Alzheimer's: The gut-brain connection

A toxin produced by gut bacteria sets off a chain reaction in the brain that leads to Alzheimer's and other neurodegenerative diseases. And what you put in your mouth can control it.

Of all the diseases that strike fear into the human heart as we grow older, Alzheimer's and other forms of dementia probably rank at the top. Arthritis causes people to lose mobility and strength; diabetes can cause the loss of eyesight or even a limb; heart disease and cancer can cause the loss of years of life expectancy. But dementia causes the loss of oneself. All the faculties, personality characteristics and memories that make us who we are, are gradually - and in some cases rapidly - stripped away, as dementia ravages the brain of the afflicted person, leaving their loved ones with just the husk of the individual they knew.

I speak from experience. My own father died of sudden cardiac arrest, after experiencing a minor heart attack from which he had been expected to make a full recovery. While he had suffered from various chronic illnesses for many years, the abruptness of his passing was a terrible shock, and I regret to this day that I never got the chance to say goodbye. The one crumb of comfort that I clung to as I wrestled with grief, was that he had not suffered a long-draw-out, painful death.

My mother-in-law, on the other hand, endured over ten years of inexorable decline as vascular dementia mercilessly stripped her of every faculty. Hers was truly a death of a thousand cuts. This remarkable individual, who had had her intellectual capacity thwarted both by growing up in poverty, and by a culture which deemed women incapable of being much more than breeding machines, went from running multiple businesses to being bed-ridden and incapable of feeding or toileting herself, or communicating with anything more than the imploring expressions in her haunted eyes. I would not wish this soul-crushing demise on anyone - no, not even Klaus ‘eat ze bugs’ Schwab or Bill ‘one of these numbers is going to have to get pretty near to zero’ Gates!

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Yet despite the eye-popping sums poured into research on pharmaceuticals to treat Alzheimer's - over US$42.5 billion of private funding between 1995 and 2021, and billions more in public funds - there are still no medical treatments that slow the progression of this devastating disease, or mitigate the underlying biological processes that cause it.

So there's more than a touch of irony in the discovery that one of the key drivers of the neurodegeneration that characterises Alzheimer's disease is a potent neurotoxin produced by humble gut bacteria... and that the abundance of these bacteria can be suppressed with an even more humble dietary intervention: eating more fibre.

In a paper with the catchy title 'Downregulation of Neurofilament Light Chain Expression in Human Neuronal-Glial Cell Co-Cultures by a Microbiome-Derived Lipopolysaccharide-Induced miRNA-30b-5p', researchers identified a chain of events precipitated by bacteria-derived lipopolysaccharide (LPS) in the brain, that ultimately results in the death of neurons (brain cells) and the loss of connections between them. They they trace the process by which LPS, a component of the cell wall of certain bacterial species (known as 'gram negative') in the gut, gets through the gut wall into the bloodstream, and then makes its way through the blood-brain barrier into the brain itself, where it decimates neurons.

As you might guess from the title, the paper delves into some exceptionally complex biological processes. If you're not into the nerdy details, you might want to skip over this quick-and-dirty summary; if you're a serious nerd, you should of course go and read the paper. In a nutshell (or should that be, in a bacterial cell wall?):

• Lipopolysaccharide (LPS) induces cells to make nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), a protein complex that controls gene expression, production of cytokines (cell signalling molecules) and cell survival.

• NF-kB upregulates a set of microRNAs, which are small non-coding RNA (sncRNA) that recognise and bind to specific messenger RNAs (mRNAs), altering the proteins that are built from the instructions encoded by the mRNA.

• These microRNAs

  • Cause inflammation in the brain;

  • Impede the 'cleaning' of toxic proteins such as amyloid from the brain by microglia (immune cells of the central nervous system); and

  • Impair production of a protein called neurofilament light chain (NF-L), causing atrophy of the cytoskeleton of neurons, and disrupting the synaptic connections between them.

Depleted NF-L within the neurons of the neocortex has been found to be a hallmark of the brain degeneration that characterises Alzheimer's disease. Without this vital protein, neurons cannot maintain their normal shape and function, and as they collapse and lose connection with each other, the brain itself shrinks dramatically.

Other neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and human prion disease are also characterised by depletion of NF-L within neurons.

Several research groups have found LPS - a substance made only by bacteria, and not by human cells - inside the brain cells and central nervous system tissues of Alzheimer's patients, and reduced NF-L has been known to play a pivotal role in neurodegeneration for some time. But up until the publication of this study, the molecular-genetic mechanism that links LPS to decreased NF-L abundance had never been identified.

As the authors of the paper explain, there are many different versions of LPS produced by bacteria that comprise the gut microbiota. Some forms of LPS are fairly benign, while others are highly pro-inflammatory and neurotoxic. Certain strains of the anaerobic bacterium Bacteroides fragilis produce a particularly pathogenic form, known as BF-LPS, which easily penetrates physiological barriers, including the gut lining, the blood-brain barrier, and the plasma membranes of brain cells.

Overabundance of Bacteroides fragilis has also been found in the intestines and faeces of patients with colorectal (bowel) cancer and precancerous lesions (polyps).

Diets high in both red meat and fat increase the proportion of pathogenic Bacteroides fragilis (and other bacterial species associated with cancer, Alzheimer's and other degenerative diseases). Conversely, high-fibre diets increase the abundance of bacterial species that promote intestinal health, including the integrity of the gut wall - and hence reduce the translocation of LPS from the gut into other body compartments, including the central nervous system.

The handful of drugs approved to treat Alzheimer's disease are either directed at controlling cognitive and behavioural symptoms, or - in the case of aducanumab (Aduhelm) - break down the beta-amyloid plaques found in the brains of sufferers, but without any clinically significant effect on symptoms of cognitive decline, such as memory loss, wandering, daily function, and personality and behaviour changes.

Given the high expense, low efficacy and terrible side effect profile of Aduhelm, the authors of this paper think that focusing further upstream in the disease process makes sense, especially since depleted NF-L plays a key role not just in Alzheimer's but in other neurodegenerative diseases:

"Targeting and modulating GI-tract microbiome LPS-mediated miRNA-30b-regulated NF-L pathways and other miRNA-mediated gene expression circuitry should be valuable in the design of future therapeutic strategies... The overall goals of these strategies are that the support and maintenance of cytoskeletal structures essential for synaptic plasticity may more effectively manage the many neurological diseases in which NF-L gene expression and abundance play a determinant and defining role. Lastly, dietary-based modifications of microbial dysbiosis may be an attractive means to modify the abundance, speciation, and complexity of enterotoxigenic forms of AD [Alzheimer’s disease]-relevant microbes and their potential for the pathological discharge of highly neurotoxic microbial-derived secretions that include LPS."

Downregulation of Neurofilament Light Chain Expression in Human Neuronal-Glial Cell Co-Cultures by a Microbiome-Derived Lipopolysaccharide-Induced miRNA-30b-5p

Or, to put it more simply, fostering a healthier gut microbiome will help prevent, and possibly even treat, an array of neurological conditions, and the simplest way to do this is change what you're eating.

I'm sure my readers don't need to be reminded of this, but foods of animal origin (meat, poultry, fish, seafood, eggs and dairy products) are completely devoid of fibre. Take heed, all you carnivore diet enthusiasts! But oils, sugars and highly refined starches are also entirely lacking in fibre. So don't think you're doing your brain any favours if you cut out animal products and replace them with ultraprocessed vegan junk food.

If you want more fibre in your diet - not to mention other types of microbiota-accessible carbohydrate, and polyphenols that promote the growth of beneficial gut microbes - you need to be piling your plate high with fruits, vegetables, legumes, whole grains, nuts, seeds, herbs and spices. I encourage my adult clients to eat a minimum of 40 grams of fibre per day - double the average Australian intake. When I’ve taken the trouble to track my own dietary fibre intake for a couple of days, I usually rack up 70-80 grams per day.

Back when I was in naturopathic college in the early 1990s, my lecturers were fond of quoting a maxim attributed to the ancient Greek physician, Hippocrates of Kos:

"All disease begins in the gut."

Hippocrates knew nothing of the gut microbiota, or how lipopolysaccharides induced NF-kB which upregulated microRNAs that impaired the production of neurofilament light chain, causing neurons to collapse and lose their connections with each other. Neither did any of my lecturers; the study of the microbiome was in its infancy back in the 1990s, and the first microRNA was only described in 1993, in a 1 mm long nematode called Caenorhabditis elegans.

I find it deliciously ironic that high-tech methods for investigating the interaction between bacteria, molecules, genes and proteins, are now being deployed to verify a piece of ancient wisdom, formulated by someone who simply carefully observed the relationships between diet, symptoms and disease. Perhaps, somewhere in the time-space continuum, Hippocrates is rolling his eyes and saying "I told you so!"

For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.