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Connection between A and various inflammation markers/symptoms
Markers of Innate Immune Function Are Associated with Vitamin A Stores in Men
https://academic.oup.com/jn/article/139/2/377/4750929
Human studies of vitamin A and innate immune function are limited and most investigated cytokine response as an indirect measure of monocyte and macrophage functions. Vitamin A supplementation among patients with common variable immune deficiency with low serum retinol concentrations resulted in increased IL-10 and decreased neopterin (a metabolic product of activated macrophages) and TNFα in plasma
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This result is reminiscent of recent animal studies showing that retinoic acid inhibits the generation of Th17 (which produce IL-17) cells by IL-6 (48,49). These findings suggest that vitamin A may diminish Th17 development in humans, which suggests that high dietary vitamin A could decrease the risk or severity of autoimmune disease but also suggests that Th17-mediated protective responses (e.g. against Klebsiella pneumoniae and Candida albicans) might also be diminished (47). In vivo data from human or mouse studies would be needed to evaluate these possibilities and illustrate the balance between protective and destructive responses mediated by the immune system. Such factors need to be considered when evaluating the impact of nutritional interventions on infectious and chronic diseases in human populations.
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https://pubmed.ncbi.nlm.nih.gov/10692003/
[..]Our findings that vitamin A supplementation in vivo in CVI induced a marked rise in IL-10 levels, a decrease in neopterin levels[..]
Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease
https://www.atherosclerosis-journal.com/article/S0021-9150(08)00330-4/abstract
Neopterin is released from human monocyte-derived macrophages upon stimulation with interferon-γ and is a sensitive indicator for cellular immune activation. Furthermore, reactive oxygen species (ROS) are produced in case of immune activation and inflammation.
In a cross-sectional approach, plasma concentrations of neopterin and of antioxidant compounds and vitamins were compared in 1463 patients investigated by coronary angiography, which were recruited within the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study.
Serum neopterin concentrations were higher in patients with coronary artery disease (CAD; mean ± S.D.: 8.7 ± 7.3 nmol/L) compared to controls (7.4 ± 5.0 nmol/L; Welch's t-test: p < 0.001). Mean concentrations of ascorbic acid ( p < 0.0001), γ-tocopherol ( p < 0.05), lycopene ( p < 0.001), lutein + zeaxanthin ( p < 0.05), α-carotene ( p < 0.05) and β-carotene ( p < 0.05) were lower in CAD than in controls. Neopterin concentrations correlated with CAD-score ( r s = 0.156; p < 0.0001) and inversely with antioxidants lycopene ( r s = −0.277; p < 0.0001) and lutein + zeaxanthin ( r s = −0.175; p < 0.0001) levels and with vitamins ascorbic acid ( r s = −0.207; p < 0.0001) and α-tocopherol ( r s = −0.105; p < 0.0001).
The study demonstrates that higher neopterin production is associated with lower concentrations of antioxidant compounds in patients at risk for atherosclerosis. Results suggest that lower concentrations of antioxidant compounds may relate to higher grade of chronic immune activation in patients.
http://www.neopterin.net/neopterin_e.pdf
Viral infections:
In almost all patients with acute viral infections neopterin levels are increased, this was demonstrated in patients with acute hepatitis A or B [36], patients with Epstein-Barr-virus infection (infectious mononucleosis) and cytomegalovirus (CMV) infection [37] but also in patients with measles.
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Infections with parasites and intracellular bacteria:
Increased neopterin levels are detected in infections with intracellularly living bacteria and parasites such as tuberculosis [57,58], leprosy [59], melioidosis [60], malaria [61,62] and schistosomiasis [63]. In nearly every patient with acute malaria increased neopterin levels are found, moreover even asymptomatic children with low-grade parasitaemia present with increased neopterin levels.
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Lung sarcoidosis:
In the majority of patients with active sarcoidosis neopterin levels are increased correlating to disease activity. Neopterin concentrations in serum and urine and also in the bronchoalveolar lage fluid rise in a direct relationship to the roentgenologic stages [80]. In the follow up of patients clinical improvement is indicated by decreasing, worsening by increasing neopterin levels.
Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
https://pubmed.ncbi.nlm.nih.gov/31449879/
[..]Serum neopterin levels were significantly elevated in patients with MAS[macrophage activation syndrome] and those were correlated positively with disease activity. In conclusion, serum neopterin levels may be used as a promising indicator of disease activity in s-JIA and MAS and for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active-phase s-JIA[..]
Elevated local production of neopterin from alveolar macrophages in patients with internal lung diseases
https://pubmed.ncbi.nlm.nih.gov/8723531/
1. We measured the neopterin level in the supernatant of cultured alveolar macrophages from patients with interstitial lung diseases (ILD patients) as a marker for the activation of alveolar macrophage. 2. In ILD patients, the supernatant neopterin level (40.1 +/- 7.8 pmol/ml) was significantly higher (P < 0.01) than that in control subjects (10.0 +/- 1.6 pmol/ml). 3. We also found that macrophage-colony stimulating factor (M-CSF) and interleukin-2 (IL-2) augmented neopterin production from alveolar macrophage in both ILD patients (51.6 +/- 10.4 and 60.1 +/- 10.8 pmol/ml, respectively, P < 0.01) and control subjects (28.1 +/- 6.0 and 25.7 +/- 4.9 pmol/ml, respectively). 4. These findings suggest that alveolar macrophages produce neopterin by M-CSF or IL-2.
Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses
https://pubmed.ncbi.nlm.nih.gov/10692003/
Results: (i) The majority of CVI patients had decreased vitamin A levels compared with healthy controls, as found in both cross-sectional and longitudinal testing. (ii) Low vitamin A levels were associated with the occurrence of chronic bacterial infections and splenomegaly as well as high neopterin levels. Decreased levels of carrier protein and malabsorption were not observed. (iii) Vitamin A supplementation in patients with low vitamin A levels resulted in increased interleukin-10 (IL-10) and decreased tumour necrosis factor-alpha (TNFalpha) levels, as found in both plasma and monocyte supernatants, possibly favouring anti-inflammatory net effects. (iv) Vitamin A supplementation in vivo also enhanced anti-CD40-stimulated IgG production, serum IgA levels and phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cell (PBMC) proliferation.
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After initiating vitamin A substitution there was a marked increase in plasma vitamin A levels (Fig. 4). Concomitantly, there was a marked rise in plasma levels of IL-10 and a significant decrease in TNFa and neopterin (*Fig. 4).
Simultaneously, vitamin A induced a significant increase in IL-10 release from both LPS stimulated monocytes [795(546±865) vs. 1249(988±1434) and anti-CD3-stimulated T cells, as well as a significant decrease in TNFa levels in unstimulated, but not LPS stimulated (data not shown), monocytes. In contrast, vitamin A did not induce any changes in IL-2 release from anti-CD3-stimulated T cells (data not shown).
Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin
https://pubmed.ncbi.nlm.nih.gov/21975140/
Results: Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms(*), and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection.
Conclusions: The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI(cell-mediated immunity). The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα.
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The correlations between increased IL-1, TNFα, neopterin and PMN-elastase, on the one hand, and specific FF symptoms, such as fatigue, autonomic and neurocognitive symptoms, a flu-like malaise and sadness, on the other, suggest that inflammatory mediators may play an important role in the characteristic symptoms of ME/CFS (Maes, 2009; Maes and Twisk, 2010). In translational models, inflammatory cytokines, such as IL-1 and TNFα, and CMI-related cytokines, such as IFNγ and IL-2, may generate fatigue and somatic symptoms. IL-1 and TNFα play a role in immunologically-mediated fatigue (Cavadini et al., 2007; Sheng et al., 1996). Injection of Corynebacterium parvum antigen to C57BL/6 mice induces fatigue that is accompanied by increased mRNA expression of IL-1 and TNFα (Sheng et al., 1996; 2001). Fatigue associated with recovery from muscle damage is associated with brain macrophage activation and increased IL-1β production (Carmichael et al., 2010). In IL10 deficient mice, LPS administration causes increased peripheral and central inflammation that is associated with increased fatigue (Krzyszton et al., 2008).
* autonomic symptoms:
- dizziness and fainting upon standing up, or orthostatic hypotension
- an inability to alter heart rate with exercise, or exercise intolerance
- sweating abnormalities, which could alternate between sweating too much and not sweating enough
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Study Finds Chronic Fatigue Clues in Overactive Immune Response
https://www.the-rheumatologist.org/article/study-finds-chronic-fatigue-clues-in-overactive-immune-response/
Scientists exploring what may trigger chronic fatigue syndrome (CFS) have found clues in the way some people’s immune systems respond to interferon alpha.
The researchers used the drug to create a model of the disease in people without CFS but with hepatitis C. Many patients who receive interferon alpha experience extreme fatigue during treatment, and some continue to feel chronic fatigue for many months after the drug course is completed.
The researchers measured fatigue and immune system markers in 55 patients with hepatitis C before, during and after treatment with interferon alpha.
Eighteen of the 55 went on to develop a CFS-like illness—and all 18 had a hyperactive immune system before treatment, and a highly overactive response during treatment, they reported Dec. 17 in Psychoneuroendocrinology.
“[This suggests] people who have an exaggerated immune response to a trigger may be more at risk of developing CFS,” Alice Russell of King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN), told reporters at a briefing about the findings.
“For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system,” said Ms. Russell, who led the work.
The condition, as well as research into it, is highly contentious, in part because its possible causes and range of debilitating symptoms are poorly understood.
IoPPN Professor Carmine Pariante stressed that while the study’s main finding is a useful addition to scant scientific knowledge about CFS—also known as myalgic encephalopathy (ME)—it offers few clues on how to treat, cure or prevent it.
“It’s a light in the fog,” he told reporters.
“But a better understanding of the biology underlying the development of CFS is needed to help patients.”
Influence of infection and inflammation on biomarkers of nutritional status with an emphasis on vitamin A and iron
https://www.who.int/nutrition/publications/micronutrients/background_paper4_report_assessment_vitAandIron_status.pdf
Many plasma nutrients are influenced by infection or tissue damage. These effects may be passive and the result of changes in blood volume and capillary permeability. They may also be the direct effect of metabolic alterations that depress or increase the concentration of a nutrient or metabolite in the plasma. Where the nutrient or metabolite is a nutritional biomarker as in the case of plasma retinol, a depression in retinol concentrations will result in an overestimate of vitamin A deficiency. In contrast, where the biomarker is increased due to infection as in the case of plasma ferritin concentrations, inflammation will result in an underestimate of iron deficiency. Infection and tissue damage can be recognized by their clinical effects on the body but, unfortunately, subclinical infection or inflammation can only be recognized by measuring inflammation biomarkers in the blood. It is therefore important to measure biomarkers of inflammation as well as of nutrition in prevalence surveys of nutritional status in apparently healthy people. The most commonly used biomarkers of inflammation are the cytokines and acute phase proteins. Cytokines have very short half-lives but the acute phase proteins remain longer in the blood, and their lifespans can be matched with the changes in plasma retinol and ferritin concentrations. Using meta-analyses to determine the mean effect of inflammation on retinol and ferritin in different stages of the infection cycle, it was possible to determine correction factors that can be used either to modify raw data to remove the effects of inflammation or to modify cut-off values of nutritional risk to use when inflammation is detected in a blood sample.
Plasma nutrients that appear to be influenced by infection and inflammation with an emphasis on vitamin A and iron and where possible a quantitative estimate of the effects.
The plasma concentrations of several important nutritional biomarkers are influenced by inflammation:
- retinol
- 25-hydroxy cholecalciferol (vitamin D)
- iron
- ferritin
- transferrin receptors
- zinc
- carotenoids
- selenium
- pyridoxal phosphate
- α-tocopherol and total lipids
- vitamin C
In addition, concentrations of the transport proteins albumin, retinol-binding protein (RBP) and transferrin are often low in children frequently exposed to infections (15) or trauma (2).
In the above reports the abnormal nutrient biomarker concentration was associated with a raised concentration of the acute phase protein (APP) C-reactive protein (CRP) or other evidence of inflammation.
However, in a cross-sectional survey or single time-point observation there is no way of telling from the nutrient measurement alone whether a low or abnormal value represents poor nutritional status or the effect of inflammation or both.
Children with acute infections display varying degrees of anorexia and it is customary for parents and physicians to accept a limited intake of food during infections. In the nutritionally normal child such transient malnutrition is rapidly compensated for during infection-free intervals but in the child with chronic illness or those exposed to frequent infections with associated anorexia, there is the possible risk of more long-standing malnutrition of clinical significance (15). Thus an apparently healthy child living in a region where there is a high exposure to disease may be genuinely malnourished, but there is also the possibility of subclinical inflammation and that the biomarkers used to measure nutritional status may also be influenced by disease and over- or underestimate the extent of malnutrition.
In the case of vitamin A, there are numerous reports of low retinol concentrations where inflammation is known to be, or is probably, present and where the retinol concentrations normalized when the subjects recovered without any vitamin A intervention (2, 16, 17).
Louw and colleagues’ (2) study is particularly important with respect to vitamin A and is described more fully later. However, these authors also reported longitudinal data on a number of other nutritional biomarkers in 26 men and women with no underlying pathology who underwent uncomplicated orthopaedic surgery. No patient fasted postoperatively for more than 12 hours and intake was considered normal within 48 hours of surgery. The authors also monitored fluid intake postoperatively and found no evidence of overhydration.
Carotenoids
Low plasma carotenoid concentrations in the presence of infection and inflammation have
been described by a number of workers. Smoking is frequently associated with low concentrations of carotenoids (28); this may be partly a dietary effect (29) but in all studies inflammation
is strongly linked to the low concentrations (10–12).
Interaction of inflammation, vitamin A and iron
Serum retinol concentrations have been shown to be positively associated with haemoglobin, haematocrit, serum iron and % transferrin saturation (for references see Strube et al. (32)).
Further work suggested that anaemia did not or only poorly responded to medicinal iron in the
presence of vitamin A deficiency but was ameliorated when vitamin A was given (33, 34).
These data suggested that vitamin A played a role in regulating plasma iron concentrations. However, many studies have shown the vitamin A supplementation can reduce mortality (35) and morbidity, especially in measles (36, 37). Thus vitamin A supplementation may simply reduce inflammation and in so doing promote the release of iron into the circulation (38). Strube et al. (32) carried out 2 × 2 experiments with vitamin A (±) and iron (±). There was no evidence of inflammation but the authors reported lower plasma iron and % transferrin saturation in marginal vitamin A deficiency and an elevation of liver vitamin A in iron deficiency. This study suggested that severe deficiencies of the two nutrients do have an impact on each other but in human studies the deficiencies are unlikely to be as severe, therefore other explanations must be sought. Nevertheless the authors concluded that providing vitamin A may be more likely than treatment with iron alone to improve the iron and vitamin A status of human populations in which both deficiency conditions coexist (32).
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As indicated in the earlier sections of this review, plasma retinol concentrations fall rapidly with the onset of infection or trauma. The extent of the fall will depend on the severity of the trauma. In the case of subclinical inflammation, however, the effects on nutritional status will be, by definition, only mild and there should be little variation between populations or between people exposed to or recovering from different diseases. This, of course, assumes that normal nutritional status will be the same in different populations and it has been generally accepted, as the same cut-offs are applied to plasma retinol concentrations regardless of population (50).
As described above, two APPs, CRP and AGP, are useful to identify those with inflammation and also characterize the temporal aspects of inflammation. We identified 15 studies with data on retinol and one or more APPs. Six of these had sufficient data in all subgroups on CRP and AGP and an additional study included ACT and AGP. ACT has similar characteristics to CRP (47) but all analyses were run with and without the latter study to ensure comparability of data. To define inflammation we used the cut-off values of >5 mg/L for CRP, >1 g/L for AGP, >0.6 g/L for ACT and >5 mg/L for SAA and then allocated the apparently healthy subjects in each study into four groups: reference (those with no raised APP), incubating (those with a raised CRP only), early convalescence (those with raised CRP and AGP) and late convalescence (those with a raised AGP only).
Seems like ATRA enhances response to toxins(LPS = endotoxin):
All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage
https://pubmed.ncbi.nlm.nih.gov/32630207/
All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1β, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1β following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1β via the regulation of signal transduction pathways, like NF-κB, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.
All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection
https://pubmed.ncbi.nlm.nih.gov/29852080/
Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy.
Inhalable poly(lactic-co-glycolic acid) (PLGA) microparticles encapsulating all-trans-Retinoic acid (ATRA) as a host-directed, adjunctive treatment for Mycobacterium tuberculosis infection
https://pubmed.ncbi.nlm.nih.gov/30385419/
Ending the tuberculosis (TB) epidemic by 2030 was recently listed in the United Nations (UN) Sustainable Development Goals alongside HIV/AIDS and malaria as it continues to be a major cause of death worldwide. With a significant proportion of TB cases caused by resistant strains of Mycobacterium tuberculosis (Mtb), there is an urgent need to develop new and innovative approaches to treatment. Since 1989, researchers have been assessing the anti-bacterial effects of the active metabolite of vitamin A, all trans-Retinoic acid (ATRA) solution, in Mtb models. More recently the antibacterial effect of ATRA has been shown to regulate the immune response to infection via critical gene expression, monocyte activation and the induction of autophagy leading to its application as a host-directed therapy (HDT). Inhalation is an attractive route for targeted treatment of TB, and therefore we have developed ATRA-loaded microparticles (ATRA-MP) within the inhalable size range (2.07 ± 0.5 µm) offering targeted delivery of the encapsulated cargo (70.5 ± 2.3%) to the site of action within the alveolar macrophage, which was confirmed by confocal microscopy. Efficient cellular delivery of ATRA was followed by a reduction in Mtb growth (H37Ra) in THP-1 derived macrophages evaluated by both the BACT/ALERT® system and enumeration of colony forming units (CFU). The antibacterial effect of ATRA-MP treatment was further assessed in BALB/c mice infected with the virulent strain of Mtb (H37Rv). ATRA-MP treatments significantly decreased the bacterial burden in the lungs alongside a reduction in pulmonary pathology following just three doses administered intratracheally. The immunomodulatory effects of targeted ATRA treatment in the lungs indicate a distinct yet effective mechanism of action amongst the formulations. This is the first study to-date of a controlled release ATRA treatment for TB suitable for inhalation that offers improved targeting of a HDT, retains antibacterial efficacy and improves pulmonary pathology compared to ATRA solution.
I can't read study-ese, as usual just begging for personal overviews en englais...
The key point is if there is an endotoxin based inflammation currently running over the body, ATRA will additionally boost pro inflammatory cytokines (so extra fatigue, etc) - maybe this could explain why some people are getting a symptomatic relief with A withdrawal.
Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: Effects of age, duration of illness and the translocation of LPS from gram-negative bacteria:
https://www.researchgate.net/publication/23709068_Normalization_of_leaky_gut_in_chronic_fatigue_syndrome_CFS_is_accompanied_by_a_clinical_improvement_Effects_of_age_duration_of_illness_and_the_translocation_of_LPS_from_gram-negative_bacteria
Gut inflammation in chronic fatigue syndrome:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964729/
...
https://www.healthrising.org/blog/2019/12/07/antivirals-gut-gwi-chronic-fatigue-syndrome-treatment/
In 2017, Chatterjee and his team showed that exposing GWI mice to chemicals and stress altered their gut microflora and caused the junctures of their gut lining to loosen – producing a “leaky” gut. As their gut bacteria spilled into their blood stream, it triggered a condition called “systemic endotoxemia”. The same leaky gut problem has been found in chronic fatigue syndrome (ME/CFS) and fibromyalgia.
...
As for vit A as an antibiotic - as a net effect it could bring more harm than good through toxicity(also resistance and immune system inhibition) - the body is capable of emitting many different lines of antibiotics though vitamin D pathways (cathelicidins, beta-defensins), so maybe with A withdrawal immune system boosts(or partly reverts to) production of its own antimicrobial peptides.
(Vitamin A metabolites appear to be VDR antagonists or weak VDR agonists preventing more robust VDR activation via calcitriol and thus more complete induction of antimicrobial peptides)
What Vitamin A, Glucocorticoids and Coffee have in common? Lets see...
https://www.nutraingredients.com/Article/2006/10/06/More-support-for-vitamin-A-against-inflammation
Vitamin A supplements could reduce the levels of a marker for inflammation by 30 per cent, says a randomized intervention study with Mexican children, a result that adds to the benefits of the vitamin, particularly among the young. The vitamin is thought to aid the immune system in fighting certain infections and inflammations, such as measles and infections caused by some food-poisoning organisms.
Indeed, the impact of vitamin A supplements on diarrhoea in children is reported to be due to an effect on the immune response in the intestine. The body's response to a gastrointestinal infection by organisms such as E. coli is inflammation, which reduces the colon's ability to absorb water and results in diarrhoea. In the developing world, diarrhoea is said to b the most common cause of death of young children, with over 1.5 million deaths annually.
The new science, published in the current issue of the Journal of Nutrition (Vol. 136, pp. 2600-2605), looked at the effect of vitamin A supplements on levels of the molecule, monocyte chemoattractant protein-1 (MCP-1), which is associated with a state of increased inflammation and is also involved in the pathogen-specific mucosal immune response.
The researchers, from ten different universities and hospitals in the US and Mexico including Harvard, the University of Texas, and the Universidad Autonoma de Queretero, recruited 127 Mexican children between the ages of 5 and 15 months and randomly assigned them to receive either a vitamin A supplement or a placebo at two month intervals.
The age of the child determined the dose of the supplement, with children under one year of age receiving bi-monthly doses of 20,000 international units (IU) of retinol, and children over one receiving 45,000 IU.
Stool samples were collected during the summer months were analysed for MCP-1 concentrations as well as gastrointestinal pathogens and symptoms of diarrhoea.
"Overall, children who received the vitamin A supplement had reduced fecal concentrations of MCP-1 compared with children in the placebo group (median pg/mg protein: 284.88 versus 403.39, [respectively])," reported lead author Kurt Long from Harvard School of Public Health.
Reduce levels of MCP-1 is associated with less inflammation, which in term suggests less diarrhoea.
The supplementation also impacted on MCP-1 levels in children with infections, like the bacteria Escherichia coli or the human roundworm Ascaris lumbricoides. For children infected with E. coli and given the vitamin A supplement, MCP-1 levels were 62 per cent lower than the placebo group, while children infected with A. lumbricoides had MCP-1 levels 38 per cent lower after vitamin A supplementation than placebo.
"These findings suggest that vitamin A has an anti-inflammatory effect in the gastrointestinal tract by reducing MCP-1 concentrations," concluded the researchers.
Further research is needed, particularly in other populations and age groups, as well as detailed mechanistic studies to find how the vitamin A impacts on MCP-1 levels.
Monocyte chemoattractant protein 1(MCP-1) contributes to an adequate immune response in influenza pneumonia
https://pubmed.ncbi.nlm.nih.gov/17827068/
Monocyte chemoattractant protein 1 (MCP-1) and its receptor CCR2 have been shown to play an import role in leukocyte recruitment to sites of infection and inflammation. To investigate the role of MCP-1 during infection with influenza we inoculated wild-type (WT) and MCP-1 knockout (KO) mice with a non-lethal dose of a mouse adapted strain of influenza A. Influenza infection of WT mice resulted in a profound increase in pulmonary MCP-1 levels. MCP-1 KO mice had enhanced weight loss and did not fully regain their body weight during the 14-day observation period. In addition, MCP-1 knockout mice demonstrated elevated viral loads 8 days after infection, which was accompanied by reduced leukocyte recruitment into the infected lungs, primarily caused by a diminished influx of macrophages and granulocytes. Moreover, pulmonary levels of IgA were reduced in MCP-1 KO mice. The pulmonary concentrations of tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein 2 and interferon-gamma were higher in MCP-1 KO mice. This study shows that MCP-1 contributes to an adequate protective immune response against influenza infection in mice.
IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19
https://molmed.biomedcentral.com/articles/10.1186/s10020-020-00230-x
The serum IP-10 and MCP-1 level in critically ill patients was significantly higher than that in severe patients (P < 0.001).
More Than Suppression: Glucocorticoid Action on Monocytes and Macrophages
https://www.frontiersin.org/articles/10.3389/fimmu.2019.02028/full
In fact, Glucocorticoids inhibit the transcription of several pro-inflammatory cytokines produced by human monocytes and macrophages including IL-1β, IL-6, IL-12, TNFα, or GM-CSF and down-regulate the expression of chemokines like IL-8, RANTES, and MCP-1
+ Some bonus material:
https://www.biorxiv.org/content/10.1101/241539v1.full
TNF and PPARG were suppressed even with the lowest caffeine dose tested, which corresponds to the serum concentration of caffeine after administration of one cup of coffee.
Cytokine levels of IL-8, MIP-1β, IL-6, IFN-γ, GM-CSF, TNF, IL-2, IL-4, MCP-1, and IL-10 were decreased significantly with caffeine treatment.
https://pubmed.ncbi.nlm.nih.gov/29678503/
Chemokines are crucial for regulating leukocyte recruitment to the inflamed tissue therefore play key roles in the development and progression of autoimmune diseases. In our study we showed that caffeine treatment significantly lowered chemokine levels such as MCP-1 and IL-8 released by PBMCs. Serum levels of MCP-1 (also known as CCL2) were found to be elevated significantly in patients with lupus [26-29], systemic sclerosis (SSc) [30, 31], or rheumatoid arthritis (RA) [32-34] compared to healthy controls. In SSc, higher serum levels of MCP-1 have also been reported in patients with pulmonary fibrosis
Effect of retinoic acid on human adrenal corticosteroid synthesis
https://doi.org/10.1016/j.lfs.2016.03.023
5. Conclusions
Our findings indicate that retinoic acid exerts a stimulatory effect on cortisol synthesis and release by the normal adrenal. Concurrently, retinoic acid markedly reduces expression of the adrenal ACTH receptor. These findings suggest that the effect of retinoic acid in Cushing's disease is the result of the interplay between its action at pituitary and at adrenal level.
All-trans retinoic acid-induced hypothalamus–pituitary–adrenal hyperactivity involves glucocorticoid receptor dysregulation
https://doi.org/10.1038/tp.2013.98
Taken together, we propose that RA activates the HPA axis through (i) an increased hypothalamic CRH production, mediated via RAR-α transcriptional activation; (ii) a deficient negative feedback at the level of hypothalamic GR expression, which implicates changes in GR sensitivity to underlie RA-induced hyperactivity of the HPA axis. In humans, such maladaptive changes in the HPA axis after excessive RA treatment or vitamin A consumption may set the stage for stress-related neuropsychiatric disorders. The rapid reversal by mifepristone may hence be of interest for the development of therapeutic options for HPA-related aspects of depression.
Note the below (if you are not already seriously suffering from septic condition / toxemia), primary suggests that vit A is highly anti-metabolic (slows metabolism), so if you'll find out that you've started to suddenly lose fat/protein mass on a low A diet that could be actually a very good sign to raise calories(carbs).
Also it suggests that high level of D is anti-metabolic too... probably there is a sweet spot for D25 to be around 15..25ng, at most 30ng if you are good at avoiding overeating "healthy" foods(like vegs nuts & fruits) enough.
The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements
https://pubmed.ncbi.nlm.nih.gov/25701092/
Background: Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements.
The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 μg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant.
Conclusions: 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.
@rockarolla when you speak of vitamin D concentrations, you are speaking of blood level, not liver reserves? I spoke to a naturopath, the one that put me onto bile salts (lost another inch off my waist in the past two weeks) and he said the liver can store a LOT of vitamin D, and you can take massive doses before it shows up in the blood. He considered 10,000 IU a small dose. Grant got benefits from detoxing vitamin A, but if he takes even a little bit of vitamin A, the symptoms come back ferociously. What will it take to fortify the body so it can handle future mistakes with vitamin A? Is it possible having large stores of vitamin D will "block" vitamin A in the future? I know some people here have talked about having adverse reactions from adding vitamin D. Could it be one of those things where there is an initial hump, and once you are over it, things get better? A nurse once told me that in old folks homes, they give the residents bottles of 4000 IU vitamin D, because it reduces the number of hip fractures they get. Also the nurse told me FIRST the bone breaks, then they fall. The fall isn't the cause of the fracture, the fracture causes the fall.
If vitamin A is a deliberate poisoning, then those sites on the web saying they suffered from following Grant Genereux protocol would make sense.
Some of these thoughts are driven by a brief experience I had living on the beach in Mexico, away from the Canadian winter. I am back in Mexico, trying to recreate it. So far the results are encouraging. More to follow in the coming days.
Quote from Moebius on July 17, 2021, 9:10 am@rockarolla when you speak of vitamin D concentrations, you are speaking of blood level, not liver reserves? I spoke to a naturopath, the one that put me onto bile salts (lost another inch off my waist in the past two weeks) and he said the liver can store a LOT of vitamin D, and you can take massive doses before it shows up in the blood. He considered 10,000 IU a small dose. Grant got benefits from detoxing vitamin A, but if he takes even a little bit of vitamin A, the symptoms come back ferociously. What will it take to fortify the body so it can handle future mistakes with vitamin A? Is it possible having large stores of vitamin D will "block" vitamin A in the future? I know some people here have talked about having adverse reactions from adding vitamin D. Could it be one of those things where there is an initial hump, and once you are over it, things get better? A nurse once told me that in old folks homes, they give the residents bottles of 4000 IU vitamin D, because it reduces the number of hip fractures they get. Also the nurse told me FIRST the bone breaks, then they fall. The fall isn't the cause of the fracture, the fracture causes the fall.
If vitamin A is a deliberate poisoning, then those sites on the web saying they suffered from following Grant Genereux protocol would make sense.
Some of these thoughts are driven by a brief experience I had living on the beach in Mexico, away from the Canadian winter. I am back in Mexico, trying to recreate it. So far the results are encouraging. More to follow in the coming days.
Blood levels since this is what checked in labs..
I think the cause of less bone breaks from more vitamin D is due to anti biological effects of high levels of D25 over D1.25 i.e. too high D25 paradoxically locks spending of itself i.e. conversion from D25 to D1.25 and this in turn slows leeching calcium from the bones. For those ultra low D25(if tolerable) could be actually better than high level of this pre hormone since then there will be less VDRs to bind to and less pre hormone to be converted to D1.25 and activate VDRs...