Hippocrates famously claimed that all disease originated in the gut. Although this is of course untrue, it is clear that conditions in the gut play an important role in determining many aspects of health and disease, including a number of conditions that affect the brain. It works both ways; brain function impacts the gut as well, and this two-way street is popularized as the gut / brain connection. The vagus nerve is an important element in this connection, as are a range of gut hormones and bacterial metabolites. Almost all of these are influenced by dietary factors.
The first clinical study of the gut / brain connection was carried out over a century ago. In 1909 Hubert Norman wrote to the BMJ reporting his use of soured milk to treat melancholia, the term then used to describe what we know today as depression. He was undoubtedly aware of the work of the great Russian zoologist Ilya Metchnikoff, who attributed the long life of the Bulgarian peasants to their consumption of fermented milk products and had recently described soured milk as an ‘intestinal antiseptic’.
A scientific and an ethical man (he abjured his colleagues’ forced feeding of the suffragettes), Norman made no claims and stated his position with care. “The cases have been too few in number and the treatment has been carried out for too short a time to warrant me in making any generalization, and my sole object is to suggest that this method of treatment may be given a trial.”
Norman’s communication was well received and a few months later George Phillips, Physician-Superintendent of London’s Bethlem Royal Hospital, ran the first such trial. He had observed that his melancholic patients were often constipated, believed that this could be the cause of their melancholia and thought that an ‘intestinal antiseptic’ might do them good. His small and open study on the impact of khefir on melancholia was published in 1910, in the Journal of Mental Science (1). 11 of his 18 patients were cured, and another 2 showed significant improvement, giving an overall response rate of nearly 70%. This was the first piece of systematic evidence that suggested that the microbiome might affect the brain, an area of study that is flourishing today.
In the modern era, for example, khefir has been found to reduce symptoms of depression (2) and anxiety (3) in animal models, with other probiotic bacteria showing similar effects (ie 4). The clinical application of these ‘psychobiotics’ however, remains unclear. The data for probiotics (5, 6) and prebiotics (7, 8) show some promise but are not yet good enough to warrant their use in primary or secondary care.
So were Norman and Phillips wrong? Maybe not. The population they were treating before the Great War had very different nutritional habits to ours, and their metabolic chemistry and physiology was unlike ours in many ways. It is possible that an intervention which was once effective has become less so, as our nutritional standards and physical health have declined.
Osteopaths and chiropractors know this. Manipulative techniques that once produced good results after 3 to 4 treatments now require 10, 15 or even more (9). This is most likely because our omega 6:3 ratios have increased about 5-fold (10, 11), our polyphenol intakes have been reduced by approximately 90% (12-13) and our consumption of prebiotic fibre has fallen by up to 95% (14-16). For these and other nutritional reasons we have considerably more chronic inflammation than was the case a century ago, and the inflammation we have is much more likely to persist. Hence the progressive failure of chiropractic techniques, as well as our high and increasing incidence of chronic degenerative disease.
Back to the probiotics. It may be that the ‘intestinal antiseptics’ have become less effective because we consume far less prebiotic fibre, so that when the probiotics enter our gut they enter an environment that is totally unlike that of a century ago. Bereft of fuel, the probiotics are unable to grow and are displaced and killed by the overwhelming numbers of gram-negative bacteria that live inside today’s ultra-processed citizens. We know that the ability of probiotic species to colonise the gut is highly individual (17), and is determined by the existing microbiome (and therefore by dietary factors); and it is hard to make a case that our declining intakes of prebiotic fibre could NOT have impacted on this.
The above is mere speculation, of course, but if there is a connection between bacteria and mood, how might it be modulated?
There are many possible effector molecules. Bacteria in our colons produce metabolites identical to the neurotransmitters in our brains, some of which influence mood and behavior. These include serotonin, dopamine, gamma amino butyric acid (GABA) and acetylcholine. Some strains produce butyrate which is not only a potent anti-inflammatory compound but also an anti-depressant (18). It also enhances the synthesis of brain derived neurotrophic factor (19, 20), a compound that supports the growth and survival of neurons, aids memory and learning and has anti-depressant effects of its own.
Some good research has attempted to identify bacterial strains which may be particularly involved in enhancing mood, such as the butyrate-producing gram-positive species Coprococcus and Faecalibacterium (ie 21), but I believe that a generally gram-positive microbiome is more likely to be both health and mood-promoting; and this, for me, is a persuasive argument for blended prebiotics.
There is an odd wrinkle here in the science-time continuum that is worth mentioning.
Low levels of the long chain omega 3 fatty acids in the diet and brain are linked to depression, and I and others have found that among the hundred thousand or so consumers who use Balance oil, a small proportion consistently fail to show a reduction in their erythrocyte membrane 6:3 ratio, and any improvement in their mood. These are termed ‘slow responders’. Until recently we had no idea why they were so slow to respond but now we have, at least, a theory. It may be yet another link between the gut and mood.
When slow responders are given blended prebiotic fibers, their microbiome shifts markedly from gram-negative to gram-positive; and their omega 6:3 ratios finally start to fall. This is hard to explain, give that the prebiotic fibers work down-stream from the small intestine where the omega 3’s and polyphenols in Balance oil are absorbed. How could this work?
I suspect that what we are seeing here is a remarkable illustration of the complex nature of the relationship between man and microbe.
Whereas the gram-positive butyrate-producing probiotic species prefer to ‘eat’ prebiotic fibers, which are non-digestible carbohydrates, some of the gram-negative species like to eat lipids. They can only obtain significant amounts of these if they can prevent fat absorption in the small bowel, thus allowing dietary fats to pass through the small bowel and enter into the large bowel. I believe that if these gram-negative bacteria are not subdued by a healthy gram-positive population and can achieve large enough numbers, they may secrete a substance that enters the blood, accesses the pancreas, reduces pancreatic lipase secretion and thus increases their food supply. (Whatever this substance is, it does not appear to impact the liver as pre-emulsified Balance oil does not help the slow responder).
The oral microbiome is also linked to brain function.
Dementia is now the 5th leading cause of death worldwide, and Alzheimer’s accounts for about 70% of cases of dementia. It was long thought that Beta Amyloid Plaque and Tau tangles, characteristic histological components in Alzheimer’s affected brains, were causing the loss of brain cells. Arguments raged between the BAPtists and the Tauists. I leant towards Tauism, back in the day …
New research however indicates that beta amyloid and tau may not be driving the disease process at all, but represent attempts by the brain to protect itself against the real causes of Alzheimer’s (22-25); which may in some cases be bacterial. There is evidence that alpha-synuclein, a malfolded protein thought to be involved in causing some types of Parkinsonism, may also be a defensive response – at least in part – to an infective factor (26).
Several different lines of evidence suggest that the bacterium Porphyromonas gingivalis, which causes periodontal disease, may be an important cause of Alzheimer’s (27-29). Let me refine this statement: there are several sub-types of Azheimer’s, and Porphyromonas gingivalis is a probable driver in one or possibly more of these sub-types.
In this situation it makes sense to improve your oral hygiene, and to supplement with fucoidans and funorans. These interesting compounds, found in edible seaweeds, are anti-adhesins. They have been shown to prevent pathogens in the oral microbiome from sticking to the teeth, and thus prevent plaque and tartar formation (30, 31).
Perhaps I can best sum up this unruly mass of data by saying that providing nutrition for a health-supportive microbiome is a critical part of your nutrition, and your health prospects.
Parts of the microbiome are increasingly regarded as your cooperative defence system, and they are influenced by dietary factors (32). Parts of the microbiome (not necessarily the same parts) work particularly closely with your innate immune system (33), and are also influenced by dietary factors.
Blended prebiotics given orally appear to be very effective in restoring healthy gut function and will probably also be developed in pessary form to support vaginal health (34). They cannot be used in the mouth, however, as they are metabolised by probiotic species to short chain fatty acids which would cause dental erosion. In order to optimise the oral microbiome, food-derived anti-adhesins and quorum-sensor inhibitors are a more promising way forward.
I’ll end with a quote from Lewis Thomas, a most astonishing polymath who lived between 1913 and 1993. He said, among many other wise things,
‘As a people, we have become obsessed with Health. There is something fundamentally, radically unhealthy about all this. We do not seem to be seeking more exuberance in living as much as staving off failure, putting off dying. We have lost all confidence in the human body.’
I may obsess about the relationship between food and health to an unhealthy degree, but in the final analysis one has to step away from the lab desk to the dinner table, and preferably via the vegetable patch. Food is one of the great pleasures, along with music, conversation and love. It is vastly more than the sum of it parts.
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