The result of this large population-observational study showed that high dietary acid load intake had a direct association with odds of migraine. Participants with higher PRAL scores, that had high daily intake of protein as well as phosphorus as acid-producing components and less potassium, magnesium, and calcium consumption per day as base-producing components (30, 33, 34), had approximately seven times increased odds of migraine, compared to those who had the lowest scores. Also, increased scores of NEAP and protein/potassium ratio that shows higher daily consumption of protein divided by potassium (31, 32) were related to about four-fold elevation in migraine odds.
In this study we used different methods for calculating dietary acid load, including PRAL, NEAP, and protein/potassium ratio. These methods are based on protein, potassium, phosphorus, calcium, and magnesium intake, which are acid-base precursors and probably related to PH homeostasis in the human body (22, 30, 32). The higher value of PRAL, NEAP scores, and protein/potassium ratio are indications of more acidic food, while the lower amount of these measurements are pointing to more basic food consumption. Individuals with high dietary acid load had a lower intake of fruits and vegetables and more meat and protein consumption (22). In the present study, we found that high PRAL, NEAP, and protein/potassium ratio, which might be related to meats, grain, and sugar consumption, have a positive association with odds of migraine. Therefore, these findings demonstrated that a high acidic load in the human body, which could be induced by acidic food intake (21), may have an essential contribution to migraine pathogenesis and developing odds of this disorder.
To our knowledge, the association between the dietary acid load and odds of migraine has not been studied yet. Previous studies have only reported the consumption of single acidic and basic food items with odds of migraine (35, 36). In agreement to our finding, one case-control research showed that odds of migraine decreased by about 50 percent and 70 percent as consumption of vegetables and fruits increased in paediatrics (35). Furthermore, a study reported individual with migraine has a significantly higher frequency of using red meat than individuals without migraine (36). Also, according to the available evidences, individuals with western dietary patterns defied by high intakes of red and processed meat and lowe intake of fruits and vegetables had higher frequency of migraine attacks (23). Due to the high amount of acidic food items in the western dietary pattern, this type of diet may give an example of a high dietary acid load (24), which at least in part is in line with our findings.
Although protein intake can influence acid-base balance in the human body because of containing sulphuric amino acid (22), a recent study revealed that there were no differences in dietary protein intake among women with and without migraine (37). In the present study, we found that high PRAL, NEAP, and protein/potassium ratio, which significantly associated with high total protein intake, had positive associations with odds of migraine. The observed difference may be related to dietary patterns and dietary habits of the studied population as well as various controlled confounders. Moreover, another explanation for these difference probably due to the fact that dietary acid load measures such as PRAL, NEAP, protein/potassium ratio calculated by comparison between the acid and base precursors intake. Therefore, perhaps total protein intake as acid precursor, in comparison with base precursors have different effects on odds of migraine than consumption of total protein alone.
Chronic consumption of a diet with a high acid load could shift the acid-base balance toward acidosis (21). Besides, with the presence of abnormalities in acid-base balance, the dietary acid load is more likely to induce acidosis in the human body (18). It has been found that people with migraine could have abnormalities in the acid-base balance due to mitochondrial dysfunction (38, 39). Several possible mechanisms have been suggested that a high acidic load may play a role in the onset of migraine attacks or increasing headache attack frequency in migraineurs (16–20); these are explicated as follows. First, animal and human studies have reported that acidosis can cause high inflammation and NO due to its damaging effect on tissues or blood vessels (16–18, 40). The physiological ways to explain this issue is that TNF-α, myeloperoxidase, and NO synthases enzymes may be produced through acidosis condition in the human body (18). Inflammation and factors such as CGRP and NO are believed to play important roles in migraine attacks initiation (41, 42). On the other hand, cytokines and inflammatory agents around nerves could activate trigeminovascular neurons and increase CGRP release by cellular mechanisms. Due to the existence of the majority of TNF-α receptors in trigeminal ganglion neurons, TNF-α, may increase CGRP gene expression in trigeminal ganglion neurons by increasing intra cellular MAP kinases signaling pathways, which might be attributed to the onset of headache (42–46). Additionally, NO can causes intense pain by increasing dilation and inflammation in cranial vessels through NO-cGMP pathway (9, 10). Therefore, acidosis condition by augmenting inflammation and NO synthesis may have a negative effect on the initiation of migraine attacks.
Second, a high acidic load might cause cortisol augmenting, which might have a negative impact on pain recovery in migraineurs (47). Also, elevated cortisol level, which may be augmented by acidosis, appeared to be associated with high blood flow and BMI in the human body (19, 20). It has been revealed that high blood flow and BMI may play negative roles in the onset of migraine pathogenesis. For example available evidence reported that the odds of migraine is increased in obese individuals (15, 48). Moreover, although there is controversial evidence regarding the association between hypertension and migraine, several findings delineated that long duration and uncontrolled hypertension, especially systolic blood pressure, may have a positive link with migraine with/without aura (49, 50).
Third, gut microbiota could be influenced by dietary acid load due to less intake of fruits and vegetables, which may lead to low microbial diversity in gastrointestinal systems then the adverse effects on human microbiomes (51). Recent shreds of evidence suggested the existence of a link between gut microbiota and migraine (7). Besides, studies have reported that there might be potential beneficial effects following probiotics supplementation in subjects with migraine headache (15, 52, 53).
Therefore, a high acidic load may be contributed with high odds of migraine through increasing inflammatory state, elevating cortisol levels, modifying NO signaling pathway, blood flow, and gut-microbiota, in addition to affecting on body weight and hypertension risk (16–20, 40, 47, 51).
The present study consists of several strengths. Dietary acid load was assessed by various methods such as PRAL, NEAP, protein/potassium ratio that were estimated using a validated FFQ. Another strength was a relatively large population of migraineurs in the case group. Additionally, all migraine patients were diagnosed by our expert neurologist-headache specialist according to the ICHDIII beta criteria. To our knowledge, this was the first study that preformed to explore the association of dietary acid load measures with odds of migraine. However, the limitations of this study are needed to be considered. First, the exact dosage of medications used, and the frequency and intensity of migraine headache attacks were not considered in the calculations. Second, body acid-base balance assessment was based on dietary calculation, and even if urinary and serum pH were available then the result would be more accurate.