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P = 0.029 and P = 0.006, respectively) higher (2.97 ± 2.35 pg/ml and 0.92 ± 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 ± 0.62 pg/ml and 0.69 ± 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P = 0.0001 and P = 0.044, respectively) in the FMS patients (849.5 ± 1005 pg/ml and 923.2 ± 1284 pg/ml, respectively) in comparison with healthy controls (1281 ± 806.4 pg/ml and 3149 ± 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.

Tolerability and benefit of a tetramethoxyluteolin-containing skin lotion

As many as 40% of people have sensitive skin and at least half of them suffer from pruritus associated with allergies, atopic dermatitis (AD), chronic urticaria (CU), cutaneous mastocytosis (CM), and psoriasis. Unfortunately, the available topical formulations contain antihistamines that are often not as effective as those containing corticosteroids. Certain natural flavonoids have anti-inflammatory actions. We recently reported that the natural flavonoid tetramethoxyluteolin has potent antiallergic and anti-inflammatory actions in vitro and in vivo. This flavonoid was formulated in a skin lotion along with olive fruit extract and was first tested for tolerability in 25 patients with mastocytosis or mast cell activation syndrome and very sensitive skin who reported back through a questionnaire. The skin lotion was then used by eight patients, four with AD and four with psoriasis, who had not received any topical treatment for at least 2 months, twice daily for 2 weeks. The use of this tetramethoxyluteolin formulation resulted in significant improvement of the skin lesions and could be useful adjuvant treatment for allergic and inflammatory skin conditions.

Neuroendocrinology of the skin.

The skin is considered the mirror of the soul and is affected by neurohormonal triggers, especially stress. Hair follicles, keratinocytes, mast cells, melanocytes, and sebocytes all express sex and stress hormones implicating them in a local “hypothalamic-pituitary-adrenal axis.” In particular, the peptides corticotropin-releasing hormone (CRH) and neurotensin (NT) have synergistic action stimulating mast cells and are uniquely elevated in the serum of patients with skin diseases exacerbated by stress. Addressing the neurohormonal regulation of skin function could lead to new targets for effective treatment of inflammatory skin diseases.

Genitourinary mast cells and survival

Mast cells (MCs) are ubiquitous in the body, but they have historically been associated with allergies, and most recently with regulation of immunity and inflammation. However, it remains a puzzle why so many MCs are located in the diencephalon, which regulates emotions and in the genitourinary tract, including the bladder, prostate, penis, vagina and uterus that hardly ever get allergic reactions. A number of papers have reported that MCs have estrogen, gonadotropin and corticotropin-releasing hormone (CRH) receptors. Moreover, animal experiments have shown that diencephalic MCs increase in number during courting in doves. We had reported that allergic stimulation of nasal MCs leads to hypothalamic-pituitary adrenal (HPA) activation. Interestingly, anecdotal information indicates that female patients with mastocytosis or mast cell activation syndrome may have increased libido. Preliminary evidence also suggests that MCs may have olfactory receptors. MCs may, therefore, have been retained phylogenetically not only to “smell danger”, but to promote survival and procreation.

Antihistamines and Mental Status.

H istamine receptor antagonists (known as antihistamines) are one of the most commonly used family of drugs. Antihistamines are typically used for allergic diseases, including asthma, food allergy, rhinitis, and atopic dermatitis. The incidence of these diseases has been steadily increasing for the last 20 years, despite better awareness and protective measures (eg, air conditioners, filters, pollen count reports, etc).1–10 Moreover, the number of other conditions with an atopic component such as chronic fatigue syndrome, fibromyalgia syndrome, interstitial cystitis/bladder pain syndrome, and psoriasis has also been on the rise. As a result, the use of antihistamines has also increased and warrants a re-evaluation of their possible adverse effects.

Anti-Allergic Compounds in Chronic Pelvic Pain

One of the most common causes of chronic pelvic pain (CPP) is interstitial cystitis/bladder pain syndrome (IC/BPS), a disorder affecting primarily women characterized by months of pain or discomfort over the supra-pubic/bladder area, along with frequency of urination in the absence of a urinary tract infection (UTI). The prevalence of IC/BPS has increased significantly and patients often present with other comorbid allergic or inflammatory diseases. The lack of precise pathogenesis has not allowed the development of curative therapies, but a combination of anti-allergic compounds can lead to substantial symptom reduction and improved quality of life.