Can Poor Gut Health Drive DEMENTIA? If so HOW?
The Intersection between DIET, MICROBIOME & INFLAMMATION
The GUT-BRAIN Axis
There has been mounting evidence that anxiety, depression and stress possesses strong links to gut health. Everyone has experienced stress and discomfort when there is a gut infection (viral, bacterial or fungal). On the flip side, anxiety and stress can affect gut function. Just ask students before a major exam or having to talk in front of a crowd, and you will learn of butterflies in the tummy, nausea, cramps, diarrhea and vomiting.
These are examples of communication that is largely neural and mediated via the vagus nerve, a two-way communication pathway between the BIG brain and the LITTLE brain that is the gut (enteric nervous system). The vagus nerve also innervates the heart so there are ramifications on cardiovascular function as well.
These can be classic acute responses that are self-resolving but what about chronic diseases that affect brain function? Could the highly visible and tragic outcomes that affect brain function (and structure) that typifies dementia originate in the gut? If so, how would that be mediated, and could gut-oriented interventions make a difference?
DYSBIOSIS and DISEASE
Through the use of remarkable advancements in research tools we have been able to get a better handle on the make-up of our gut microbiome (the bacteria, phages and fungi) that populate our gut. The microbiome is critical for our health and wellness, but then again, if it is out of balance and occupied by “the bad guys” then poor outcomes result.
The condition where the microbiome is unhealthy is called DYSBIOSIS. The corrective measures are diverse. Antibiotics are designed to kill the offending invaders, whereas probiotics and prebiotics are tools to recruit the good guys and displace the bad guys through the intestinal equivalent of gentrification of the neighborhood. This may take some time depending on the state of dysbiosis.
We now have an extensive scientific literature that has documented that a disturbed gut microbiome (dysbiosis) is a clearly associated with numerous and varied diseases. Examples include: obesity, diabetes, cancer and also neurodegenerative disease, such as Parkinson, Huntington and Alzheimer’s disease (AD). However, often the science is incomplete. We struggle to evaluate whether these are mere associations i.e., epiphenomenon or whether they are truly causative. Another alternative is that the dysbiosis a secondary response to the pathology.
If a dybiosis is the core culprit or an engine that drives these disorders, then how does it achieve that?
EXPERIMENTAL ALZHEIMER’S DISEASE & DYSBIOSIS
Obviously there are challenges in proving causation in humans, so we turn to mouse models of AD to explore the components. Recently, a fascinating study sought to unravel mechanisms that may link gut dysbiosis to dementia (Metabologenomic Analysis of Gut Microbiome in Dementia ).
Compared to control mice the Alzheimer’s Disease model mice displayed:
An altered pattern of gut flora consistent with dysbiosis
Increased levels of Candidatus Saccharibacteria phylum
An increased presence of Proteobacteria
A lower percentage of Firmicutes
Beyond just changes in the microbial makeup in AD mice there were dramatic changes in the biochemicals produced by the microbiome. This is where the confluence of the sciences of the metabolome and the mcirobiome provide impressive insights as to how dysbiosis may affect health and wellness. For example in AD mice there was a clearly disturbed metabolomic profile (the biochemicals created by the microbiome when it metabolizes ingested nutrients)
A significant decrease in the amount of certain amino acids including threonine, serine, valine, isoleucine, phenyalanine and aspartic acid
A dysregulated production of desaminotyrosine (DAT) and dihydro-3-coumaric acid
These changes increased over time with the profile of the AD mice becoming more and more divergent. Short-chain fatty acids are a common metabolic product by gut bacteria but the profile of SCFAs produced by AD mice start becoming evident at weaning, with divergence increasing over time. Compared to controls, AD mice display a dramatic and significant decrease of both acetic and propionic acid.
What is clear is that the mice that destined to develop AD later in life have disturbances in the microbiome profile and the biochemicals (postbiotics) created by these bacteria when they metabolize dietary nutrients.
INFLAMMATION and the METABOLOME
In my own research on the metabolome, the profile of metabolites generated in health and disease, I noted that during inflammation there is an alteration in which substrates are used to generate energy. Cells move away from using glucose and switch to other substrates including branched-chained amino acids. Inflammation, as a result of the dysbiosis, may then create an altered metabolome with suppressed levels of valine, isoleucine and leucine.
Supporting this link is the abundance of research that has shown that gut dysbiosis has been observed in human diseases characterized by gut inflammation such as Celiac Disease, Cystic Fibrosis, Obesity, IBD, diabetes, colon cancer, and more (Microbiome & Gut Dysbiosis , Immunity & Gut Microbiota).
While encouraging we are still determining if these events reflect whether they cause disease or are mere consequences of disease. Nevertheless, interventions aimed at rebalancing gut microbiota by using prebiotics, probiotics, nutraceuticals or fecal transplants seems to have a positive impact on some disease onset/progression, at least in animal models (Targeting the Microbiome for Managing ALS , Alzheimer's, Inflammation and the Microbiome )
The detailed metabolomic study by Favero et al (Metabolomic & Microbiomic Changes in Exptl Alzheimer's ) revealed substantial changes in phloretic and 3-3-hydroxyphenylpropanoic acids, also called desaminotyrosine (DAT) and dihydro-3-coumaric acid, which are well-known metabolites produced by microbiota enteric bacteria and linked to immunity and inflammation (Immunity & Metabolism , Microbiome Generated Desaminotyrosine & ALzheimer's , Desaminotyrosine Protects against Influenza).
It is therefore quite possible that the deranged portfolio of biochemicals that results from a dysbiosis may have far ranging systemic impacts on health and wellness, and may be important drivers of the onset of dementia.
CONCLUSION
It appears that early the gut microbiome undergoes progressive changes before the onset of cognitive decline. In concert, there are substantial alterations in the metabolome i.e., biochemicals associated with these microbes. These alterations in both the microbiome and the metabolome may well help drive the pathology leading to dementia, specifically Alzheimer’s Disease.
Understanding this sequence of events allows one to project potential solutions and interventions, especially when applied early on to maintain health and wellness.