Glaucoma, a leading global cause of irreversible vision loss, affects over 80 million individuals worldwide (1, 2). This condition is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons. Key risk factors for glaucoma include advanced age and elevated intraocular pressure (IOP) (3). The prevailing treatment strategy for glaucoma primarily revolves around the reduction of IOP. However, a significant subset of patients who effectively manage their IOP continue to experience progressive visual impairment. This phenomenon has sparked intense scientific investigation into alternative therapeutic approaches.

In glaucoma, RGC death occurs through apoptosis, triggered by various mechanisms such as mechanical damage and ischemic changes due to high IOP, both contributing to oxidative stress. Additional glaucoma risk factors, such as advanced age, genetic predispositions, and inflammatory processes, also precipitate oxidative stress through distinct biological pathways (4–7). RGCs, with their high energy demands, are particularly vulnerable to fluctuations in cellular fuel supply (8). Oxidative stress can lead to mitochondrial dysfunction and compromised ATP synthesis, causing irreparable cellular damage and ultimately resulting in the loss of RGCs (9–13). Furthermore, research suggests that oxidative stress may exacerbate damage to the trabecular meshwork (TM) in the eye, thereby increasing IOP and perpetuating a vicious cycle (14). Hence, oxidative stress is instrumental in the pathogenesis of glaucoma, constituting a crucial element of the alterations associated with glaucoma.

Emerging evidence suggests that antioxidant-rich diets, serving as an alternative therapy, can play a minimally invasive role in managing disease progression and significantly prevent glaucoma (15, 16). Specifically, vitamin B₆, known for its antioxidant properties, shows potential in neuroprotection and improving visual function (15, 17). For instance, animal model experiments by Wang et al. (18) have revealed that vitamin B₆ can counteract neuronal death in adult primate retinas following ischemia. Meanwhile, clinical trials by Mallone et al. (19) indicate that high-dose administration of vitamins B₁, B₆, and B₁₂ significantly enhances visual function metrics in cases of chronic visual impairment associated with multiple sclerosis. Furthermore, Ruamviboonsuk et al. (20) have proposed that a 6-month regimen combining vitamins B₆, B₉, and B₁₂ significantly enhances retinal sensitivity and thickness in patients with mild to moderate non-proliferative diabetic retinopathy Additionally, a case report by Xuan Cui et al. suggests that supplementation with vitamin B₆ positively affects the delay of Gyrate atrophy (21).

Concurrently, the relationship between vitamin B₆ and the broader group of B vitamins with glaucoma is increasingly being studied and discussed at various levels. Li et al. (22) conducted a meta-analysis to examine the association between serum levels of vitamins B₆, B₁₂, and D across various types of glaucoma. Their findings indicated no significant link between serum vitamin B₆ levels and glaucoma. Similarly, meta-analyses by Xu et al. (23) and Li et al. (24) on non-ocular risk factors for primary glaucoma corroborated these results. In contrast, clinical research led by Rolle et al. (25) demonstrated that supplements containing vitamins B₂, B₆, and folic acid could decelerate the progression of functional impairment in patients with primary open-angle glaucoma and enhance visual function. Additionally, a recent cross-sectional study by Lee et al. (26) exploring the relationship between niacin intake and glaucoma incorporated the intake of vitamins B₂ and B₆ as covariates in their model. However, direct research linking dietary intake of vitamin B₆ to glaucoma is relatively scarce and tends to focus on specific types of the condition (27), such as the prospective study by Walter Willet and others on exfoliative glaucoma and its suspected cases in relation to folic acid, vitamin B₆, and B₁₂ (27). As a nationally representative cross-sectional study, this research aims to utilize NHANES data to explore the potential relationship between dietary vitamin B₆ intake and glaucoma in the U.S. population.

In our study involving 3,850 Americans aged 40 and older, we discovered a significant independent linear negative correlation between dietary intake of vitamin B₆ and the risk of glaucoma. This relationship remained robust even after adjusting for multiple potential confounders. Relative to the first quartile of vitamin B₆ dietary consumption, which falls below the Recommended Dietary Allowance (RDA) of 1.6 mg/day for men and 1.4 mg/day for women, the odds of developing glaucoma dropped by 75% for individuals in the fourth quartile (>2.34 mg/day) (OR = 0.25, 95% CI 0.07–0.92). Additionally, we found no significant correlation between consumption of vitamin B₆ supplements and glaucoma risk.

In light of these results, our review of existing research indicates that there is still debate over whether vitamins from natural dietary sources and synthetic supplements are equivalent in terms of bioavailability and metabolic effects (48). While studies by Nelson et al. (49) suggest that vitamin B₆ from supplements has a higher absorption efficiency, research by Meinrad Lindschinger shows that natural and synthetic B vitamins are roughly equivalent in bioavailability. However, natural vitamin B₆ not only improves serum vitamin B₆ concentrations more effectively compared to its synthetic counterpart but also has a stronger impact on metabolic parameters like homocysteine levels and total antioxidant capacity (48). Additionally, there is currently no evidence to suggest that consuming large amounts of vitamin B₆ from food leads to adverse effects (50). However, multiple reports indicate that long-term excessive use of vitamin B₆ supplements can cause adverse reactions (50–53). Additionally, the discrepancy in our findings might be attributed to significant data loss among supplement users, reducing the sample size from 3,850 to 615, potentially introducing substantial bias into the results. Given the limitations of NHANES data, we could not further explore the relationship between these variables. Considering the controversies in existing research, we believe that comparing the efficacy of different sources of vitamin B₆ is a crucial direction for future studies.

Contrarily, our study findings diverge from those reported by JaeH Kang and his colleagues, who conducted a thorough cohort study identifying no significant link between vitamin B₆ intake and the risk of exfoliative glaucoma or its suspected cases. We hold their work in high regard for its rigor and evidential strength (27). The variations in our results likely stem from several key factors: Firstly, our research included all types of glaucoma, not just exfoliative glaucoma, which is estimated to constitute about 25% of all open-angle glaucoma cases (54). Secondly, our method for assessing vitamin B₆ intake, based on 24-h dietary recall interviews, differed from Kang’s team, who used a long-term average intake method. Additionally, in the study populations, Kang and colleagues included female registered nurses and male health professionals, whereas our study population is based on NHANES data and broadly involves non-institutionalized civilians across the United States. There may be some degree of demographic and sociological differences between the two study populations. These factors highlight the diversity of research designs, which may explain differences in study outcomes. These key elements are worthy of further exploration and discussion in future research.

Given the discrepancies in existing research findings, a deep understanding of the biochemical roles and mechanisms of vitamin B₆ is particularly crucial. Vitamin B₆, a coenzyme essential for countless biochemical reactions, comprises six compounds (55). These include pyridoxal, pyridoxamine, pyridoxine, and their 5′-phosphate esters (56). Pyridoxal-5′-phosphate (PLP), known as the biologically active form of vitamin B₆ in humans, is often used interchangeably with the term “Vitamin B₆” (57, 58).

One potential protective mechanism of vitamin B₆ against glaucoma may be its antioxidant activity. Pioneering work by Margaret Daub’s team has shown that vitamins are highly effective in quenching reactive oxygen species (ROS), with potential comparable to carotenoids and tocopherols (58, 59). Vitamin B₆, by quenching excess ROS, can reduce damage to ocular structures such as RGCs in the eye mitochondria caused by ROS imbalance, and play a certain role in the prevention of glaucoma and intervention in disease progression (13). On the other hand, vitamin B₆ has also been found to be involved in maintaining normal homocysteine (Hcy) levels, and its circulating levels often decrease concurrently with hyperhomocysteinemia (60). High levels of Hcy can promote the progression of glaucoma by stimulating cytochrome c release and ROS production, and by inducing mitochondrial dysfunction and oxidative stress through the ERK1/2 signaling pathway (60). Emerging research increasingly substantiates that hyperhomocysteinemia is a substantial risk factor in the progression of glaucoma (60, 61). A study carried out in Russia involving participants with glaucoma and early-stage cataracts has demonstrated that a 20-day course of low-dose pyridoxine hydrochloride eye drops can impact visual parameters, such as changes in visual acuity and expansion of the visual field. This regimen also showed a reduction in intraocular pressure and the Becker’s coefficient (62).

Another potential protective mechanism of vitamin B₆ against glaucoma may be its role in promoting the synthesis of myelin phospholipids, which have been shown to play a significant role in nourishing axons (63, 64). PLP, as a coenzyme in myelin synthesis, plays a positive role in slowing disease progression (63). Considering these potential mechanisms, it’s plausible that boosting vitamin B₆ consumption could strengthen the resilience of RGCs against glaucomatous neurodegeneration.

This study’s strength lies in its use of stringent inclusion and exclusion criteria to enroll a large, nationally representative sample of American adults, which enhances the reliability of the results to a certain extent. Additionally, we validated the robustness of our conclusions through various sensitivity analyses, including subgroup analyses. On another note, our analysis of the relationship between vitamin B₆ supplements and glaucoma offers a preliminary exploration of the equivalence in efficacy between different sources of vitamin B₆.

This study presents several limitations that warrant consideration. First, to mitigate the impact of confounding factors, we implemented stricter inclusion and exclusion criteria that excluded individuals with stroke and retinal diseases. This approach limited the generalizability of our findings to the excluded groups and potentially introduced selection bias. Moreover, due to the cross-sectional nature of NHANES data, we could not explore causal or temporal associations between dietary vitamin B₆ consumption and glaucoma risk. Dietary intake data, based on self-reporting, may be subject to recall bias. Additionally, given the potential variability in daily food consumption, using data from only two interviews may not accurately reflect participants’ regular dietary habits. Furthermore, we defined glaucoma using the Rotterdam criteria, which, despite being internationally validated, have inherent false positive and negative rates (34). The lack of comprehensive eye examinations to differentiate among the various subtypes of glaucoma also limited our understanding of the correlation between vitamin B₆ dietary consumption and various subtypes of the condition.

To better understand the role of vitamin B₆ in preventing and treating glaucoma, future research should employ less restrictive criteria to include a more diverse group of participants, thereby enhancing the generalizability of the findings. Additionally, more frequent dietary assessments or extended dietary tracking periods could enhance the accuracy of dietary intake estimates. It is also important to take into account other influencing factors such as genetics and environmental conditions, and to conduct further investigations through randomized controlled trials or epidemiological cohort studies. Furthermore, distinguishing between different types and stages of glaucoma will help identify the most effective ways to use vitamin B₆ in prevention and treatment, offering more precise guidance for clinical practice.

Our findings indicate an inverse linear correlation between vitamin B₆ dietary consumption and glaucoma risk. Thus, sufficient dietary consumption of vitamin B₆ may serve as a preventive measure against glaucoma.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found a: https://www.jianguoyun.com/p/DagglMEQ_cmbDBjDrqgFIAA.

The studies involving humans were approved by the NCHS Research Ethics Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The manuscript presents research on animals that do not require ethical approval for their study.

ZY: Formal analysis, Methodology, Writing – original draft. JZ: Conceptualization, Writing – original draft. YZ: Conceptualization, Funding acquisition, Methodology, Writing – review & editing.