Everything Everywhere All at Once Pt 2: microbiome connected to the metabolome

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A good friend sent me a truly fascinating recent paper which sheds new light on the old gut-brain connection (1). It focuses on the relationship between the endocannabinoids (eCBs) and tryptophan (and therefore serotonin) metabolism, all of which are profoundly affected by the microbiota.

Clinical data ‘showed a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay between inflammation, stress, and depression.’ What the Italian / Canadian team actually found was that serum levels of eCB’s and kynurenine correlated positively with the severity of depression, while tryptophan and serotonin levels were negatively associated.

This all seems convergent.

Neuroinflammation is increasingly regarded as a causative and exacerbating factor for depressive illness (2, 3). Neuroinflammation occurs after chronic stress and social defeat (4), and when the body experiences systemic chronic inflammation (5). Chronic inflammation increases both endocannabinoids and cannabinoid receptors (6-8). In other words, it up-regulates an early buffering / protective / anti-inflammatory system.

Chronic inflammation is rife today, as witnessed by the proliferation of chronic non-communicable degenerative diseases, and is driven by the modern, ultra-processed and pro-inflammatory diet in a number of complementary ways. For example, our diet contains excessive levels of pro-inflammatory compounds (9). At the same time, it is deficient in key anti-inflammatory nutrients such as the omega 3 PUFAs, polyphenols and 1-3, 1-6 beta glucans (10).

It is also deficient in prebiotic fibers (ie 11, 12).

A lack of prebiotic fiber causes colonic dysbiosis, with subsequent chronic inflammation in the colon (13, 14). Chronic inflammation activates the enzyme indoleamine 2, 3-dioxygenase (IDO) in gut-associated lymphoid and other tissues (15), switching the metabolism of ingested tryptophan away from the serotonin and indole routes, and towards the kynurenine pathway (16).

The modern diet would therefore be exactly predicted to cause the chemical shifts described in the first two paragraphs, namely raised kynurenine and eCB’s, lowered tryptophan and serotonin (1); and to predispose to depressive illness.

The increased kynurenine / IPA ratio is linked to depressive and other illness via a second and intertwined route, this one involving the mitochondria.

Mitochondrial dysfunction, with impaired energy production, is increasingly recognized as a critical element in the road to depression. Neurons starved of ATP not only develop neuroinflammatory stress but also degraded synaptic function together with reduced neuroplasticity (17). This is a combination positively designed to create repetitive negative thought patterns (18, 19); there is even evidence that many anti-depressants may exert their effects by improving mitochondrial function (20). In the longer term, mitochondrial dysfunction would be expected to increase the risk of neurodegenerative disease (ie 21-23).

Eagle-eyed readers will have spotted a feed-forward loop here.

Inflammation activates IDO, which produces more kynurenine, which degrades mitochondrial function, which contributes to more inflammation, which activates IDO, which produces more inflammation … which degrades the ECM and disrupts immune function. This is what the industrial diet does, and it is a likely major link between the diet and the current epidemics of cancer, depression, Parkinsonism and doubtless other degenerative diseases.

Back to the microbiota, and their connection with our mitochondria.

A diet low in prebiotic fiber causes dysbiosis and predisposes to chronic colonic inflammation (24). This boosts kynurenine production in the gut while simultaneously reducing IPA synthesis (13-16), as described above.

Kynurenine metabolites such as quinolinic acid and hydroxykynurenine are neurotoxic. They disrupt the mitochondrial membrane and the electron transport chain, thus contributing to neuronal dysfunction and damage (21-23). IPA, in contrast, is a potent neuroprotectant (25, 26).

The industrial diet caused colonic dysbiosis and chronic inflammation. By raising kynurenine while lowering IPA, this diet therefore predisposes to neuronal mitochondrial insufficiency, depression, neuroinflammation and, in the longer term, neurodegenerative disease. QED, more or less, and yet another argument for switching back to an old-school and minimally processed diet.

Over-activation of the kynurenine pathway also seems to be involved in cancer-related fatigue (CRF), a common complication that can really degrade quality of life in cancer patients. CRF generally correlates with tumour aggressiveness and with increased levels of inflammatory cytokines in the blood (27). By producing these cytokines the tumour achieves enhanced survival and spread (28), partly by down-regulating local immune surveillance.

This takes us back, full circle, to the mitochondria.

There is rather good evidence that CRF is in part a consequence of inflammation-induced activation of the IDO enzyme, which boosts the kynurenine pathway at the expense of serotonin and IPA synthesis (29). The mitochondria become less effective so energy declines, together with mood; a pattern which can emerge even before cancer is diagnosed (30).

The level of IDO activation and therefore intestinal and other inflammation is captured in Zinzino’s gut test, which shows improvement in the kynurenine / IPA ratio after increased prebiotic fiber intake (31). That could explain reports of prebiotic fiber improving energy levels (32) and mood (33, 34).

If IDO is such a problem then why, I hear you ask, do we all possess this troublesome enzyme?

Like all other systems in the body, it is a matter of balance. There are times when the ability of IDO to remove tryptophan by dumping it down the kynurenine route is extremely valuable.

IDO is a key component in the innate immune system. When intracellular pathogens cause inflammation, inflammation activates IDO which inhibits the growth of many pathogens by depriving them of the key nutrient tryptophan. (M. Tuberculosis gets around this by synthesizing its own tryptophan (35). IDO is also important during pregnancy, when kynurenine metabolites promote immune tolerance.

For most people, however, toning down IDO activity makes therapeutic sense. For example …

Among the small percentage of cancer cells which succeed in becoming clinically important cancers, many do so by expressing high levels of IDO. As noted above, the kynurenines enhance cancer growth by dampening local immune surveillance (36). In this situation, therefore, IDO down-regulation should help to restore local immune surveillance. IDO inhibitors are currently under investigation as adjuncts in cancer treatment with checkpoint inhibitors (37).

In the ageing brain, increased IDO activity causes a fall in neuroprotective IPA and in serotonin, with a corresponding increase in the neurotoxic kynurenines (36). It also triggers down-regulation of the anti-ageing protein SIRT6, due to kynurenine-induced mito-toxicity (38, 39). This would raise the risk of depression and neurodegeneration, and looks to be to be a significant part of unsuccessful neurological ageing.

IDO inhibitors are therefore likely to find a role in the prevention and early treatment of neurodegenerative disease (40). They may also be helpful in the treatment of depression in the elderly (40).

In the current public health landscape, the growing numbers of patients with dysbiosis, IBD, colon and other cancers, depression and neurodegenerative disease indicates that chronic inflammation is prevalent, and IDO activity is generally excessive. There are several dietary ingredients which can be used to rectify this.

Prebiotics and the omega-3 PUFAs (see next post) help to bring IDO back under control in the gut. Polyphenols such as cyanidin (food sources include blackberries, black elderberries and raspberries) reduce IDO activity in the brain, which they do by damping inflammation and up-regulating the foundational anti-ageing protein SIRT6 (39, 41).

Other natural compounds inhibit IDO directly; coenzyme Q10 and vitamin K3 are moderately effective, as are a number of polyphenols (42). If added to a prebiotic, they may provide some additional skew away from kynurenine and towards the IPO pathway. Brassinin, an indole which occurs in cruciferous vegetables such as white cabbage, broccoli and mustard, is also moderately effective (42).

Prebiotic fibers come in here too. They support the growth of Clostridium sporogenes, a gut microbe profoundly involved in the intestinal production of IPA (43), and its sister compound indole-3 acetic acid aka IAA (43). IPA is good for mitochondria (25, 26) and therefore for muscle development (43), while IAA likely adds significant cardiovascular health benefits (44).

You can certainly eat your way to better health, but it is not only about what you eat. How you vote is equally important.

Back to that first paper again (1). The authors specifically mention stress as a component in the mix of factors that tend to lead to depression, and they were right to do so. In a separate study, increased stress (in a pre-clinical model) induced changes in the microbiome including a likely reduction of C sporogenes, leading to IAA reduction, increased stress signaling and a subsequently increased risk of cardiovascular damage (44).

In this way, chronic stress induced in the general public by the current crop of self-serving, second-rate politicians and the social damage they cause, increases vulnerability to cardiovascular disease (44, 45) and directly triggers neuroinflammation by activating the microglia (46, 47). The microglia (the brain’s immune cells) then release pro-inflammatory cytokines, creating a neurotoxic environment inside your skull which impairs neuronal and brain function (48, 49).

There is a parallel disturbance in the endocannabinoid system (48, 49), resulting in exaggerated stress responses which contribute to depression (50, 51) and anxiety disorders (52-53). All of this is exacerbated by the omega-6-heavy industrial diet (54).

Repeated social defeat inflicted on us as our freedoms are stripped away add to this toxic mix by activating the Cell Danger Response (55, 56), which is among other things a neuro-inflammatory and mito-toxic process. Chronic activation of the CDR is believed to be involved in PTSD, depression, anxiety disorders, social withdrawal, substance abuse and, in the longer term, degenerative diseases (4, 55, 56).

Our kakistocratic overlords are killing us softly with their dissonance so that they may cling to the pathetic vestiges of their power. Shield yourself and your family by adopting an anti-inflammatory regime, both nutritionally and politically (57, 58).

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