Microbes for Mental Health

September 11, 2015

SAN DIEGO—The human gut microbiome may be the solution to prevention and treatment of many of the most common modern degenerative diseases, including depression, anxiety, Parkinson’s disease, Alzheimer’s disease, HIV, dementia, autism spectrum disorders (ASD), obesity, diabetes, and heart disease, according to a presentation by David J. Scheiderer, MD, MBA, DFAPA, of Integrative Psychiatry, Inc, in Sarasota, Florida. 
All of these diseases, he said, are associated with decreased gut microbial diversity, increased intestinal permeability, dysbiosis, and chronic-low grade inflammation, or “metaflammation.”

Chronic degenerative conditions, including most mental disorders, are on the rise and have overtaken infections as a major cause of death and illness. This is likely due in part to environmental changes, but is also associated with low-grade, chronic, systemic inflammation. Multiple, converging lines of evidence have shown the primary cause of this inflammation may be dysfunction of the ‘gut-brain axis.’ This system-wide inflammation disturbs psycho-neuroimmunological parameters such as neurotransmitters, hormones, growth factors, and immune reactivity. 

Dr. Scheiderer explained that individuals may be predisposed to such stress-induced inflammation by negative in utero and early life experiences that alter initial gut colonization. Because the gut ecology is modified, stressors become magnified, stress response is amplified, and corrective homeostatic mechanisms are inhibited and result in chronic sustained inflammation. 

Dysbiosis 

Dysbiosis is the alteration of a microbiome caused by a change in the composition of the microbiota, a change in microbial metabolic activity, and/or a shift in local distribution of the communities of microbes. Dysbiosis provides a plausible clue as to the origin of systemic metabolic disorders encountered in clinical practice that may explain the epidemic of chronic diseases. 

Lipopolysaccharides (LPS) 

LPS are structural fragments of the external membrane of gram-negative bacteria. In healthy adults, only miniscule amounts of LPS are found in the blood, indicating intact intestinal barrier function. However, even at low levels, he continued, LPS administration causes acute anxiety, depressed mood, cognitive blunting, and increased visceral pain sensitivity. Higher circulating LPS levels are associated with abdominal obesity, metabolic syndrome parameters (elevated insulin, triglycerides, and total cholesterol), and diabetes. Circulating LPS causes and perpetuates increased permeability of the intestinal and blood-brain barriers. 

Microbiome Disturbances and Autism Spectrum Disorder 

Subsets of children with autism spectrum disorder display gastrointestinal abnormalities, including increased intestinal permeability, or “leaky gut,” Dr. Scheiderer said. It is believed that autism may be, in part, a disease involving the gut that impacts immune, metabolic, and nervous systems, and that microbiome-mediated therapies may be a safe and effective treatment for autism spectrum disorder. 

Considerable evidence has linked various diets to gut microbiota changes and subsequent health effects. For example, diets containing noncaloric artificial sweeteners have been linked to dysbiosis and glucose intolerance. In patients with autism spectrum disorder, diets free of gluten and casein may treat some of the core and behavioral symptoms these patients display by having a favorable influence on gut microbiota populations and intestinal barrier function. 

Administering probiotic bacteria to address the changes in microbiota may have the ability to reduce inflammation, restore epithelial barrier function, and possibly ameliorate the behavioral symptoms associated in children with ASD. Clinical studies linking the therapeutic impact of probiotics on neuropsychological disorders are limited and in the early stages. However, results thus far support those from preclinical studies and suggest the modulation of microbiota may indeed be targeted for their therapeutic potential in neuropsychological disorders. 

Non-Celiac Gluten Sensitivity 

Non-celiac gluten sensitivity (NCGS) has been linked to many extraintestinal systemic symptoms, including ‘brain fog,’ headaches, fatigue, depression, anxiety, pain, and eczema/rash. Additionally, NCGS increases vulnerability for dementia. Dr. Scheiderer indicated that evidence has shown that as many as 57% of individuals with neurological dysfunction of unknown origin test positive for anti-gliadin antibodies. 

One study showed that the prevalence of anti-gliadin antibodies was significantly higher in people with schizophrenia compared to the general population; another study showed patients with recent onset schizophrenia had increased levels of IgA and IgG antibodies to gliadin compared with a control population. 

There is also mounting evidence that Parkinson’s disease is not only a brain disease but also a digestive disorder, as expression of the tight junction (TJ) protein occludin is decreased in those with Parkinson’s. This suggests that morphological changes in the intestinal epithelial barrier occur in these patients. 

HIV and Gut Microbiota 

The human immunodeficiency virus (HIV) is capable of drastically altering the immune system and the gastrointestinal environment, leading to significant changes to the gut microbiota and mucosal permeability that results in microbial translocation from the gut extending to the blood and even brain. This microbial translocation and subsequent downstream effects create a self-sustaining feedback loop that enhances HIV disease progression and constitutes a vicious cycle of inflammation and immune activation combining viral and bacterial factors. He went on to say that an understanding of this self-perpetuating cycle could be a key element in developing new therapies that are aimed at the gut microbiota and its fallout after infection. 

Weight Gain Induced by Antipsychotics and Gut Microbiota 

Certain agents, such as olanzapine and risperidone, induce alterations in the gut microbiota of rats when administered chronically, with other metabolic abnormalities occurring at the same time: weight gain, increased visceral fat, and a proinflammatory phenotype. As such, the gut microbiota represent both a biomarker and a potential therapeutic target for obesity, metabolic disease, and drug-induced weight gain. 

Pro- and Anti-Inflammatory Inducers of Metaflammation and the Inflammatory Microbiome 

Some of the pro-inflammatory inducers of metaflammation include aging, inactivity, obesity, smoking, sleep deprivation, stress/anxiety/depression, air pollution, and a high omega-6 to omega-3 intake ratio. Anti-inflammatory inducers include exercise, restricted energy intake, fish/fish oils, and weight loss. Dietary antioxidant sources such as coffee, cocoa, green tea, blueberries, and curcumin have all been linked to a lowered risk of depression and/or cognitive decline. These agents have also been shown to have beneficial effects on gut microbiota, including promoting the growth of Lactobacilli and Bifidobacteria. Curcumin prevents LPS-induced intestinal permeability and green tea reduces LPS-induced sickness behavior and blood-brain barrier permeability. 

Treatment: Prebiotics, Probiotics, Fecal Microbiota Transplant 

Data suggest pretreatment with a probiotic formulation consisting of Lactobacillus helveticus and Bifidobacterium longum restore TJ barrier integrity; reduce apoptosis in the limbic system; prevent stress-induced reductions in hippocampal neurogenesis; and attenuate HPA axis and ANS activity, suggesting that chronic stress-induced abnormal brain plasticity and reduction in neurogenesis can be prevented by pretreatment with a probiotic formulation. Specifically, a L. helveticus/B. longum combination may interfere with the development of post-myocardial infarction (MI) depressive behavior and restore intestinal barrier integrity, as has been seen in rat studies. 

In humans, this probiotic formulation when taken for 30 days showed improvement in somatization, depression, and anger-hostility as well as beneficial effects on anxiety- and depression-related behaviors. Possible mechanisms of probiotics include decreased levels of pro-inflammatory cytokines, production of neutrotransmitters that act directly on central nervous system targets, regulation of glycemic control, and reduction of substance P. Through their immunoregulatory effects, probiotics have also shown benefit in treatment of nonalcoholic fatty liver disease (NAFLD), which is associated with alterations in the gut microbiota, small intestinal bacterial overgrowth, insulin resistance, hepatic steatosis, necroinflammation, and fibrosis. 

Fecal microbiota transplant (FMT) is another treatment option that is gaining ground, with 613 reports of its use in the literature by 2014, up from 8 reports before the year 2000. Four types of FMT exist: single donor, multiple donor, autologous feces transplantation, and anaerobically cultivated feces from a healthy donor. FMT is primarily used to treat antibiotic-associated diarrhea, post-infectious irritable bowel syndrome, metabolic syndrome, heart disease, autoimmune and allergic diseases, neurodegenerative disorders, and chronic fatigue syndrome. 

In conclusion, Dr. Scheiderer said that “metaflammation,” associated with the interplay of genetics, early life adversity, modern man-made environments and lifestyles, suggests an underlying basis for chronic disease that could provide a 21st century equivalent of the germ theory, and that manipulation of the human gut microbiome, using a variety of approaches that include lifestyle, prebiotics, probiotics, and FMT, represents a potent opportunity for the prevention and treatment of disease and the promotion of health.

—M. Mihalovic