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The Gut Microflora-Brain Connection and Neurologic Disorders - A Review of the Evidence - Part II

01/01/2018 - MNR Report #277

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MORE ON THE RELATIONSHIP BETWEEN GUT MICROFLORA AND NEUROLOGICAL DISORDERS

Part I of this series ended with a discussion on the relationship between gut microflora and neurological disorders as outlined in the paper "Microbiota-gut-brain axis and the central nervous system" by Zhu et al (1).  Now in part II I would like to continue this discussion by highlighting a quote from the Zhu et al paper (1) on the neurodegenerative disease multiple sclerosis (MS).  As you will see, MS is associated with several gut microflora imbalances:

"Vartanian et al. found the colonization of Clostridium perfringens type B in patients with recurrent MS, and the ε-toxin produced by this pathogen could cause damage to the blood-brain barrier (BBB), thereby damaging neurons and oligodendrocytes.  Consequently, Clostridium perfringens type B is thought to be the initiating factor for susceptible individuals to experience the pathological change of autoimmune demyelination in the future.  In addition to the toxic effects, MS patients may have an imbalance of various bacteria of the Bacillus genus and species.  For example, Jhangi et al. found that MS patients have an increase in the genus Methanobrevibacter, whereas the Lachnospiraceae content was reduced.  Tremlet H et al. found that child MS patients had an increase in Desulfovibrio, whereas the Lachnospiraceae and rumen bacteria contents were decreased."

While I realize that many of the organisms mentioned in the above quote are not familiar to most of us, it should be clear from the above quote that many MS patients will demonstrate imbalances in gut microflora which, in ways discussed in part I of this series, can contribute to neurologic dysfunction and expression of symptoms consistent with MS.

Next, Zhu et al (1) focus on the relationship between gut microflora and Parkinson's disease (PD).  The first quote on this subject I would like to highlight emphasizes the fact that was the subject of my previous newsletter series on the relationship between chronic inflammation and neurologic disorders.  PD, like virtually all neurologic disorders, is an inflammatory illness that involves activation of the microglia in the CNS:

"The neuroinflammatory response in PD patients is associated with the upregulation of Toll-like receptor-2 (TLR2) and the activation of microglia."

The next quote discusses the relationship between CNS inflammation, destruction of the dopaminergic neurons that forms the traditional basis of PD, and dysbiotic gut microflora:

"Proinflammatory factors associated with chronic bowel diseases can induce intracranial inflammation, lead to the death of dopaminergic neurons, and eventually cause the development of PD.  Scheperjans F et al. found that PD patients had a decrease in Prevotella.  By comparing the stools of 34 PD patients and 34 normal controls, Unger MM et al. found that PD patients had a decrease in Bacteroidetes and Prevotella in their stool, which was accompanied by a reduction in SCFAs.  As symbiotic gut bacteria, Prevotella are involved in the mucus formation of the mucosal layer of the gut and the production of the neuroactive SCFAs through fiber fermentation.  The reduction in Prevotella causes a decrease in gut mucus and an increase in gut permeability, increasing local and systemic susceptibility to the influence of bacterial antigens and endotoxins..."

The authors continue with more information on the creation of increased gut permeability in PD patients:

"The inflammatory changes observed in PD patients and PD animal models are associated with increased gut permeability.  Lipopolysaccharides (LPS) is a gut-derived proinflammatory bacterial endotoxin that can cause changes in the substantia nigra and it can act as a PD-promoting substance."

With the above in mind, given that PD is traditionally defined by destruction of the substantia nigra and dopaminergic neurons, it appears readily obvious that, while it may not be the whole story, gut dysfunction and gut dysbiosis is going to be a major contributing causative factor for many PD patients.

What about the relationship between microbial dysbiosis and Alzheimer's disease (AD)?  Zhu et al (1) focus on this relationship by first pointing out the traditional definition of AD:

"AD is a degenerative disease of the CNS, its onset is recessive, and its disease course is chronically progressive.  The pathological markers of AD include intracellular β-amyloid (Aβ) senile plaques and intracellular neurofibrillary tangles."

The next quote discusses the role of inflammation and loss of blood-brain-barrier (BBB) integrity and the contribution of dysbiosis to this situation:

"The integrity of the BBB is important for brain function and development.  The inflammation caused by the changes in gut microorganisms will lead to changes in BBB integrity, which in turn affects brain function.  Under normal conditions, LPS cannot enter the bloodstream due to the tight junction between intestinal epithelial cells.  However, when the tight junction of cells is disrupted and the permeability is increased, LPS can enter the bloodstream and induce an inflammatory response.  Studies found that the plasma LPS concentration in AD patients is three times that of normal patients."

With the above in mind, Zhu et al (1) conclude the following about AD causation:

"The increased concentration of plasma LPS in AD patients implies an impairment of the gut barrier function and increased gut inflammation and permeability, which further suggests that gut microbiota may participate in the pathophysiological process of AD."

Is there more to the relationship between AD and gut dysbiosis than just leaky gut and upregulation of inflammatory mediators?  Zhu et al (1) suggest in the next quote that certain gut microorganisms might actually directly contribute to the formation of amyloid that is found in excess quantities in the AD brain:

"The Aβ production and clearance in the CNS is a dynamic change, and some bacteria and fungi can secrete amyloid, resulting in an increase of amyloid levels in the CNS that disrupts the dynamic balance of the Aβ protein, which leads to Aβ-protein aggregation in the brain and a high AD risk.  Therefore, an imbalance in gut microflora may promote the development of AD by affecting intestinal function and the synthesis and secretion of substances."

With all of the above in mind, Zhu et al (1) conclude their paper with the following statement:

"The interactive relationship between the brain and the gut includes neurology, metabolism, hormones, immunity, and other aspects, and changes in any component may lead to functional changes in the two interactive systems.  The normal ecological balance of gut microorganisms plays an important role in the maintenance of this relationship."

MORE ON DYSBIOSIS AND ALZHEIMER'S DISEASE

If you are like me, you are probably unaware that gut microflora can actually be involved in the production of amyloid in the AD patient.  Therefore, I would like to focus on this vital and largely unknown relationship in more detail.  To do so, I would now like to review the paper "Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer's disease" by Pistollato et al (2).  The authors begin their paper with a general review of the relationship between AD, insulin resistance, inflammation and disturbances in gut microflora:

"It has been suggested that type 2 diabetes, metabolic syndrome, and AD might be connected.  In particular, alterations of the gut microbiome can activate proinflammatory cytokines and increase intestinal permeability, leading to the development of insulin resistance, which has also been associated with AD.  Additionally, bacteria populating the gut microbiome are known to excrete immunogenic mixtures of amyloids, lipopolysaccharides (LPSs), and other microbial exudates into their surrounding environment."

Next Pistollato et al (2) discuss the production of amyloid by gut microflora:

"Bacterial amyloids might activate signaling pathways known to play a role in neurodegeneration and AD pathogenesis, while the gut microbiome might enhance inflammatory responses to cerebral accumulation of Aβ."

This quote emphasizes a crucially important point in terms of understanding the role of gut dysbiosis in neurologic dysfunction.  Since many papers that address the role of gut microflora in neurologic dysfunction tend to address the detrimental properties of gut microflora on an individual, isolated basis, it might be assumed that these detrimental properties impact the brain on an individual, isolated basis.  In fact, this is not true.  As stated above, these properties can occur concurrently, leading to a much more powerful impact. 

The next two quotes I would like to feature from the Pistollato et al (2) paper discuss specifically how amyloid produced by gut microflora could contribute to the development of AD.  First, consider the following:

"To explain how gut microbiota might contribute to the pathogenesis of AD, it has been hypothesized that bacteria-derived amyloids might leak from the gastrointestinal tract and accumulate at the systemic and brain level.  This might cause an increase in reactive oxygen species and the activation of nuclear factor-kB (NF-kB) signaling, which upregulates the proinflammatory microRNA-34a (miRNA-34a).  As a consequence, miRNA-34a would downregulate the expression of TREM2 (triggering receptor expressed in microglial/myeloid cell-2), leading to impairment of phagocytosis that contributes to accumulation of Aβ42 peptide."

What does this mean in simpler terms?  Amyloid produced by gut microflora leads to increased activity of the proinflammatory factor NF-kB.  This, in turn, leads to inhibition of cells that reduce levels of amyloid in the brain, resulting in increased brain accumulation of amyloid. 

The next quote points out that gut microflora-derived amyloid contributes to leaky gut, promoting the process described above:

"Additionally, bacterially derived LPSs and amyloids can further exacerbate the gut's leakiness and can increase the levels of cytokines and other small proinflammatory molecules, such as interleukin (IL) 17A and IL-22, which are directly associated with AD."

Still more information on the relationship between gut microflora-derived amyloid and AD was provided by the paper "The gut microbiota and Alzheimer's disease" by Jiang et al (3):

"Bacteria populating the gut microbiome are capable of excreting enormous quantities of lipopolysaccharides (LPSs) and amyloids, which may contribute to the pathogenesis of AD, especially during aging when both the GI tract epithelium and blood-brain barrier (BBB) become more permeable.  It has been proposed that LPS and amyloids may directly pass through a compromised GI tract or BBB and/or indirectly pass through these protective physiological barriers via LPS/amyloid-triggered cytokines or other small proinflammatory molecules that are normally transited."

The next quote I would like to highlight from this paper discusses the organisms involved in creating amyloid:

"In addition to LPS, a significant quantity of functional amyloid can be generated by many bacterial strains, including Escherichia coli, Bacillus subtilis, Salmonella typhimurium, Salmonella enterica, Mycobacterium tuberculosis, and Staphlococcus aureus, and may contribute to the pathology of AD through accumulation of proteinaceous misfolded Aβ oligomers and fibrils."

The next quote makes an interesting and extremely controversial suggestion that the misfolded amyloid created by the above mentioned organisms can act like prions, making AD a "prion-like disease":

"A number of recent studies suggest that clumping of proteins with prion-like behavior might be a phenomenon shared by several common neurodegenerative diseases, including Parkinson's disease and AD.  It has been hypothesized that functional amyloids produced by gut bacteria may be the source of misfolding of neuronal proteins such as alpha-synuclein, Aβ via cross-seeding, priming of the innate immune system, and activation of neuroinflammation.  According to this hypothesis, AD should be considered a prion-like disease, and AD-related Aβ as prion-like proteinaceous nucleating particles.  When prions accumulate and exceed a certain threshold, the may induce a self-propagating process, leading to CNS dysfunction."

As many of you know, for years AD has first and foremost been considered a disease that revolves around amyloid production and accumulation in the brain.  While it may seem logical, were researchers premature in assuming that, since amyloid is found in the brain of AD patients, it must have been produced in the brain?  While there is no reason to assume that the idea of brain-derived amyloid is lacking validity, as suggested above, brain-derived amyloid may only be part of the story.  Gut microflora could also be an important, almost completely ignored, source. 

The idea that AD is an illness that revolves around neuroinflammation as well as buildup of amyloid is nothing new and is gaining increased acceptance every day in both the clinical and research communities.  However, right now there appears to be little knowledge and even less support for the idea that these two major causational factors can be derived from gut bacteria.  Hopefully, starting with those who are reading the research highlighted in this newsletter series, this gut-brain relationship will become fully realized, leading to treatment scenarios where treatment of the gut is considered paramount in addressing the needs of the AD patient.   

GUT PATHOGENS AND AD

Up to this point, I have been reviewing papers that primarily discuss the relationship between disturbances in normal gut microflora and development of neurological disorders.  However, as we know, many patients will not only demonstrate disturbances of resident microflora but increased growth of overt pathogens.  Could these pathogens lead to the development of AD?  This possibility was discussed in the paper "Alzheimer's disease and gut microbiota" by Hu et al (4):

"Infections of Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, Herpes simplex virus (HSV), Human cytomegalovirus (HCMV) and other common pathogens are all considered to be associated with the pathogenesis of AD."

The next quote I would like to feature from this paper provides more detail on the relationship between H. pylori and AD:

"Recent case-control studies showed the correlation between H. pylori infection and AD.  AD patients infected with H. pylori display lower scores mini-mental state examination (MMSE) and more serious cognitive impairment.  The eradication of H. pylori in AD patients can prolong AD survival, potentially suggesting that H. pylori infection may participate in the pathogenic process of AD.  H. pylori infection may influence the pathophysiology of AD through releasing proinflammatory cytokines and inducing oxidative stress."

The next quote discusses the impact of fungal infections in relation to the development of AD:

"Chronic fungal infection can also increase the risk of AD.  Recent research found yeast and fungal proteins in the peripheral blood of AD patients, including 1,3-β-glucan and fungal polysaccharides.  Pisa et al researched the postmortem brain tissues of 11 AD patients and 10 control individuals using specific antibodies against several fungi, and found fungal cell and hyphae in the CNS of AD patients, but not in control individuals."

LACK OF OPTIMAL GUT MICROFLORA POPULATIONS (THE "HYGIENE HYPOTHESIS"') AND AD

Many of you are probably aware of a relationship that has been discussed in alternative medicine circles for the last 20-30 years called the "hygiene hypothesis."  In simple terms, this hypothesis suggests that, since proper development of immune activity is dependent on exposure to optimal levels and types of microorganisms, increased use of antibiotics and excessive sanitation efforts that are often seen in developed countries could reduce microfloral levels and diversity, thereby leading to immune dysfunction and increased development of allergic and inflammatory disorders.  

Could this type of imbalance referred to in the hygiene hypothesis also lead to the development of AD?  Hu et al (4) discuss this possibility.  The authors begin their discussion of this subject by providing a general overview of the hygiene hypothesis:

"The 'hygiene hypothesis' that was put forward in the 1980s points out that improved sanitation in early life is associated with lower exposure to microorganisms and can lead to increased probability of allergic diseases in the future.  Exposure to microorganisms is vital for the development of the immune system, and studies show that immune dysfunction is related to inadequate exposure to microorganisms.  Certain aspects of modern life, such as abuse of antibiotics, use of food additives and preservatives, clean drinking water, improved sanitation, all result in lower and lower amounts of microorganism exposure, including some harmless microbes and parasites."

What is the relationship between the hygiene hypothesis and AD?  Hu et al (4) suggest:

"The hygiene hypothesis for AD predicts the occurrence of AD may be negatively correlated with microbial diversity and positively associated with environmental sanitation.  Dysfunction of the immune system induced by inadequate stimulation to immunity may result in increased risk of AD..."

Evidence for this relationship has been provided by several studies:

"In 2013, Dr. Fox Molly and colleagues compared the relationship between microbial environment and the incidence of AD in 192 countries.  Countries with a lower degree of sanitation have significantly reduced incidence of AD.  In countries with a higher degree of sanitation, which have lower levels of parasites and less diversity of gut microbiota, the prevalence of AD is rising."

Furthermore:

"People living in developed countries have a higher incidence of AD compared to developing countries and AD prevalence at age 80 is higher in North America and Europe than other countries.  A meta-analysis indicates that incidence of AD in Latin America, China and India is lower than in Europe and lower in rural compared to urban areas.  Among populations with the same ethnic backgrounds, living in a low sanitation environment exhibits lower AD risk than living in a high sanitation environment."

Before leaving this discussion, please realize that neither I nor the authors I have quoted are suggesting that we would be better off if the advances in sanitation and antibiotic therapy that primarily occurred in the 20th century had never occurred.  Even a casual perusal of the history of pre-20th century life, particularly in larger cities, makes it crystal clear that improvements in sanitation and the development of antibiotics are two of mankind's greatest creations.  However, as with virtually all aspects of life on earth, balance is key.  The hygiene hypothesis makes a powerful suggestion that developed countries may have gone too far with sanitation efforts and antibiotic usage leading to microbial imbalances and increased incidence of illnesses that are primarily prevented by microbial balance.      

TREATMENT OPTIONS FOR OPTIMIZATION OF THE GUT-BRAIN CONNECTION

The vast majority of you are undoubtedly aware of basic lifestyle and supplemental approaches to optimization of gut function and reduction of systemic inflammation.  Therefore, I will not belabor them here.  What I would like to address, though, is how we can clinically address the under-appreciated role of microflora-derived amyloid in contributing to the development of AD.  To do so  I would like to return to my discussion of the paper "Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease" by Pistollato et al (2).  Before delving into specifics, though, I would like to highlight two quotes that make it clear that the gut microflora are fundamental modulators of the bidirectional relationship between the gut and the brain:

"The gut brain-axis plays a key role in regulating the physiology of both the gut and the brain."

In addition:

"The bidirectional communications that characterize the gut-brain axis are modulated by the presence of the gut microbiome.  Under conditions of dysbiosis, the gut microbiota becomes perturbed and, as a consequence, chronic inflammation occurs, together with a plethora of metabolic and immunogenic reactions that might contribute to the onset of obesity, type 2 diabetes, metabolic syndrome, and AD."

Diet and amyloid production

As you might expect, diet can have both a positive and negative impact on brain amyloid and neurologic function:

"Certain nutrients can also affect amyloid production or represent a source of amyloids, possibly affecting neuroinflammation and dementia-related risk."

What kind of diet might reduce amyloid?  Pistolatto et al (2) state:

"Clinically and cognitively normal individuals with and without AD risk factors, following dietary patterns characterized by high intakes of whole grains, fresh fruits, vegetables, legumes, fish, and low-fat dairy products (which provide higher intakes of vitamin B12, vitamin D, and n-3 polyunsaturated fatty acids) and by low intakes of refined sugars, French fries, high-fat dairy products, butter, and processed meat, show lower accumulation of Aβ in the brain and higher cerebral glucose metabolism, as evidenced by neuroimaging analysis of gray matter volumes (a marker of brain atrophy), C-Pittsburgh compound B (to measure the accumulation of fibrillar Aβ), and F-fluorodeoxyglucose (to assess brain glucose metabolism."

What foods promote amyloid clearance?  The authors note:

"Several studies have described the beneficial effects of natural phenols present in plant-derived foods, such as green tea, red berries, spices, extra virgin olive oil, red wine, and aromatic herbs, in reducing amyloid aggregation and the incidence of amyloid-related diseases.  In particular, oleuropein aglycone and oleocanthal, two phenolic components of extra virgin olive oil, have been shown to promote Aβ clearance and autophagy as well as inhibition of tau aggregation and neuroinflammation.  Oleocanthal has been found to stimulate Aβ clearance by upregulating two major transporters of Aβ expressed in the blood-brain barrier (ie, P-glycoprotein and low-density lipoprotein receptor-related protein 1), consequently increasing the brain efflux rate..."

While the above findings come from animal studies and have yet to be confirmed in human studies, I feel they are compelling enough to make sure these foods are included in the diet of those we are assisting in relationship to AD. 

What else might be helpful?  Consider the following:

"Analogously, the polyphenol (-)-epi-gallocatechin gallate, mainly present in green tea, and theaflavins, found in fermented black tea, are known to inhibit the formation of amyloid fibrils.  Both (-)-epi-gallocatechin gallate and theaflavins have shown neuroprotective action against Aβ toxicity.  They have also been shown to inhibit the fibrillogenesis of both Aβ and α-synuclein fibrils into larger toxic aggregates in vitro.  For this reason, they might have preventive effects against both AD and Parkinson disease.  Coconut-derived phenols and phytohormones (ie, cytokinins) might also be suitable to prevent the aggregation of Aβ proteins, as suggested by in vitro observations."

Other foods that have been shown to reduce amyloid formation and/or aggregation include date palm fruits, garlic extracts, and walnut extracts.  The supplement resveratrol has also been found to be helpful. 

What about herbs?  Pistollato et al (2) point out:

"...plants such as turmeric, Salvia miltiorrhiza, Panax ginseng, rosemary, cinnamon, ginger, sage...have been shown to inhibit aggregation of amyloid proteins and subsequent plaque formation."

Please see the diagram at the end of this newsletter (page 8) that comes from the Pistollato et al paper (2).  It provides an excellent overview of all that has been discussed in this section.

SOME FINAL THOUGHTS TO CONCLUDE THIS SERIES

As I hope I have demonstrated, the evidence is quite clear that, when attempting to assist patients suffering from behavioral and neurodegenerative disorders, addressing gut function is crucial.  Why?  While many reasons have been pointed out in the published literature, perhaps the most important, because of their intimate and vastly under-appreciated involvement with neurologic function, is optimization of gut microflora populations.  Pistollato et al (2) eloquently confirm this need:

"Bacteria populating the microbiome have been shown to produce amyloids, LPSs, and other immunogenic compounds that might contribute to the regulation of signaling pathways implicated in neuroinflammation, brain Aβ deposition, and AD pathogenesis.  Knowing the cellular and molecular mechanisms underlying gut dysbiosis and inflammation might enable the discovery of biomarkers suitable for the early diagnosis of AD and the design of novel therapeutics and preventive strategies."

While some of you may be regularly treating patients with active neurodegenerative disease, it is my guess that most of you are encountering people whose main concern is prevention or early onset.  For these individuals I feel the research I have reviewed in this series makes it clear that addressing the gut dysfunction that is epidemic in most nutritional/functional medicine practices will be a powerful first step.  What tools will we use to accomplish this?  As noted by Pistollato et al (2), they will be the basics that we employ with virtually every other patient:

"Nutritional interventions associated with the use of probiotics, prebiotics, and plant-derived nutrients and phytocompounds, by ameliorating gut inflammation and dysbiosis, might stimulate a positive modulation of the gut-brain axis, reduce neuroinflammation, and retard or regress cognitive impairments associated with AD.  Additionally, nutritional patterns characterized by a high intake of plant foods and specific plant-derived compounds have been shown to reduce Aβ aggregation and, for this reason, are currently considered suitable for the prevention of AD."

Furthermore:

"Knowing the effects and functions of specific phytocompounds, prebiotics, and probiotics could aid the design of novel oral therapeutics for AD and other CNS diseases."

To conclude I would like to briefly review a clinical study that demonstrates the idea of addressing gut microflora to assist Alzheimer's disease patients is not just an ivory tower, academic mental exercise but one of very practical significance.

In "Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized double-blind and controlled trial" by Akbari et al (5), 60 AD patients aged 60-95 years were evaluated.  The research protocol was as follows:

"At the onset of the study, all subjects were matched for disease severity based on gender, BMI, and age.  The participants were then randomly divided into two groups to receive either milk (control group, n = 30; 24 females and 6 males) or milk containing a mixture of probiotics (probiotic group, n = 30, 24 females and 6 males) for 12 weeks.  The patients were requested not to change their ordinary physical activity and not to take any nutritional supplements during the 12-week trial."

The specific supplementation of the probiotic group was the following:

"In the intervention group (n = 30), patients received 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 x 109 CFU/g for each) for 12 weeks."

What were the results of the study?  Akbari et al (5) point out:

"The current study demonstrated that the probiotic administration for 12 weeks has favorable effects on Mini-mental state examination (MMSE) score, malondialdehyde (MDA), hs-CRP, markers of insulin metabolism and triglyceride levels of the AD patients..."

Thus, as I hope you can see, the axiom that we have lived by for years about "treating the gut" is not just about traditional clinical pursuits such as IBS and somatic disorders such as rheumatoid arthritis, asthma and other ailments we have long put into the "autoimmune" category.  Rather, the "treating the gut" axiom now needs to be expanded to include virtually all behavioral and neurodegenerative disorders. 

REFERENCES

1. Zhu X et al. Microbiota-gut-brain axis and the central nervous system. Oncotarget. 2017;published online ahead of print 2017.

2. Pistollato F et al. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev. 2016;74(10):624-34.

3. Jiang C et al. The gut microbiota and Alzheimer's disease. J Alzheimer's Dis. 2017;58:1-15.

4. Hu X et al. Alzheimer's disease and gut microbiota. Science China Life Sciences. 2016;59:1006-23.

5. Akbari E et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: A randomized, double-blind and controlled trial. Frontiers in Neuroscience. 2016;8(Published online).                               

Diagram from Pistollato F et. al. Paper

 

 

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