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DiscussionLet's talk about it: The science of it"Vitamin" A supplementation may c …

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"Vitamin" A supplementation may cause immune system to 'forget' past infections.

#1 · January 24, 2021, 11:13 am

Quote from rockarolla on January 24, 2021, 11:13 am
Vitamin A supplementation may cause immune system to 'forget' past infections.
https://www.sciencedaily.com/releases/2015/06/150630121406.htm

Although vitamin A supplementation can have profound health benefits when someone is deficient, new evidence is emerging to show that vitamin A supplementation above and beyond normal levels may have negative health consequences. A new research report published in the July 2015 issue of the Journal of Leukocyte Biology may help to explain why too much vitamin A can be harmful. Too much vitamin A shuts down the body's trained immunity, opening the door to infections to which we would otherwise be immune. This study adds to the arguments that vitamin A supplementation should only be done with clear biological and clinical arguments. Furthermore, it also suggests that low vitamin A concentrations in certain situations may even be "normal."

"This study helps to explain the mechanisms of anti-inflammatory effects of vitamin A and by doing so opens the door to identifying novel ways to modulate the immune response and restore its function in situations in which it is dysregulated," said Mihai G. Netea, M.D., Ph.D., a researcher involved in the work from the Department of Internal Medicine at Radboud University Medical Center in Nijmegen, The Netherlands.

To make this discovery, Netea and colleagues stimulated immune cells, isolated from volunteers, with Vitamin A and saw that the cells produced fewer cytokines, key proteins that help ward off microbes, upon stimulation with various mitogens and antigens.

Furthermore, the cells were also stimulated with various microbial structures, which resulted in long-term activation or training of the cells. When the same experiments were performed in the presence of vitamin A, the microbial structures were no longer able to activate the immune cells.

"The interface of nutrition and immunity is an area of considerable importance, especially in an age when dietary supplements and vitamins are quite common," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "These new findings shed light on an importance balance in vitamin A levels for optimal immunity. These studies have implications for how we think about daily vitamins, but also for the developing world, where improving diet could have dramatic benefits on how the immune system is trained to respond to different infections."

Vitamin A supplementation may cause immune system to 'forget' past infections.
https://www.sciencedaily.com/releases/2015/06/150630121406.htm

Although vitamin A supplementation can have profound health benefits when someone is deficient, new evidence is emerging to show that vitamin A supplementation above and beyond normal levels may have negative health consequences. A new research report published in the July 2015 issue of the Journal of Leukocyte Biology may help to explain why too much vitamin A can be harmful. Too much vitamin A shuts down the body's trained immunity, opening the door to infections to which we would otherwise be immune. This study adds to the arguments that vitamin A supplementation should only be done with clear biological and clinical arguments. Furthermore, it also suggests that low vitamin A concentrations in certain situations may even be "normal."

"This study helps to explain the mechanisms of anti-inflammatory effects of vitamin A and by doing so opens the door to identifying novel ways to modulate the immune response and restore its function in situations in which it is dysregulated," said Mihai G. Netea, M.D., Ph.D., a researcher involved in the work from the Department of Internal Medicine at Radboud University Medical Center in Nijmegen, The Netherlands.

To make this discovery, Netea and colleagues stimulated immune cells, isolated from volunteers, with Vitamin A and saw that the cells produced fewer cytokines, key proteins that help ward off microbes, upon stimulation with various mitogens and antigens.

Furthermore, the cells were also stimulated with various microbial structures, which resulted in long-term activation or training of the cells. When the same experiments were performed in the presence of vitamin A, the microbial structures were no longer able to activate the immune cells.

"The interface of nutrition and immunity is an area of considerable importance, especially in an age when dietary supplements and vitamins are quite common," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "These new findings shed light on an importance balance in vitamin A levels for optimal immunity. These studies have implications for how we think about daily vitamins, but also for the developing world, where improving diet could have dramatic benefits on how the immune system is trained to respond to different infections."

tim, lil chick and 2 other users have reacted to this post.

#2 · January 24, 2021, 11:13 am

An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality
https://academic.oup.com/ije/article/44/3/906/633272?login=true
..
Vitamin A is known to affect the Th1/Th2 balance and, in addition, recent evidence suggests that vitamin A may also induce epigenetic changes leading to down-regulation of the innate immune response. Thus VAS[vitamin A supplementation] protects against VAD[Vitamin A deficiency] but has also important and long-lasting immunological effects, and the effect of providing VAS may vary depending on the state of the immune system.
..
The existing evidence supports that besides preventing vitamin A deficiency, vitamin A supplementation also has long-lasting immunological effects; and, worryingly, the effect of vitamin A supplementation may be harmful in some subgroups.

tim, Ourania and 2 other users have reacted to this post.

#3 · January 26, 2021, 5:43 pm

It's an enigma wrapped in a mystery wrapped in an orange pita.

ggenereux, salt and 3 other users have reacted to this post.

#4 · February 12, 2021, 8:09 am

Quote from rockarolla on February 12, 2021, 8:09 am
Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes
https://pubmed.ncbi.nlm.nih.gov/25934925/

Because incubation of monocytes for 24 h with ATRA has an effect on the cytokine production 6 d later and because ATRA is known to modulate epigenetic marks in other cells [26–28], it is likely that epigenetic mechanisms have a role in the long-lasting effect of ATRA.

The epigenetic reprogramming, induced by ATRA, which leads to a decreased cytokine production as shown in this study, may account, at least partially, for the contrasting effects on mortality reported in epidemiologic studies of VAS [11]. BCG vaccination has the opposite immunologic effects that ATRA has [15] and is associated with strong reductions in all causes of mortality [12, 13]. Our observations support the hypothesis that BCG vaccination and VAS interact [39]. It is still speculative to directly link our in vitro ATRA experiments with in vivo VAS, but it could be hypothesized that VAS also leads to long-term downregulation of cytokine production, and—depending on the situation—that could have harmful or beneficial effects.

Thus, our findings could help explain why VAS[Vitamin A Supplementation] may increase overall mortality in some situations. Nevertheless, to assess the long-term effects of VAS on the innate immune system, a study should be performed with immunologic endpoints, such as ex vivo monocyte stimulations and determination of epigenetic changes at different time points before and after VAS. In conclusion, short-term exposure of human monocytes to ATRA results in long-term immune inhibition characterized by lower cytokine responses upon stimulation with a second stimulus. These immunomodulatory effects of ATRA are induced by a decreased H3K4me3 and an activation of the histone methyltransferase SUV39H2, which increases H3K9me3 at the promoter sites of several cytokines, leading to epigenetic reprogramming and inhibition of gene transcription.

--------

So basically Vit A kills innate immune system? Plus short term exposure leading to long term consequences as a "bonus".

Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes
https://pubmed.ncbi.nlm.nih.gov/25934925/

Because incubation of monocytes for 24 h with ATRA has an effect on the cytokine production 6 d later and because ATRA is known to modulate epigenetic marks in other cells [26–28], it is likely that epigenetic mechanisms have a role in the long-lasting effect of ATRA.

The epigenetic reprogramming, induced by ATRA, which leads to a decreased cytokine production as shown in this study, may account, at least partially, for the contrasting effects on mortality reported in epidemiologic studies of VAS [11]. BCG vaccination has the opposite immunologic effects that ATRA has [15] and is associated with strong reductions in all causes of mortality [12, 13]. Our observations support the hypothesis that BCG vaccination and VAS interact [39]. It is still speculative to directly link our in vitro ATRA experiments with in vivo VAS, but it could be hypothesized that VAS also leads to long-term downregulation of cytokine production, and—depending on the situation—that could have harmful or beneficial effects.

Thus, our findings could help explain why VAS[Vitamin A Supplementation] may increase overall mortality in some situations. Nevertheless, to assess the long-term effects of VAS on the innate immune system, a study should be performed with immunologic endpoints, such as ex vivo monocyte stimulations and determination of epigenetic changes at different time points before and after VAS. In conclusion, short-term exposure of human monocytes to ATRA results in long-term immune inhibition characterized by lower cytokine responses upon stimulation with a second stimulus. These immunomodulatory effects of ATRA are induced by a decreased H3K4me3 and an activation of the histone methyltransferase SUV39H2, which increases H3K9me3 at the promoter sites of several cytokines, leading to epigenetic reprogramming and inhibition of gene transcription.

--------

So basically Vit A kills innate immune system? Plus short term exposure leading to long term consequences as a "bonus".

Ourania has reacted to this post.

#5 · March 2, 2021, 3:56 pm

Quote from rockarolla on March 2, 2021, 3:56 pm
OMG, vitA could be that bad:

https://en.wikipedia.org/wiki/Macrophage_colony-stimulating_factor
The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types

Retinoic Acid Inhibits Monocyte to Macrophage Survival and Differentiation
https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing monocytes for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells.

Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF.

Cytokine secretion is modulated by RA.

Besides the morphology and antigen-expression, the functional activity of MO[human blood monocytes] changes during the differentiation into MAC[monocytes-derived macrophages]. Especially the lipopolysaccharide (LPS)-induced cytokine production can serve as a maturation marker for MO-derived MAC. We therefore analyzed whether monocytes cultured with or without RA would differ in their ability to produce IL-6 and TNF-α after LPS stimulation.

Control MAC cultured in the presence of serum showed a normal MAC LPS response, ie, a high secretion of TNF-α and a low secretion of IL-6.

However, MAC derived from RA-containing cultures showed an inverse pattern of cytokine secretion after LPS stimulation (Fig 7) that is a typical feature of freshly isolated MO, indicating that MO[human blood monocytes] do not differentiate into functionally normal MAC[monocytes-derived macrophages] in the presence of RA.

^^^ monocytes-derived macrophages cytokine pattern is modulated by Retinoic Acid.

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068229/

Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus. M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation.

https://www.jstor.org/stable/4460372?seq=1

Management of fungal infections is a major medical problem. The risk of developing a fungal infection is higher for patients who are undergoing dose-intensive therapy, are immunocompromised, have neutropenia, are receiving prophylactic antibiotics, have other infections, have invasive catheters, or have a history of severe trauma or burns. Survival is decreased among patients who develop fungal infection in these situations. In view of the high morbidity and mortality associated with fungal infections in transplant recipients, cytokines that enhance cell function, such as macrophage colony-stimulating factor (M-CSF), have been investigated. M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages. Animal models and clinical data suggest efficacy of M-CSF in controlling fungal infection.

OMG, vitA could be that bad:

https://en.wikipedia.org/wiki/Macrophage_colony-stimulating_factor
The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types

Retinoic Acid Inhibits Monocyte to Macrophage Survival and Differentiation
https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing monocytes for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells.

Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF.

Cytokine secretion is modulated by RA.

Besides the morphology and antigen-expression, the functional activity of MO[human blood monocytes] changes during the differentiation into MAC[monocytes-derived macrophages]. Especially the lipopolysaccharide (LPS)-induced cytokine production can serve as a maturation marker for MO-derived MAC. We therefore analyzed whether monocytes cultured with or without RA would differ in their ability to produce IL-6 and TNF-α after LPS stimulation.

Control MAC cultured in the presence of serum showed a normal MAC LPS response, ie, a high secretion of TNF-α and a low secretion of IL-6.

However, MAC derived from RA-containing cultures showed an inverse pattern of cytokine secretion after LPS stimulation (Fig 7) that is a typical feature of freshly isolated MO, indicating that MO[human blood monocytes] do not differentiate into functionally normal MAC[monocytes-derived macrophages] in the presence of RA.

^^^ monocytes-derived macrophages cytokine pattern is modulated by Retinoic Acid.

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068229/

Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus. M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation.

https://www.jstor.org/stable/4460372?seq=1

Management of fungal infections is a major medical problem. The risk of developing a fungal infection is higher for patients who are undergoing dose-intensive therapy, are immunocompromised, have neutropenia, are receiving prophylactic antibiotics, have other infections, have invasive catheters, or have a history of severe trauma or burns. Survival is decreased among patients who develop fungal infection in these situations. In view of the high morbidity and mortality associated with fungal infections in transplant recipients, cytokines that enhance cell function, such as macrophage colony-stimulating factor (M-CSF), have been investigated. M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages. Animal models and clinical data suggest efficacy of M-CSF in controlling fungal infection.

Ourania has reacted to this post.

#6 · March 2, 2021, 6:03 pm

Thank you @rockarolla. I hope you are doing well.

rockarolla has reacted to this post.

#7 · May 25, 2021, 2:36 pm

Quote from rockarolla on May 25, 2021, 2:36 pm
Effects of Vitamin A Supplementation on Immune Responses and Correlation with Clinical Outcomes
https://cmr.asm.org/content/18/3/446
A few supplementation studies with humans included indirect measures of monocyte and macrophage function, mostly related to cytokine secretion. In a non-placebo-controlled, nonrandomized study of six patients with common variable immunodeficiency who had low serum retinol concentrations, supplementation with vitamin A at 6,500 IU/day for 6 months resulted in decreased concentrations of TNF-α compared to their baseline levels (3). Preliminary results from a trial with Mexican infants showed that the concentration of IL-6 in stool was lower in those who received vitamin A, but this effect appeared to be limited to the period following an infection with enterotoxigenic Escherichia coli (82). Vitamin A andβ -carotene supplementation to HIV-infected pregnant women had no effect on the concentration of IL-1β in cervicovaginal secretions (40) or on urinary neopterin excretion, an indicator of macrophage activation (115), in studies from Tanzania and South Africa, respectively.

The trials described above suggest that supplementation with preformed vitamin A might down-regulate the secretion of specific proinflammatory cytokines (e.g., TNF-α and IL-6) by macrophages, but seemingly only in response to infections by particular pathogens. Additional, more robust data from human trials would be needed to support this potential mechanism.

In light of the results from several in vitro experiments and animal studies, it has been proposed that vitamin A deficiency induces a shift in the immune response towards Th1-cell-mediated activity whereas vitamin A supplementation would tend to boost Th2-type responses, as recently reviewed by Stephensen (145). Results from trials that examined the effect of vitamin A on clinical outcomes from infections that elicit either a Th1 or a Th2 response suggest that the immunological mechanisms through which vitamin A exerts an effect are pathogen specific and may involve aspects other than the Th1/Th2 balance. Future studies are warranted to assess the role of vitamin A supplementation in humans on differential Th1/Th2 responses according to the baseline vitamin A status of the population and the specific pathogens causing infection.

More support for vitamin A against inflammation
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.

Vitamin A deficiency (VAD) is a public health problem in more than 50 per cent of all countries, especially in Africa and South-East Asia, according to the World Health Organisation, and causes blindness in up to 500,000 children each year. The human body converts beta-carotene in the diet into vitamin A.

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.

Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders
https://ucdavis.pure.elsevier.com/en/publications/associations-of-impaired-behaviors-with-elevated-plasma-chemokine
Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p < 0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance.

Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study
https://pubmed.ncbi.nlm.nih.gov/29122693/

A weekly vitamin A supplementary program alleviates social impairment in Chinese children with autism spectrum disorders and vitamin A deficiency
https://www.nature.com/articles/s41430-020-00827-9

Effects of Vitamin A Supplementation on Immune Responses and Correlation with Clinical Outcomes
https://cmr.asm.org/content/18/3/446
A few supplementation studies with humans included indirect measures of monocyte and macrophage function, mostly related to cytokine secretion. In a non-placebo-controlled, nonrandomized study of six patients with common variable immunodeficiency who had low serum retinol concentrations, supplementation with vitamin A at 6,500 IU/day for 6 months resulted in decreased concentrations of TNF-α compared to their baseline levels (3). Preliminary results from a trial with Mexican infants showed that the concentration of IL-6 in stool was lower in those who received vitamin A, but this effect appeared to be limited to the period following an infection with enterotoxigenic Escherichia coli (82). Vitamin A andβ -carotene supplementation to HIV-infected pregnant women had no effect on the concentration of IL-1β in cervicovaginal secretions (40) or on urinary neopterin excretion, an indicator of macrophage activation (115), in studies from Tanzania and South Africa, respectively.

The trials described above suggest that supplementation with preformed vitamin A might down-regulate the secretion of specific proinflammatory cytokines (e.g., TNF-α and IL-6) by macrophages, but seemingly only in response to infections by particular pathogens. Additional, more robust data from human trials would be needed to support this potential mechanism.

In light of the results from several in vitro experiments and animal studies, it has been proposed that vitamin A deficiency induces a shift in the immune response towards Th1-cell-mediated activity whereas vitamin A supplementation would tend to boost Th2-type responses, as recently reviewed by Stephensen (145). Results from trials that examined the effect of vitamin A on clinical outcomes from infections that elicit either a Th1 or a Th2 response suggest that the immunological mechanisms through which vitamin A exerts an effect are pathogen specific and may involve aspects other than the Th1/Th2 balance. Future studies are warranted to assess the role of vitamin A supplementation in humans on differential Th1/Th2 responses according to the baseline vitamin A status of the population and the specific pathogens causing infection.

More support for vitamin A against inflammation
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.

Vitamin A deficiency (VAD) is a public health problem in more than 50 per cent of all countries, especially in Africa and South-East Asia, according to the World Health Organisation, and causes blindness in up to 500,000 children each year. The human body converts beta-carotene in the diet into vitamin A.

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.

Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders
https://ucdavis.pure.elsevier.com/en/publications/associations-of-impaired-behaviors-with-elevated-plasma-chemokine
Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p < 0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance.

Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study
https://pubmed.ncbi.nlm.nih.gov/29122693/

A weekly vitamin A supplementary program alleviates social impairment in Chinese children with autism spectrum disorders and vitamin A deficiency
https://www.nature.com/articles/s41430-020-00827-9

Jenny has reacted to this post.

#8 · May 26, 2021, 3:56 am

Interesting. Many in the autism treatment community think that vA helps autistic symptoms. I obviously think this is a mistake as I suspect that vA toxicity is the (or a) cause of autism (see Anthony Mawson papers). I have commented on a number of autism pages but have been met with negatively. However, I’ve banned (very politely) my nephews’ practitioner giving them vA. I think it is a huge mistake. Short term gain, long term pain.

rockarolla has reacted to this post.

#9 · May 26, 2021, 4:43 am

Quote from Jenny on May 26, 2021, 3:56 am

Interesting. Many in the autism treatment community think that vA helps autistic symptoms. I obviously think this is a mistake as I suspect that vA toxicity is the (or a) cause of autism (see Anthony Mawson papers). I have commented on a number of autism pages but have been met with negatively. However, I’ve banned (very politely) my nephews’ practitioner giving them vA. I think it is a huge mistake. Short term gain, long term pain.

Treating autism(basically central nervous system & brain inflammation) with ordinary pharma drugs/vitamins brings only temporary remission followed by relapse.

Jenny has reacted to this post.

#10 · June 22, 2021, 7:28 am

Quote from rockarolla on June 22, 2021, 7:28 am

Quote from rockarolla on March 2, 2021, 3:56 pm

OMG, vitA could be that bad:

https://en.wikipedia.org/wiki/Macrophage_colony-stimulating_factor
The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types

Retinoic Acid Inhibits Monocyte to Macrophage Survival and Differentiation
https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing monocytes for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells.

Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF.

Cytokine secretion is modulated by RA.

Besides the morphology and antigen-expression, the functional activity of MO[human blood monocytes] changes during the differentiation into MAC[monocytes-derived macrophages]. Especially the lipopolysaccharide (LPS)-induced cytokine production can serve as a maturation marker for MO-derived MAC. We therefore analyzed whether monocytes cultured with or without RA would differ in their ability to produce IL-6 and TNF-α after LPS stimulation.

Control MAC cultured in the presence of serum showed a normal MAC LPS response, ie, a high secretion of TNF-α and a low secretion of IL-6.

However, MAC derived from RA-containing cultures showed an inverse pattern of cytokine secretion after LPS stimulation (Fig 7) that is a typical feature of freshly isolated MO, indicating that MO[human blood monocytes] do not differentiate into functionally normal MAC[monocytes-derived macrophages] in the presence of RA.

^^^ monocytes-derived macrophages cytokine pattern is modulated by Retinoic Acid.

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068229/

Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus. M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation.

https://www.jstor.org/stable/4460372?seq=1

Management of fungal infections is a major medical problem. The risk of developing a fungal infection is higher for patients who are undergoing dose-intensive therapy, are immunocompromised, have neutropenia, are receiving prophylactic antibiotics, have other infections, have invasive catheters, or have a history of severe trauma or burns. Survival is decreased among patients who develop fungal infection in these situations. In view of the high morbidity and mortality associated with fungal infections in transplant recipients, cytokines that enhance cell function, such as macrophage colony-stimulating factor (M-CSF), have been investigated. M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages. Animal models and clinical data suggest efficacy of M-CSF in controlling fungal infection.

https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

The effect of RA on MO(blood monocytes)/MAC(monocytes-derived macrophages) differentiation has also been studied by others, including the differentiation of the human monoblastic cell line U937 and the differentiation of osteoclasts in chicken. Both studies found an antagonistic effect of 1,25-dihydroxyvitamin D3[1,25(OH)2D3] and RA on the differentiation process, with RA being dominant over 1,25(OH)2D3.

1,25(OH)2D3, which is a potent inducer of MO differentiation, could also not overcome the differentiation block by RA in our system (data not shown).

+++

Identification of 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol in human plasma after liver consumption
https://pubmed.ncbi.nlm.nih.gov/8809215/

Vitamin A is a well-established teratogen in several animal species. Case reports as well as a recent epidemiological study suggest that vitamin A intake in excess of 25,000 or 10,000 IU respectively, can result in retinoid-specific defects in the offspring. A single meal of liver contains, on the average, a 10- to 20-fold higher amount of vitamin A than what is already suspected to be teratogenic. To evaluate the risk of liver consumption during pregnancy, we have studied levels of vitamin A and a number of potentially active retinoid metabolites in plasma of ten healthy male volunteers following consumption of fried turkey liver (2 g raw weight/kg body weight). HPLC, UV spectroscopy and mass spectrometry were used for identification and quantitation of retinoids in plasma. As shown previously, vitamin A intake via liver consumption resulted in greatly increased plasma levels of 13-cis-retinoic acid (13-cis-RA) and 13-cis-4-oxo-RA, and low levels of all-trans-RA and all-trans-4-oxo-RA. In our present investigation 9-cis-RA, 9,13-di-cis-RA, and 14-hydroxy-4,14-retro-retinol (14-HRR) were identified for the first time in humans as physiological metabolites of vitamin A. 9-cis-RA is a potent teratogen as well as a high affinity ligand of retinoid receptors, and 14-HRR was previously shown to promote lymphocyte activation in vitro. The present study bears on the issue of a possible teratogenic risk of liver consumption, as active retinoids were identified in human plasma, and their levels could be related to previous human studies as well as to experimental studies in sensitive animal species.
[..]
Fried turkey liver was given as part of a light meal to ten healthy male volunteers (2 g raw weight/kg body weight). The vitamin A content in the liver (retinol plus retinyl esters) was determined by HPLC to be 0.5 +- 0.04 mg total retinal/g raw weight (n=3). Hence, the vitamin A intake was approximately 3,300 IU or 1 mg/kg body weight. Blood samples were taken into heparinized syringes before the meal and at eight time intervals after the meal (1, 2, 4, 6, 8, 10, 12, and 24 hours), and plasma was prepared. Three different methods were used for determination of retinoids by reversed-phase HPLC.
[..]
Plasma concentrations before liver consumption (C-end) represent the endogenous retinoid levels under fasting conditions. The maximum plasma concentrations (C-max) and time to maximum plasma concentrations (T-max) are the observed values.

Areas under the plasma concentration-time curves (AUC 0..24h) were determined by the trapezoidal method for a time period of 24 hours after the meal.

Quote from rockarolla on March 2, 2021, 3:56 pm

OMG, vitA could be that bad:

https://en.wikipedia.org/wiki/Macrophage_colony-stimulating_factor
The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types

Retinoic Acid Inhibits Monocyte to Macrophage Survival and Differentiation
https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing monocytes for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells.

Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF.

Cytokine secretion is modulated by RA.

Besides the morphology and antigen-expression, the functional activity of MO[human blood monocytes] changes during the differentiation into MAC[monocytes-derived macrophages]. Especially the lipopolysaccharide (LPS)-induced cytokine production can serve as a maturation marker for MO-derived MAC. We therefore analyzed whether monocytes cultured with or without RA would differ in their ability to produce IL-6 and TNF-α after LPS stimulation.

Control MAC cultured in the presence of serum showed a normal MAC LPS response, ie, a high secretion of TNF-α and a low secretion of IL-6.

However, MAC derived from RA-containing cultures showed an inverse pattern of cytokine secretion after LPS stimulation (Fig 7) that is a typical feature of freshly isolated MO, indicating that MO[human blood monocytes] do not differentiate into functionally normal MAC[monocytes-derived macrophages] in the presence of RA.

^^^ monocytes-derived macrophages cytokine pattern is modulated by Retinoic Acid.

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068229/

Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus. M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation.

https://www.jstor.org/stable/4460372?seq=1

Management of fungal infections is a major medical problem. The risk of developing a fungal infection is higher for patients who are undergoing dose-intensive therapy, are immunocompromised, have neutropenia, are receiving prophylactic antibiotics, have other infections, have invasive catheters, or have a history of severe trauma or burns. Survival is decreased among patients who develop fungal infection in these situations. In view of the high morbidity and mortality associated with fungal infections in transplant recipients, cytokines that enhance cell function, such as macrophage colony-stimulating factor (M-CSF), have been investigated. M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production in monocytes and macrophages. Animal models and clinical data suggest efficacy of M-CSF in controlling fungal infection.

https://ashpublications.org/blood/article/91/12/4796/260916/Retinoic-Acid-Inhibits-Monocyte-to-Macrophage

The effect of RA on MO(blood monocytes)/MAC(monocytes-derived macrophages) differentiation has also been studied by others, including the differentiation of the human monoblastic cell line U937 and the differentiation of osteoclasts in chicken. Both studies found an antagonistic effect of 1,25-dihydroxyvitamin D3[1,25(OH)2D3] and RA on the differentiation process, with RA being dominant over 1,25(OH)2D3.

1,25(OH)2D3, which is a potent inducer of MO differentiation, could also not overcome the differentiation block by RA in our system (data not shown).

+++

Identification of 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol in human plasma after liver consumption
https://pubmed.ncbi.nlm.nih.gov/8809215/

Vitamin A is a well-established teratogen in several animal species. Case reports as well as a recent epidemiological study suggest that vitamin A intake in excess of 25,000 or 10,000 IU respectively, can result in retinoid-specific defects in the offspring. A single meal of liver contains, on the average, a 10- to 20-fold higher amount of vitamin A than what is already suspected to be teratogenic. To evaluate the risk of liver consumption during pregnancy, we have studied levels of vitamin A and a number of potentially active retinoid metabolites in plasma of ten healthy male volunteers following consumption of fried turkey liver (2 g raw weight/kg body weight). HPLC, UV spectroscopy and mass spectrometry were used for identification and quantitation of retinoids in plasma. As shown previously, vitamin A intake via liver consumption resulted in greatly increased plasma levels of 13-cis-retinoic acid (13-cis-RA) and 13-cis-4-oxo-RA, and low levels of all-trans-RA and all-trans-4-oxo-RA. In our present investigation 9-cis-RA, 9,13-di-cis-RA, and 14-hydroxy-4,14-retro-retinol (14-HRR) were identified for the first time in humans as physiological metabolites of vitamin A. 9-cis-RA is a potent teratogen as well as a high affinity ligand of retinoid receptors, and 14-HRR was previously shown to promote lymphocyte activation in vitro. The present study bears on the issue of a possible teratogenic risk of liver consumption, as active retinoids were identified in human plasma, and their levels could be related to previous human studies as well as to experimental studies in sensitive animal species.
[..]
Fried turkey liver was given as part of a light meal to ten healthy male volunteers (2 g raw weight/kg body weight). The vitamin A content in the liver (retinol plus retinyl esters) was determined by HPLC to be 0.5 +- 0.04 mg total retinal/g raw weight (n=3). Hence, the vitamin A intake was approximately 3,300 IU or 1 mg/kg body weight. Blood samples were taken into heparinized syringes before the meal and at eight time intervals after the meal (1, 2, 4, 6, 8, 10, 12, and 24 hours), and plasma was prepared. Three different methods were used for determination of retinoids by reversed-phase HPLC.
[..]
Plasma concentrations before liver consumption (C-end) represent the endogenous retinoid levels under fasting conditions. The maximum plasma concentrations (C-max) and time to maximum plasma concentrations (T-max) are the observed values.

Areas under the plasma concentration-time curves (AUC 0..24h) were determined by the trapezoidal method for a time period of 24 hours after the meal.

"Vitamin" A supplementation may cause immune system to 'forget' past infections.

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