Everything Everywhere All at Once Pt 3. Microbiome connected to the funeral home

This is the day of the expanding man (1).

Governmental health policies have failed utterly to stem the aggressive marketing of addictive, toxic and calorie-dense foods, which is why the latest data show continuing human inflation.

By 2050, if current trends persist, more than half of adults and almost a third of children and young people will be overweight / obese (2). The degenerative diseases linked to excessive body weight will continue to increase and health expectancy will continue to fall, even if propped up by increasing volumes of pharmaceuticals.

This is a catastrophic societal failure. Our political compradors have not even tried to bring the food sector under control, and the medical profession’s lack of involvement has not helped.

In a 2017 interview David Eisenberg, then adjunct professor of nutrition at Harvard’s T.H. Chan School of Public Health, spilled the beans (3). 80% of US medial schools did not require undergrads to study nutrition, and those that did taught less than 25 hours of nutrition in a 4-year course. As a direct result, only 14% of American medics feel able to discuss nutrition with their patients (4) – and this at a time when diet-related diseases are recognized as the leading cause of death (5).

(I studied medicine and then medical science at Edinburgh University between 1968 and 1979, and received less than 8 hours of nutritional education during that time.)

Bobby Kennedy’s attempts to mandate the inclusion of comprehensive nutrition education in medical schools (6) will doubtless help, but he is starting from a low point. He is facing pushback from medical professionals who have little understanding of medical history, medeconomics, the ongoing collapse in public health (7) or the basics of evidence-based pharmaconutrition (ie 8). And Big Pharma, of course, is at their side.

Until doctors resolve their dilemma, what can we do to protect ourselves from the unscrupulous hawkers of industrial food? A deep dive into man v food (9) might provide a few clues …

.. and we could start with two systems that constantly talk to and influence each other: the gut microbiota and the hypothalamus.

The gut microbiota profoundly affects hypothalamic development and function (10, 11), and
changes in hypothalamic activity exert rapid and profound effects on the gut microbiota (12, 13). The hunger / feeding center sits in the lateral hypothalamus, and the primary satiety center is located in the ventromedial nucleus of the hypothalamus, so it is only natural that this and other parts of the brain and the gut speak to each other. How could the microbiota not be an integral part of this conversation?

The gut, microbiota and hypothalamus communicate via endocrine mechanisms such as ghrelin and cortisol, which promote hunger, and leptin, GLP-1, insulin (and others) which promote satiety. Ghrelin is produced by the stomach, leptin by fat cells and GLP-1 by the colon; and ghrelin, leptin and GLP-1 messaging are all influenced by the gut microbiota (14-16).

This delicate balancing act mitigates against obesity in the wild, and in traditional cultures. It fails comprehensively under the onslaught of the industrial diet, which damages the hypothalamus (see below) and skews our endocannabinoidome and microbiota in a deeply unhealthy direction.

The 30,000 foot view.
Traditional diets plus physical activity support a healthy microbiota, as evidenced by very low rates of chronic degenerative disease (ie 17), and they promote leanness and health (17). The industrial diet and a sedentary lifestyle create dysbiosis and chronic inflammatory stress. These pathogenic mechanisms degrade gut/brain communications in ways which promote hunger (16, 18), reduce satiety (16, 18, 19) and drive both obesity and disease.

The close-up view.
GLP-1 is produced by L-cells in the distal ileum and colon. When prebiotics are consumed, saccharolytic bacteria produce short chain fatty acids (butyrate, acetate) which stimulate the L-cells to produce GLP-1 (16). GLP-1 then regulates insulin and appetite (16). The industrial diet is deficient in prebiotic fiber (ie 20). This reduces endogenous GLP-1 synthesis, and is therefore intrinsically obesogenic.

There are other factors in our unhappy lifestyle that impair GLP-1 activity. Endogenous oleolylethanolamide and extra-virgin olive oil exert positive GLP-1 tone, changes to our diet and lifestyle have likely reduced these also (21-23).

Dysbiosis disturbs the leptin and ghrelin components too. It induces leptin resistance so that satiety signals are no longer acknowledged (24), and the chronic inflammation associated with dysbiosis may also increase ghrelin levels, which among other things promote hunger (25). The resulting neuroinflammation encourages addiction, including addiction to deliberately addictive ultra-processed foods (26-30).

In the metabolic background, excessive levels of omega-6 PUFAs in the industrial diet and thus in our cell membranes distort the endocannabinoid system, increasing cravings for these hyper-palatable (and did I mention addictive?) ultra-processed foods (31-33).

Craving for junk foods maintains or increases the 6:3 ratio in the tissues, including the gut. And this adds another turn of the screw.

Intestinal epithelial cells are continuously shed into the gut, and bacteria in the intestines harvest fatty acids from the membranes of those shed cells. In this way, the omega-6/3 composition of epithelial cell membranes (which reflects our diet) directly shapes the microbiota. Omega-3-enriched epithelial cells favor anti-inflammatory species such as Bifidobacterium and Lactobacillus, while omega-6-dominant membranes tilt the balance toward pro-inflammatory
Proteobacteria (34-36). This is made worse by the lack of prebiotic fiber in the modern, industrial diet (37).

The ultra-processed diet thus hits us with a lethal flurry of kicks and punches.

The abnormally high 6/3 ratio in UPFs drives chronic inflammation in the tissues including our brains (38), skewing food preferences towards hyper-palatable, ultra-processed foods (31-33). This applies not only to us, but also to those children unlucky enough to be exposed to mum’s degraded metabolism while in utero (39, 40).

High omega-6 levels in colonocyte membranes encourage the growth of strongly proteolytic, pro-inflammatory microbes in the gut (34-36). Simultaneously, the lack of prebiotic fiber in today’s industrial diet starves the saccharolytic, anti-inflammatory species, causing further damage to the gut epithelium (41).

The now dominant proteolytic species consume and erode the mucous layer, and come into contact with our colonocytes. Their lipopolysaccharide coats (they are Gram-negative) initiate severe chronic inflammation in the gut wall, which causes endotoxemia, which drives liver damage (42) and contributes to further inflammatory stress in every other tissue in the body.

Neuroinflammatory stress redoubles, and our over-heated hypothalami encourage us to continue to over-eat these foods even while they make us fat, sick and old before our times.

It is not our fault. Our stone-age reflexes and taste preferences have been hijacked by a predatory and uncaring food industry which stuffs our diet with sugar, salt, seed oils and pro-inflammatory advanced glycation end-products, while robbing us of prebiotic fiber, omega-3 PUFAs and a host of other anti-inflammatory compounds. This diet causes dybiosis, chronic inflammatory stress, glycative stress, endocannabinoidomal stress, neuroinflammation and food cravings.

It also rots our brains.

After only a few days of junk food, changes in brain insulin (43) and probably ghrelin (44) activity start to modify neurotransmitters involved in reward and feeding behaviours (44-46), together with altered appetite (44, 45), impaired memory (47) and increased inflammatory signalling (48, 49).

After only a few weeks this diet induces hypothalamic gliosis (forebrain damage), due inter alia to chronic inflammation (50, 51).

These short-term changes are reversible (50, 51) but after only a few decades this same diet increases the risk of hippocampal damage (51, 52) and neurodegenerative disease (48, 49). The fact that dysbiosis reduces BDNF synthesis (24) is likely also involved here.

All the above adverse effects are likely amplified in the young consumer (53), who is more likely to become addicted to industrial food (54) and is therefore most aggressively targeted by the food industry (55).

Pop tarts today, diabetes tomorrow and dementia the day after (56) is not too much of a stretch. The wretches who design and market these foods to our children should have millstones hung around their necks and be drowned in the depths of the sea.

There are other links between better diet and long-term neuroprotection.

Traditional (healthier diets) contained higher level of 1-3, 1-4 and 1-3, 1-6 beta glucans. Together, these essential carbohydrates very likely reduced the burden and infectivity of cytomegalovirus in the gut (57, 58).

This common herpes virus is associated with an increased risk of Alzheimer’s disease, probably via vagal transfer (59); and this and other aspects of the dysbiotic gut are linked to Parkinsonism and multiple sclerosis also (60, 61).

Another connection involves the musculature.

Recent posts described interactions between the microbiota and cartilage, bones and the lungs, but there is also a gut / muscle axis (62). Dysbiosis is linked to increased risk of sarcopenia (62, 63), and sarcopenia damages the brain via disturbed myokine production together with cerebrovascular pathology (61).

Conversely, microbiotal modulation via fecal transplant has been shown to enhance muscle mass and function in the elderly (62). You might prefer to consume prebiotic fibers – an easier option – and there is evidence that this approach may be useful too (63). Roseburia inulinvorans, a microbial species suspected to protect against sarcopenia (65), thrives on prebiotic fibers such as inulin, as implied in its name.

As already described above, the connection is two-way: exercise (17) –– myokines  microbiotal transformation (66)  muscle support (62).

A Muscular Sidebar:
Recent research shows that sarcopenia, which causes so much disability and premature death, is driven inter alia by the progressive failure of a cellular house-keeping mechanism called chaperone-mediated autophagy (CMA) (67, 68). Drugs have been developed to dis-inhibit CMA, but are not yet available for human use.

In the meantime, consider urolithin A. This is a gut metabolite of pomegranate ellagitannins which promotes mitophagy and might, via mitophagy, stimulate CMA (69). This is only a semi-informed guess, and while pomegranate has been reported to improve muscle function (70), this could involve totally different mechanisms.

The other way to inhibit CMA is, amazingly, to take physical exercise (71), which also induces mitophagy (72). Exercise mimetics appear to do the same things (73, 74). So basically, all the new CMA findings show is that if you don’t exercise, you will lose muscle. For those excused gym class there are pills, which may be better in some ways because age-related CMA run-down drives ageing in all tissues, and exercise only affects CMA in muscle.

Dysbiosis caused by an excessive omega-6:3 ratio and lack of dietary fiber is rapidly emerging as a major cause of ill health in our time. Should we all be adding more fiber to our diet?

Those who know me know I am deeply influenced by Claude Bernard, Ilya Mechnikov, Walter Cannon and others who bequeathed us the principle of biological and metabolic non-linearity. Prebiotic fibers, however essential, should seldom be used in isolation and may be counter-productive in some (ie 75). Combining these fibers with an anti-inflammatory and immuno-modulatory regime will, in my necessarily limited experience, produce better outcomes.

This introduces the idea of colonic, non-linear ecology. Omega-3 PUFAs combined with polyphenols appear to create conditions in the gut conducive to a prebiotic-induced microbiotal shift. These are some of the key actives in the Mediterranean diet, and together they form a virtuous circle of microbiota / GALT that supports a physiological level of immune-surveillance and health. The ultra-processed diet is depleted in these compounds and creates a maladaptive circle of chronic unresolved inflammation and disease.

So now it comes out. These last three posts are not really about omega-3 PUFAs, prebiotic fibers, or even the microbiota. They are about the intensive, dynamic, homeostatic and competitive (76) connectivity between our inner workings and the environment, and the ways in which the modern lifestyle damages those connections, and detracts from healthy homeostasis.

Let us return, finally, to the wreckage of our public health, and try to change it.

When you next see your doctor, shake him / her warmly by the throat. Point out that the experts at IMHE agree that poor diet is a leading contributor to disease and death globally (77), and that average healthy life expectancy is falling (7). Since 2011 British men have lost an average of 2 years of health expectancy while women have lost 3 years (7). In parallel, healthy life expectancy in the USA fell by 1.41 years (78).

Remind them that over that same time period, health costs have approximately doubled (79-81).

Explain that we are on the road to ruin, and must change course. Enquire earnestly about your doctors’ knowledge of basic nutrition, and then – if you think it appropriate – point them to this blog. I will respond to all serious enquiries / arguments.

Everything and everywhere, if not all at once.

I am indebted to Stefan Broselid and Martina Torrisen, whose ideas about the endocannabinoidome and colonic ecology contributed materially to this post. Any errors of interpretation are mine.

One reference is duplicated: 20 and 37. My apologies.

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