Association between vitamin D supplementation and fatigue

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In a recent review published in Nutrients, researchers reviewed existing data on the mechanisms underlying vitamin D’s effects on fatigue.

Study: Vitamin D and Its Role on the Fatigue Mitigation: A Narrative Review. Image Credit: Iryna Imago/Shutterstock.comStudy: Vitamin D and Its Role on the Fatigue Mitigation: A Narrative Review. Image Credit: Iryna Imago/


Studies have associated vitamin D with bone metabolism. However, recent research has indicated vitamin D involvement in the physiological processes of humans, potentially influencing the pathophysiology of neurodegenerative and cardiovascular disorders, rheumatological disorders, diabetes, fertility, fatigue-related conditions, and cancer.

About the review

In the current review, researchers presented fatigue mitigation by vitamin D based on Web of Science, Scopus, and PubMed database records.

Vitamin D regulates fatigue by controlling inflammation and neurotransmitters

Vitamin D regulates fatigue pathophysiology, associated with biochemical variables such as oxidative stressors and inflammatory cytokines.

The vitamin participates in various processes like redox reactions, reactive oxygen species (ROS) formation, and mitochondrial functioning. Vitamin D reduces oxidative stress by decreasing levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa β (NFkβ).

Vitamin D activation increases during cellular stress, and supplementation can improve skeletal muscle mitochondrial functions by decreasing oxidative stress.

The vitamin modulates the nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor gamma coactivator 1-alpha-sirtuin 3 (Nrf2/PGC-1-SIRT-3) axis, promoting transcriptional processes of Nrf2, the primary redox regulator and promotes antioxidant activity by upregulating associated genes.

Vitamin D also regulates the development of Klotho, a protein that exerts anti-aging effects by increasing oxidative stress tolerance and preventing ROS overproduction.

Vitamin D influences the epigenome by enhancing genomic vitamin D receptor (VDR) binding, regulating CCCTC binding factor (CTCF) levels, and affecting topologically associated domain (TAD) generation.

The vitamin also regulates immunological functions and inflammatory processes, with a causal relationship between inflammation and vitamin D, promoting anti-inflammatory actions by cytokines such as interleukin (IL)-4, 5, and 10 and direct effects on immune cells.

In addition, vitamin D reduces the levels of pro-inflammatory cytokines such as interleukin-2, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFNγ).

Active vitamin D can alter immune cell epigenomes, particularly those of monocytes (and subtypes), lowering type 1 T helper (Th1) lymphocyte differentiation and enhancing inflammatory cytokine release.

It can elevate vitamin D levels in monocytes and macrophages through vitamin D receptor upregulation in activated T lymphocytes.

Vitamin D is essential to control fatigue-related neurotransmitters such as serotonin and dopamine and upregulates growth factors such as nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT-3).

Further research on the relationship between plasma vitamin D and Parkinson's disease or other neuronal diseases is needed to justify its usage in neurodegeneration prevention efforts.

Association between vitamin D and fatigue in rheumatological, neuropsychiatric, and musculoskeletal diseases and cancer

Serum vitamin D levels below 20 ng/mL indicate deficiency, and those between 21 and 29 ng/mL indicate insufficiency. A daily consumption of 600–800 IU of the vitamin provides optimal bone health, but a daily intake of 1,000–2,000 IU is necessary to maintain plasma levels above 30 ng/mL.

Chronic hypovitaminosis D is associated with cardiovascular disease and metabolic dysfunction and could be a significant comorbidity or risk factor for early mortality. Several studies have found inverse associations between vitamin D deficiency and lower all-cause mortality and cancer risk.

Current data on the consequences of addressing hypovitaminosis D is contradictory, indicating that other variables may be involved. Fibromyalgia, a systemic and persistent painful disorder with the most common symptom of fatigue, is the primary source of this insufficiency.

Researchers have linked hypovitaminosis D to an improvement in fibromyalgia fatigue, with promising results on the amelioration of numerous fibromyalgia ACR criteria and the "chronic fatigue" symptom.

Fatigue is a common denominator in many autoimmune diseases. Researchers advocate a plasma vitamin D test in patients with fatigue symptoms since low blood vitamin D levels are frequent in these individuals, and treatment resulted in a significant decrease in fatigue severity.

Vitamin D is associated with gene regulation related to neuroplasticity and neuroprotection. Preclinical research has indicated a malfunction in the transport of neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA) in hypovitaminosis D.

Early childhood vitamin D insufficiency affects neuronal development, axonal connections, dopamine ontogeny, and brain structure and function.

The review findings highlighted fatigue modulation by vitamin D primarily through a reduction in oxidative stress and regulation of neurotransmitter levels.

However, there is mixed evidence from human cohort studies and insufficient data on its effect on fatigue. While there is a definite link between fatigue and vitamin D in the elderly and multiple sclerosis patients, there is limited evidence for other pathologies such as fibromyalgia, rheumatological disorders, myasthenia gravis, and cancer.

Further research, such as randomized controlled clinical trials, is required to determine the causal effects of vitamin D supplementation on fatigue reduction.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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  1. Jacqueline Staples Jacqueline Staples United Kingdom says:

    I have been taking vitamin D for over three months now and as of yet have no change in my conditions at all and as for fatigue irs worse than ever i am 66 and just retired i am now coming off them to see if i feel better and less tired.

    • Sally Chang Sally Chang Thailand says:

      Are you taking vitamin D3?  D3 is important, not just Vit D.  Also, D3's bio-availability is improved if taken with Vitamin K2.
      Also, you could be deficient in some other essential nutrient which is keeping you down.  Our system is so complex.  If you are out in the sun a lot, with sunlight directly touching your skin, you may not be Vit D3 deficient.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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