Entries in Neurodegenerative Diseases (2)

Saturday
Apr112015

Gut Bacteria And Parkinson's Disease

Based on: Gut Bacteria May Influence Parkinson's Risk, Phenotype. Medscape. Apr 06, 2015.

 

Researchers in Finland have discovered what could be an important clue to what drives Parkinson's disease (PD). Their new study has shown a reduced abundance of the Prevotellaceae bacteria family in the gut microbiome of PD patients compared with healthy control persons.

 

The boxer Muhammad Ali and the actor Michael J. Fox suffer from Parkinson's disease

Although the new findings only "scrape the surface," they "give us good reason to dig deeper," said lead author Filip Scheperjans, MD, PhD, Department of Neurology, Helsinki University Central Hospital, and Department of Neurological Sciences, University of Helsinki, Finland.

If further research verifies that PD is caused by dysbiosis and a diminished number of Prevotellaceae in the gut, boosting levels of these bacteria by probiotics or gut microbiome transplantation might slow the progression of the disease, or even prevent it.

 

"Intriguing" Theory

 "It's an intriguing theory," said Dr Scheperjans. "I think it's something we will be looking at, because the ultimate goal of why we're doing the study is that we want to find something that we can correct."

However, perhaps a more pressing goal is to confirm that these changes in gut microbiome occur before patients develop PD. It has already been shown that PD patients tend to have gastrointestinal dysfunction, particularly constipation, and that these symptoms may precede motor symptoms by several years. "So from a clinical point of view, we know that the gut is basically affected very early in PD," said Dr Scheperjans.

The human body contains some 10 times more microbial cells than human cells, and these microbes carry about 100 to 200 times more protein- coding genes than the human genome. Almost all of these genes are of bacterial origin.

Intestinal microbiota influence epigenetics (unlike genetics based on changes to the DNA sequence, i.e. the genotype, the changes in gene expression or cellular phenotype of epigenetics have other, not inheritable causes in our immediate environment), the immune system, and the absorption of nutrients, vitamins, medications, and toxic compounds.

There is mounting evidence of an intense bidirectional interaction between gut microbiota and the nervous system, influencing brain activity, behavior, and levels of neurotransmitter receptors and neurotrophic factors.

 

The new study included 72 PD patients (mean age, 65.3 years; 48.6% women), and 72 age- and sex-matched control individuals who were without signs of parkinsonism or potential premotor symptoms (mean age, 64.5 years; 50.0% women). The median time from motor symptom onset in PD patients was 5 years. All but two patients were receiving an antiparkinsonian medication. The study excluded individuals living in the same household and so presumably having a similar diet.

From fecal samples collected from each study participant, researchers pyro-sequenced the V1-V3 regions of the bacterial 16S ribosomal RNA gene. They used random subsamples of 4500 sequences for analysis.

They found that the mean abundance of Prevotellaceae in the feces of PD patients was reduced by 77.6% compared with control individuals. This bacteria "is a normal inhabitant of the human gut," with people having varying amounts of it, said Dr Scheperjans.

It's important to note that PD patients had less of Prevotellaceae, which may indicate dysbiosis, and additional changes in their gut microbiome. The decreased abundance of Prevotellaceae was not explained by more severe constipation in PD patients, although the abundance of other bacteria, but not Prevotellaceae, was associated with degree of constipation, or by differences in comorbidities.

Less abundance of the bacteria also was not affected by medications. Dr Scheperjans noted that the COMT (catechol-O-methyl transferase) inhibitor was the only PD drug that was associated with changes in the gut microbiome. "That was interesting, because that drug causes GI side effects like diarrhea," he said. "But we accounted for that in our analysis, so the basic finding of the difference between PD patients and controls is not explained by the medications that patients are using."

The study showed that another type of intestinal bacteria ― Enterobacteriaceae ― was linked to the severity of postural instability and gait difficulty (PIGD). These bacteria were significantly more abundant in patients with a PIGD phenotype than in patients with tremor dominant (TD) phenotype.

There is a wide variation in clinical manifestations in PD patients ― with some having mostly tremor, and others, rigidity ― and the question is whether these phenotypes represent the same disease. It is possible, said Dr Scheperjans, that different PD subtypes are linked to different bacteria in the gut.

Role of Diet?

The role of diet is also not clear. Evidence in the literature does not suggest major differences between  the diet of PD patients and that of other people, and studies of the impact on PD of particular nutrients or foods have shown small effect sizes and contradictory results, said Dr Scheperjans.

The idea that gut bacteria is involved in PD is intriguing, according to the authors. Alpha-synuclein, which is the hallmark protein for PD, has been found not only in the brain as the main component of Lewy bodies but also in the gut.

There is evidence, said Dr Scheperjans. that the alpha-synuclein "protein pathology" progresses "in a prionlike fashion," migrating from the enteric nervous system to the central nervous system. "There is a hypothesis that these pathological proteins can jump from one neuron to the next," and that the vagal nerve is involved in the spread of the pathology, he said.

In the last 2 to 3 years, scientists have learned a lot about the presence and amount of these intestinal bacteria, "but we don't know a lot about what they're actually doing; that's the next step," said Dr Scheperjans.

Remarkable Finding

In an accompanying editorial, a group of authors, including Alberto Espay, MD, University of Cincinnati, in Ohio, point out that the demonstration that selected bacterial populations could influence disease and phenotype "is a remarkable finding" and could have important implications.

"For starters, Scheperjans and colleagues have given us the opportunity to envision a future in which specific motor features of PD could be modified by controlling the relative populations of certain species of microbiota."

In addition to helping to shape novel treatment paradigms, gut microbiota also have the potential to inform the understanding of the etiopathogenesis of PD, they write.

It is "tempting" to speculate that gut microbiota might be in the pathogenic pathway that determines disease phenotypes and is "poised to become a target" for disease-modifying pharmacology, they note. "Gut microbiota may even have a role explaining the differences in PD prevalence between rural and urban environments, between countries and perhaps even between sexes."

The new information adds to the evidence suggesting "that this may be the beginning of a leap forward in our understanding of and treatment options for PD," the editorialists conclude.

Microscopic identification of the microbiota in healthy (left) and inflamed intestine (right) using specific gene probes.

 

We offer gut microbiome exchange (transplantation) as new treatment for neurologic and psychiatric disorders

We have successfully treated neurologic and psychiatric disorders by gut microbiome transplantation from young healthy human donors. Such transplants appear to prevent disease progression, benefit overall physical health, gut health and the health of the brain.

 

New hope for patients with Parkinson's disease

Tuesday
Apr072015

The Gut Microbiome and Brain Health: What's the Connection?

Based on Sarah R. Dash. The Microbiome and Brain Health: What's the Connection? Medscape. Mar 24, 2015.

 

Introduction

Researchers are now beginning to understand the ways in which bacteria living in the human gut—the gut microbiota or microbiome—communicate with and influence brain health. The concept of a faulty "gut/brain axis" has been associated with various neurologic and psychiatric outcomes and is thought to be explained, at least in part, by immune dysfunction and inflammation triggered by poor gut health.

The gut microbiota has emerged as an important focus in the understanding of noncommunicable diseases, including type 2 diabetes and cardiovascular disease, as well as disorders of the brain. Brain-related conditions place a great burden on society, and the limitations of current interventions reflects the need for ongoing investigations into understanding and treating brain disorders, in part by exploring the close relationship between our biome and our brain.

Biome and Brain Overview

The human intestinal microbiome is seeded at birth; it is influenced initially by delivery and feeding mode, and reaches an adult-like state within the first few years of life. Alterations in the composition, diversity, and stability of gut microbiota have been linked to a broad range of diseases, including cancer, autoimmune, metabolic, gastrointestinal, and brain disorders.

Although the composition of the gut microbiota remains relatively stable during our middle years, it continues to be influenced by such factors as geography, antibiotics, exercise, and diet. This is particularly important when considering possible prevention and intervention in brain disorders.

It is well known that bidirectional gut/brain communication may occur directly and indirectly via the central and enteric nervous systems, the vagus nerve, and the endocrine and immunoinflammatory systems and through the modulation of neurotransmitters. Diet could also utilize these pathways, because the gut microbiota supports optimal nutritional bioavailability—for example, by maintaining normal plasma tryptophan levels, an important building block for making serotonin, a key central nervous system neurotransmitter. Advances in this field have come from the development of DNA sequencing technology, which allows researchers to conduct large-scale screening of the bacteria in the gut and their associated physiologic functions. This has helped researchers to link disruption of the gut microbiota with biological markers of the communication pathways mentioned above.

It is important to note that there is so far no "gold standard" healthy intestinal microbial profile. Genetic and environmental factors mean that there may be significant variability in gut composition from person to person. In general, a "healthy," diverse gut microbiota promotes gut health and maintains essential structural, metabolic and signaling functions. The human gut can be "unhealthy" for a variety of reasons. Typically, a shift away from normal gut microbiota diversity and stability—termed "dysbiosis"—means it is unable to sustain one or more of the functions of a healthy gut, and this may contribute to cancer, metabolic, autoimmune, and brain disorders.

Increased intestinal permeability, often called "leaky gut," occurs when the mucosal gut barrier fails to prevent potentially harmful molecules from entering the bloodstream; these molecules include lipopolysaccharides, which are found on the outer membrane of gram-negative bacteria and may elicit inflammatory responses in the body. Increased intestinal permeability is a common feature of an unhealthy gut.

Keeping in mind that each gut microbiome looks different, the terms "healthy" and "unhealthy" used here refer to instances in which gut microbiota functioning, composition, or ratio may deviate from a person's individual-specific "normal" state.

The Biome and Brain Disorders

Microbial and neurologic development share similar windows of developmental vulnerability, during which they are particularly susceptible to damage. The mother provides an infant's first bacterial exposure; thus, maternal health is very important to a how a child's microbiome develops. Maternal illness and use of medications may disrupt an optimal microbiota transfer to the infant.

Early life continues to be developmentally critical; disruptions, such as stress or severe illness, can be damaging to gut/brain signaling and have been linked to brain disorders later in life. Several animal studies have shown that early life stress can alter the development of the key stress response system, the hypothalamic-pituitary-adrenal axis, establishing a lifelong alteration in how a mammal responds to stress. The impact on the two-way relationship between stress and the gut microbiota may be at the root of this problem. Maternal stress and infection during pregnancy have been linked to neurologic and central nervous system disorders, such as schizophrenia, autism spectrum disorders, and distinct cognitive and behavioral symptoms later in life, and these outcomes may be mediated by the bacteria living in the gut.

Microbiota and Neurologic Disease

Gut disturbances—both gastrointestinal discomfort and altered microbiota —have been linked to neurologic disorders, including multiple sclerosis (MS), autism spectrum disorders, and Parkinson disease. Environmental risk factors for neurologic disease often promote the immunoinflammatory response.

There is suggestion that the misfolding of proteins in the brain may be an etiologic explanation for some neurologic disorders. Brain inflammation, which may originate from the gut, is one notable hypothesis behind protein misfolding.

The proinflammatory state prompted by gut dysbiosis has also been linked to various autoimmune disorders, again including MS. MS is most common in Western countries, where dietary patterns thought to promote a proinflammatory profile and disrupt optimal gut microbiota states are common. Of note, lipopolysaccharides and antibodies against various antigens have been observed in patients with MS and Parkinson disease, with both markers signaling an increase in intestinal permeability.

Relatedly, neurodegenerative diseases, such as Alzheimer disease and generalized cognitive decline, are marked by age-related brain changes, along with disturbed immune function and increased oxidative stress; these factors have been shown in animals to be influenced by diet and the gut microbiota. Brain-derived neurotrophic factor, a neurotrophin that protects and encourages survival of healthy brain cells and whose production may be influenced by gut bacteria, is shown to be decreased in people with Alzheimer disease. It appears that age-related changes in the gut microbiota might be bidirectionally linked to age-related neurodegeneration.

It is notable that the unhealthy dietary patterns that negatively influence the gut microbiome are also risk factors for depression in older adults, whereas healthier diets protect against cognitive decline.

The Microbiota and Psychiatric Disorders

The notion of the gut/mental health connection has recently started to gain traction. It is now thought that various psychological disorders, depression in particular, may be inflammatory disorders, and that the gut may be an important mediator of these conditions. In numerous animal studies, microbial manipulation produced behaviors related to anxiety or depression, and one study demonstrated that the anxious phenotype could be transferred via the intestinal microbiota between animals.

The coping mechanisms for dealing with psychological stress appear to be programmed in early life, so this development may set us up to deal with stress throughout our lives—with some coping mechanisms working better than others. Given the amount of serotonin in the gut and the influence of the gut microbiota on serotonin's precursor, tryptophan, examining its role in mental health is worthwhile. Early correlational evidence has linked functional and structural damage in the gut with depression, schizophrenia, and autism.

Promoting a Healthy Biome: Strategies

In both neurologic and psychiatric conditions, it is possible that gut dysbiosis is responsible for both disease risk and the severity of a disorder.

It is clear that the causes and symptomology of some neurologic/neurodegenerative and psychiatric disorders have a similar underlying pathophysiology and that an unhealthy gut influences these through several overlapping pathways. Although it is difficult to tease out the individual contribution of each of these systems, given their complexity and the difficulty of isolating them clinically, the gut appears to be a key driver of a high-risk, inflammatory state in the body and brain and may prove to be the key in unlocking a new understanding of the etiology of brain diseases that supports new clinical and public health interventions.

Although gut microbial composition appears to be quite resilient, it is also readily modified. Lifestyle factors are particularly important to the composition, diversity, and stability of the gut microbiome. Below are several strategies that research suggests could contribute to overall gut health and that, in turn, may promote the health and protection of the brain.

Diet

There is good evidence for the role of individual nutrients, such as omega-3 fatty acids and zinc, in both physical and mental health; it is therefore useful to consume these nutrients as part of an overall healthful diet.

A healthful diet composed of fruits, vegetables, and whole grains has also been linked to higher levels of Bacteroidetes. These types of bacteria are particularly good at producing short-chain fatty acids, which help regulate gut inflammation.

Three main food components are proposed to benefit gut health: living microorganisms known as "probiotics" (found in such foods as yogurt, kefir, and kimchi); nondigestible carbohydrates (eg, dietary fiber found in fruits, vegetables, and whole grains); and secondary plant metabolites, such as flavonoids (found in brightly colored fruits, vegetables, and red wine). Persons who consume a Western-style diet experience less of the protective benefits of plant foods and simultaneously provoke other metabolic disruptions through high fat and sugar consumption, which contribute to gut dysbiosis and inflammation.

Exercise

Evidence suggests that exercise may increase the diversity of bacteria living in the gut. One study showed increased gut bacterial diversity and fewer markers of inflammation in athletes compared with controls. However, moderate exercise may be best; one study found that persons who exercised one to 30 times per month had higher levels of brain-protecting BDNF than nonexercisers or extreme exercisers. Exercise has been shown to have positive anti-inflammatory benefits, which may promote both gut and brain health.

Pre- and Probiotics and Fermented Foods

There is some support for the benefits of probiotic and prebiotic supplements and fermented foods within the gut, with some groups calling for the inclusion of probiotic or fermented foods in national food guide recommendations. The anti-inflammatory benefits of fiber fermentation in the colon occur naturally during digestion of healthy, fiber-rich foods, resulting in metabolic by-products that include various vitamins and antioxidants. Although some studies show promising results, larger, high-quality trials are needed to fully elucidate this relationship.

Future Directions

Understanding the role of the gut microbiota in neurologic and psychiatric disorders is an exciting prospect, with both conditions contributing significantly to individuals' quality of life and to global disease burden. Identifying measurable and modifiable microbial "therapies" presents a valuable opportunity for new prevention and treatment strategies for brain disorders.

The possibility of being able to prevent or alleviate neurologic or psychiatric conditions through lifestyle interventions has significant public health implications. However, a full understanding of the gut/brain connection and its health implications is still evolving, and quality clinical trials are needed that include assessments of immune, inflammatory, and gut biomarkers to elucidate the function, behavior, and modifiability of bacteria living in the gut.

We introduce gut microbiome transplantation as new treatment for neurologic and psychiatric disorders

It would be an oversimplification to imply that microbial modification is a cure-all solution. However, we have successfully treated depression, alcohol dependency, anxiety, obesity with craving for specific foods by gut microbiome transplantation from young healthy human donors. Such transplants appear to benefit overall physical health, gut health and the health of the brain.

 

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