Research published in the European Journal of Nutrition evaluated the effects of the combination supplement in 72 adults between the ages of 18 and 55 with a diagnosis of migraine headache compared to a placebo.
“The evaluation of the supplementation on some biomarkers of oxidative stress showed a marginally significant difference between the two arms of intervention regarding changes in serum levels of NO [nitric oxide],” wrote researchers from Isfahan University of Medical Sciences in Iran. “However, we did not find any significant effect of the treatment on MSQoL [migraine-specific quality of life] and other biomarkers of oxidative stress.”
Potential mechanisms
Migraines affect around 15% of the global population, but the pathophysiological mechanisms are not fully understood. Oxidative stress is thought to play a role, and scientists have investigated the potential of antioxidants to attenuate symptoms.
The current findings build on evidence previously reported by the researchers involving the same cohort, emphasizing the central role of the gut-brain axis in migraine pathophysiology and proposing probiotics and vitamin D as modulators of the mechanisms.
“Probiotic and vitamin D co-supplementation is probably effective on migraine headache in adult patients through NO synthesis inhibition,” the researchers noted.
They explained that evidence suggests an inverse association between NO and serum vitamin D levels and that vitamin D may “prevent oxidative damage to hippocampal neuron cultures by suppressing the expression of iNOS mRNA”.
In addition, short-chain fatty acids produced by probiotics may attenuate NO production and modulate oxidative stress.
The study highlights the potential synergy of the two supplements.
“It seems that vitamin D receptor plays a key role in anti-inflammatory effects of probiotics,” the researchers wrote.
Study details
The parallel randomized, triple-blinded, placebo-controlled trial divided the 72 participants into two groups to receive either a multispecies probiotic (4.5× 1011 CFU per day) plus vitamin D (50,000 IU every two weeks) or placebo for 12 weeks.
The probiotics contained eight species: Lactobacillus plantarum, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve and Streptococcus thermophilus.
The researchers assessed the participants at baseline and the end of the intervention using the migraine index (MI), which looks at frequency and severity, and the migraine-specific quality of life (MSQoL). Participants’ scores were based on data from headache diaries and questionnaires. They also evaluated other parameters, including vitamin D status, nitric oxide (NO), anthropometrics and blood pressure.
The results revealed that the intervention group showed a significant increase in mean serum levels of 25-hydroxy vitamin D, a greater reduction in mean MI and a marginally significant difference in serum NO compared to placebo.
However, the supplements did not have a significant effect on MSQoL or other biomarkers of oxidative stress. The researchers wrote that “other factors besides headaches’ frequency and severity may affect QoL in patients with migraine headache,” citing previous studies suggesting that anxiety and depression are more prevalent in migraineurs.
“Thus, to improve QoL in patients with migraine headaches effectively, it is perhaps necessary to use a combination therapy approach comprising both pharmacotherapy and cognitive behavioral therapy,” they added, calling for further research to clarify the mechanisms involved.
Source: European Journal of Nutrition 64, 179 (2025). doi: 10.1007/s00394-025-03687-w. “Effects of probiotic and vitamin D co-supplementation on migraine index, quality of life, and oxidative stress in adults with migraine headache: a randomized triple-blinded clinical trial”. Authors: S. A. Tirani et al.
