Meat Intake and the Dose of Vitamin B3 - Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?

Abstract

Meat and vitamin B₃ - nicotinamide - intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by 'welcoming' gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B₃ deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive 'meat transitions'. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic 'old friends' compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B₃ could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.

Keywords: Diet; Parkinson; allergies; cancer; disease transitions; environmental enteropathy; health inequality; hygiene hypothesis; hyper-vitaminosis B3; metabolic syndrome; nicotinamide; pellagra; tryptophan.

Figure 1

Pellagra has a very wide phenotype. The parallel with diseases of ageing are striking. NAD/NADH/nicotinamide imbalances may be the treatable underlying common factor to many common diseases whether from dietary deficiency or excess or varying needs from genetic mutation, toxic, anoxic, or other external stresses. NAD indicates nicotinamide adenine dinucleotide.

Figure 2

Diet supplies nicotinamide, nicotinic acid, and nicotinamide riboside as well as the essential amino acid tryptophan. Tryptophan can be degraded to synthesise nicotinamide when there is dietary stress by the kynurenine ‘de novo’ ‘immune tolerance’ pathway. Symbionts, whether in gut or TB, are a backup source as is ‘autocarnivory’. Salvage pathways are extensive and efficient to conserve NAD/nicotinamide as NAD consumers mean that there is a continuous need for replenishment. Many are involved in repair and disease processes and ageing. Excess nicotinamide can be excreted after a methylation reaction by NNMT. NNMT, indicates nicotinamide N-methyltransferase; TB, tuberculosis.

Figure 3

NAD is central to metabolism and the energy supply. NAD determines cell fates during development. NAD links to the epigenome and genomic expression means close interactions with our environment that in turn supplies NAD.

Figure 4

Nicotinamide/NAD and tryptophan metabolism are linked by the ‘de novo’ pathway. All these pathways have been implicated in diseases of ageing and mechanisms such as proteotoxicity, and, interventions such as caloric restriction, resveratrol, parabiosis and metformin.

Figure 5

Plant and human metabolisms have active and overlapping reactions involving nicotine and nicotinamide. Stress molecules such as nicotine, salicylate, and resveratrol have medicinal and hormetic actions in man.

Figure 6

A designer symbiont. TB produces nicotinic acid but cannot recycle it to NAD so excretes it to a ‘welcoming’ host that ‘farms’ the organism at some risk of dysbiosis if the dietary dose of nicotinamide is too low. Nicotinamide is a natural and its analogues are some of the artificial anti-tuberculous agents. NAD indicates nicotinamide adenine dinucleotide; TB, tuberculosis.

Figure 7

Infections and host NAD metabolism are intertwined. Many pathogens evolved to consume host NAD or their toxins lead to host NAD depletion. If the host is NAD deficient, this will exacerbate virulence and death rates. If severely deficient, there may not be enough NAD to allow the pathogen to replicate. Symbionts, by contrast, can improve host NAD levels.

Figure 8

Low-meat/high-fibre diets lead to symbionts that increase nicotinamide levels or produce butyrate. Butyrate is an agonist at the nicotinic acid receptor as well as having epigenetic effects. Both butyrate and nicotinic acid will affect the T-cell balances and immunologic tolerance.

Figure 9

The key switch is the kynurenine ‘de novo’ pathway. When dietary supplies of nicotinamide/NAD are not sufficient, there is Treg-induced tolerance for metabolically useful symbionts but dangers to individual health from dysbioses or pathogens. However, when dietary nicotinamide is high, there is immune intolerance with too few Tregs and an excess of pro-inflammatory T17 cells and many diseases of modernity. Many immunologic therapies from steroids to recent T-cell–targeted approaches or artificial infection try to correct this imbalance. Prevention might be more effective and safer.

Figure 10

Predisposing phenotype for inflammatory disease driven by high nicotinamide in diet leads to reduced IDO activity. The more immediate triggers to these diseases and the disease process itself may sometimes lead to the apparent paradox of induced IDO as a compensation that may exacerbate or mitigate the disease. Lack of early infections or allergens may be ultimate causes but can act later as proximate triggers. IDO indicates indoleamine 2,3-dioxygenase.

Figure 11

Diarrhoea plotted against meat intake in the United Kingdom, 1850–1950 (r = −0.642; P = .085).

Figure 12

Diarrhoea plotted against meat intake in the contemporary world across nations (r = −0.508; P < .0001).

Figure 13

Literacy rates plotted against meat consumption in the United Kingdom, 1850–1900 (r = −0.988; P < .001).

Figure 14

Literacy rates plotted against meat consumption in the contemporary world across nations (r = 0.531; P < .001).

Figure 15

IQ plotted against meat consumption in the contemporary world across nations (r = 0.538; P < .001).

Figure 16

Increased height correlates strongly with higher meat intake (r = 0.934; P < .001).

Figure 17

Increased height correlates strongly with higher meat intake (r = 0.635; P < .001).

Figure 18

Tuberculosis plotted against meat consumption in the United Kingdom, 1850–1920, before there was any drug therapy (r = −0.958; P < .001).

Figure 19

Tuberculosis plotted against meat consumption in the contemporary world across nations (r = −0.545; P < .0001).

Figure 20

Diabetes plotted against meat consumption in the United Kingdom, 1850–1950 (r = 0.756; P < .05).

Figure 21

Diabetes plotted against meat consumption in the contemporary world across nations (r = 0.247; P < .001).

Figure 22

Cancer death rates plotted against meat consumption 1850–1950 (r = 0.981409; P < .0001).

Figure 23

Cancer death rates plotted against meat consumption in the contemporary world across nations (r = 0.667; P < .0001).

Figure 24

Parkinson disease plotted against meat consumption 1850–1900 (r = 0.842; P < .001).

Figure 25

Parkinson disease plotted against meat consumption in the contemporary world across nations (r = 0.842; P < .0001).

Figure 26

Incidence of helminth infestation and tuberculosis is diametrically opposed with incidence of autoimmune disorders now. In 1850, this map would have looked more homogeneous.

Figure 27

The rapid and sequential rise of allergic and auto-immune disease in the United Kingdom is shown. During this period, meat intake on average doubled again, so if accurate figures were available for the new diseases, strong correlations would be apparent. Incidence and severity may be stabilising for some such as asthma (as is meat intake).

Figure 28

A summary of how poor diet can interact with the microbiome and with internal stresses such as mutations and with external stresses. These can all contribute to a single NAD endo-phenotype with multiple clinical phenotypes. NAD indicates nicotinamide adenine dinucleotide.

Figure 29

US map illustrates the obesity epidemic and a diabetic belt. The distribution is almost exactly the same as maps of pellagra a century ago. Has the change from very low levels of nicotinamide to high levels been the crucial inter- and intra-generational change rather than calories or allergens?

Figure 30

The presence of a detoxification pathway suggests that nicotinamide can be toxic. A balance may have been required as NAD consumers evolved to be an important control mechanism that both needs a supply of NAD from nicotinamide and whose enzyme activity is affected by nicotinamide.

Figure 31

An optimal dose of nicotinamide is suggested with trouble at the extremes. Transgenerational effects may be marked. Dysbioses that begin under these circumstances could put the affluent at risk. Within generation effects may be mismatches between early and late life exposure with poor nicotinamide in early life predisposing to the metabolic syndrome later if the dose increases. TB indicates tuberculosis; PD, Parkinson disease.

Figure 32

Nicotinamide overdosage is unlikely to be working alone. It may act in concert with other excess dietary factors known to be involved with ageing and pathological pathways and may take many years to express toxicity.

Figure 33

The ‘healthy-wealthy’ have instinctively worked this out. Can lessons learnt influence policy in developing nations?

Figure 34

Finally ancient meat gluts lead to an adaptive strategy saving lives from periods of safety not hunting and later stabilising weight. This is now maladaptive unless there are alternative strategies to increase exercise levels. Guarding against thrift may not have been as important as starvation may not have been as common as previously suspected.