Summary Hello and welcome to episode #17! This is Ralph Sanchez and today I’ll be expanding on the first episode’s overview with regard to beta-amyloid and tau protein clearance and detoxification. If you did not catch that episode (#16), I provided an in-depth overview on the role of the blood brain barrier (BBB) and the glymphatic system in clearing and transporting toxic beta-amyloid and tau protein from the brain. In today’s episode, I’ll review the emerging science and research with regard to the brain-liver axis in beta-amyloid clearance and metabolism, and how the gut fits into that, and a little on tau protein too. Now, the peripheral metabolism of beta-amyloid in the body is a very complex overview, however, I will cover two important organs that are associated with the origin and degradation of beta-amyloid in the body—the gut and liver. And, I will provide key features about that to illustrate what I term—the gut-brain-liver axis in late-onset Alzheimer’s disease (LOAD). First, there are three points I will make here with regard to the gut-brain axis, and its potential role for a healthy brain, or for neurological disease such as Alzheimer’s and Parkinson’s disease. First, the gut is potentially a powerful vector for proinflammatory cascades that induce neuroinflammation responses.Secondly, alteration of the gut barrier integrity leads to similar loss of the blood brain barrier integrity,And lastly, the generation of beta-amyloid proteins produced by bacteria in the gut.Yes, certain gut bacteria have been identified as specific beta-amyloid peptide producers linked to a beta-amyloid burden in the brain. Now note the latter point I just made about gut-derived beta-amyloid-like peptides (proteins) generated by gut microbiota which I will elaborate on more here soon. Nevertheless, the role gut-derived beta-amyloid-like proteins has in recent years been identified as drivers of neuroinflammation, AND amyloid and tau protein aggregation and deposition in the brain. Of course, pro-inflammatory pathways are driven by a host of physiological and pathological mediators that includes the gut, and numerous chronic diseases such heart disease and diabetes (cardiometabolic disease) which is well-described in the research literature. Gut-Brain Axis in Neuroinflammation The role of the gut-brain axis is a significant factor in the risk for numerous health disorders throughout life, and it can have substantial implications on your body-brain health as you age. Numerous studies that have examined the role of gut health disorders such as small intestine bacterial overgrowth or dybiosis to the detriment of brain health and the risk for cognitive decline and dementia have been accruing now for many years. BTW, for those of you who have not run into the reference to gut dysbiosis, it simply refers to the altered gut ecosystem that is reflected by unhealthy imbalances of the gut microbiota. And, as before, one significant driver of gut inflammation is the disordered ecological balance of the gut microbiota (dysbiosis). Additionally, bacterial overgrowth patterns of dysbiotic bacteria are highly associated with elevations of a potent gut-brain toxin— lipopolysaccharides. Lipopolysaccharides are bacterial surface molecules that are a major component of the outer membrane of Gram-negative bacteria. Lipopolysaccharides are normally shed by gut bacteria, but in the case of microbiome imbalances associated with bacterial overgrowth patterns (dysbiosis), a proliferation of dysbyotic bacteria—the bad guys, too much pro-inflammatory lipopolysaccharide matter is shed into the gut and peripheral circulation which can lead to powerful systemic toxic and inflammation reactions. With regard to the central nervous system and individuals at risk for dementia and Alzheimer's disease, dysbiosis and the excessive generation of pro-inflammatory lipopolysaccharides alter the integrity of the BBB and can induce beta-amyloid and tau protein aggregation and accumulation in the brain—plaques and tangles. Both gut bacteria and lipopolysaccharides can migrate into the brain and upregulate neuroinflammatory and neurodegenerative mechanisms there that include damage to the myelin. Indeed, the brain damage associated with lipopolysaccharides (LPS) also extends to myelin degradation—the critical material surrounding axons that insulate and facilitate conduction of the nerve impulse that is critical in neuronal signaling communication across the synapse. Studies have shown that blood LPS levels are much higher (e.g., 3-fold) in Alzheimer's patients, and similar brain burdens of LPS are significantly elevated in aging individuals with Alzheimer's disease. Now that you hopefully have an understanding of dysbiosis and the overgrowth patterns of potentially toxic bacteria in the gut-brain axis, there is an additional risk for neurotoxicity that dysbiotic bacteria generate. They are also a source of beta-amyloid like proteins as I mentioned a little earlier here. Yes, species of gut bacteria are known sources of amyloid-like proteins (similar but not duplicate structure), and these gut-derived amyloid proteins also are known to cross a leaky gut barrier and a leaky BBB. Plus, gut-derived amyloid-like proteins can function through a phenomenon known as “molecular mimicry”, as prion proteins (infectious pathogens made of protein) that cross-seed and stimulate aggregation of beta-amyloid in the brain. BTW, if the term molecular mimicry is new to you, it describes the molecular likeness or similarity of a foreign antigen or protein to self-proteins that can elicit immunological reactions as evident in several autoimmune disorders. Examples of amyloid secreting gut microbiota are E.coli and Clostridium that are singled out in a few recent studies. However, there are many species of E.coli and Clostridium that are not toxic. In fact, they are beneficial bacteria of the gut ecology too. And that brings us to the end of this summary, but there is much more included in the audio, so please listen in! Ralph Sanchez, MTCM, CNS, D.Hom https://www.TheAlzheimersSolution.com https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/
