Vitamin C and Immunity

By: Yekta Dowlati, PhD

Vitamin C (ascorbic acid/ascorbate) is indispensable for immune defense, yet insufficiency remains widespread even in high-income nations. Data from the U.S. NHANES 2003–2006 survey revealed that 41.8% of adults had insufficient plasma Vitamin C levels, spanning deficiency (<11 µmol/L), hypovitaminosis (11–23 µmol/L), and inadequate concentrations (23–49 µmol/L).¹ Notably, males, smokers, individuals with elevated BMI, and populations experiencing food insecurity were disproportionately affected.

While scurvy is now rare, subclinical Vitamin C insufficiency exerts significant biological consequences. Inadequate plasma levels are linked to chronic inflammation, impaired neutrophil function, reduced lymphocyte proliferation, and increased susceptibility to infection. Importantly, research suggests that achieving saturating plasma concentrations (≥70 µmol/L), rather than merely avoiding deficiency, may be necessary for optimal immune regulation and inflammatory control.¹

Importantly, the formulation of Vitamin C—whether standard ascorbic acid or buffered, metabolite-enhanced preparations—directly influences absorption, tolerability, and immune outcomes.

For clinicians, understanding the mechanistic breadth of Vitamin C and the superiority of advanced formulations is critical in optimizing patient care.

Mechanistic Insights: Vitamin C Across Layers of Immunity

Barrier Defense and Antioxidant Capacity

Vitamin C maintains epithelial integrity—the body’s first line of defense—by promoting collagen synthesis and stabilizing extracellular matrix proteins. Beyond structural roles, Vitamin C functions as a potent water-soluble antioxidant, neutralizing reactive oxygen species (ROS) generated during infection and inflammation. This dual action helps protect epithelial barriers from oxidative disruption while supporting rapid wound healing and tissue recovery.

Innate Immunity: Neutrophils, Macrophages, and NK Cells

Vitamin C is central to innate immunity. Neutrophils rely on ascorbate for chemotaxis, oxidative burst, and microbial clearance. In individuals with low serum Vitamin C, neutrophil ROS generation can be augmented by supplementation, improving pathogen elimination. Supplementation increases neutrophil ROS production by ~20% in low-status individuals.² Importantly, Vitamin C facilitates neutrophil apoptosis and macrophage-mediated clearance, limiting NETosis-driven tissue damage.²

Macrophages similarly depend on Vitamin C for efficient clearance of apoptotic neutrophils, preventing excessive inflammation and tissue damage.²

Of particular interest, Vitamin C enhances natural killer (NK) cell cytotoxicity: In vitro, ascorbate expanded NK cell populations more than 2,300-fold while preserving cytotoxic function. In clinical studies, buffered Vitamin C increased NK cytotoxicity up to tenfold in 78% of toxin-exposed patients, restoring impaired innate immunity.^3,4

Adaptive Immunity: T and B Lymphocytes

Lymphocytes concentrate Vitamin C to levels 10–100 times higher than plasma, underscoring its critical role in adaptive immunity.⁵ Ascorbate supports T-cell proliferation, enhances B-cell antibody responses, and contributes to the regulation of regulatory T cells (Tregs) through epigenetic mechanisms, including TET-dependent demethylation of the Foxp3 promoter.⁶ Collectively, these mechanisms place Vitamin C as a gatekeeper of adaptive immune homeostasis.

Inflammation Modulation

Vitamin C influences inflammatory signaling by inhibiting the NLRP3 inflammasome, thereby reducing IL-1β production and limiting cytokine storm-like responses observed in severe viral infections. This activity aligns Vitamin C not just as an immune supporter but also as a regulator of immune overactivation.^7,8

Formulation Science: Buffered Vitamin C Advantage

The clinical impact of Vitamin C depends not only on dose but also on formulation. Conventional ascorbic acid is constrained by saturable intestinal transport and dose-dependent gastrointestinal irritation, limiting its effectiveness at higher intakes. Buffered formulations—combining Vitamin C with mineral ascorbates and specialized metabolites—overcome these limitations and provide distinct advantages:

1. Greater bioavailability – Higher intracellular accumulation of Vitamin C in immune cells, resulting in more robust functional activity.
2. Sustained plasma levels – Improved capacity to reach and maintain saturating concentrations (>70 µmol/L), linked to enhanced immune outcomes.
3. Superior tolerability – Reduced gastric irritation enables safe, gram-level dosing without compromising adherence.

Clinical studies confirm these benefits. In chemically exposed patients with depressed immunity, oral buffered Vitamin C (~3 g/day) increased NK cytotoxic activity up to tenfold in 78% of participants (p<0.0001) and restored T- and B-cell mitogenic responses to normal levels.⁹ Comparative work further demonstrated 18–25% greater lymphocyte uptake with buffered Vitamin C relative to ascorbic acid.⁴ Importantly, these high-dose regimens (3–5 g/day) were well tolerated in both healthy volunteers and clinical cohorts.^4,9

Taken together, buffered Vitamin C is not simply gentler on the stomach—it is a clinically validated immunonutrient that achieves higher immune cell exposure, restores function under stress, and provides a reliable option for patients with high oxidative load, immune suppression, or toxin exposure.

Clinical Implications for Healthcare Professionals

For clinicians and KOLs, the implications are clear:

• Assessment: Subclinical Vitamin C insufficiency is common and often overlooked in patient populations at risk of chronic inflammation, obesity, smoking, and environmental toxin exposure.
• Targeting saturating levels: Clinical benefits extend beyond preventing deficiency—higher intakes that achieve saturating plasma levels may provide optimal immune modulation.
• Choosing the right form: Buffered Vitamin C offers superior uptake, tolerability, and clinical outcomes compared to standard ascorbic acid.

Conclusion

Vitamin C represents more than a simple micronutrient—it is a regulator of immune defense, inflammatory resolution, and epithelial integrity. However, achieving clinically meaningful outcomes requires more than meeting the minimal dietary requirement. Research consistently demonstrates that buffered Vitamin C formulations provide superior immune benefits, restoring NK, T, and B cell functions while ensuring better bioavailability and patient tolerance.

For healthcare providers aiming to optimize immune support, formulation science matters. Buffered Vitamin C is a safe, evidence-based approach that elevates immune resilience in populations with elevated need.

References

1. Crook J et al. Nutrients. 2021;13(11):3910.
2. Carr AC et al. Nutrients. 2017;9(11):1211.
3. Huijskens MJ et al. Cytotherapy. 2015;17(5):613-620.
4. Vojdani A et al. J Nutr Environ Med. 1997;7:187-195.
5. Evans RM et al. Br J Nutr. 1982;47:473-482.​
6. Van Gorkom GNY et al. Antioxidants (Basel). 2018;7(3):41.
7. Sang X et al. 2016;2(1):13-19.
8. Choe JY et al. 2017;40(3):980-994.
9. Heuser G et al. Immunopharmacol Immunotoxicol. 1997;19(3):291-312.

Yekta Dowlati, PhD, serves as the Medical Education Manager at Metagenics. Dr. Dowlati earned her PhD in Medical Sciences from the University of Toronto, along with her MSc in Pharmacology. Her academic credentials also include a BSc in nutrition. She furthered her expertise with a postdoctoral fellowship in Neuropsychopharmacology at the Centre for Addiction and Mental Health in Toronto. Dr. Dowlati’s research portfolio includes multiple clinical trials, and she has contributed to the scientific community through her authorship and co-authorship of articles in prestigious journals, alongside presenting her work at numerous national and international conferences. Before her tenure at Metagenics, she excelled as a senior medical writer and led medical writing teams, demonstrating her passion for learning and education to improve public health. Beyond her professional commitments, Dr. Dowlati cherishes family time, indulging in travel, fitness, and cooking, which speaks to her balanced approach to life.