Vitamin B12, Autoimmunity and ‘Leaky Gut’

A paper released on 20th Nov 2023 in the BMJ takes a close look at B12, common practice, and determination of need[1]. This interesting review is aimed at primary care clinicians but represents a good reference paper for all healthcare professionals utilising B12 supplements and nutritional guidance to resolve B12 deficiency or dietary inadequacy. Importantly the paper explores the interindividual variations in absorption, biliary B12 excretion and the somewhat insecure determination of need and adequacy. Whilst the interventions recommended include a focus on intramuscular injections, oral supplementation is also discussed.

The key clinical takeaways are:

• The clinical picture is crucial in assessing B12 deficiency as there is no definitive test for it.
• Neurological symptoms from B12 deficiency may take months or years to resolve.
• Serum biomarkers like B12 or methylmalonic acid are not entirely useful in assessing or monitoring clinical improvement, and injection frequency should not be based on biomarker levels.
• Self-administration of B12 injections can improve patient satisfaction and health outcomes.
• Oral supplementation may not meet the physiological needs until injections have resolved the deficiency.
• B12 is essential for nervous system function, red blood cell development, and has antioxidant properties.
• B12 is found in animal products and fortified foods, with an average daily intake of 4-7 mcg needed for healthy adult function.

Nitrous Oxide and B12

Whilst ‘recreational use’ of Nitrous oxide has been banned in the UK, be aware that when inhaled it can cause or progress gross B12 deficiency. Nitrous oxide (N₂O) inactivates vitamin B12 (cobalamin) by oxidising its cobalt ion, which leads to a decrease in the function of B12-dependent enzymes. This inactivation can result in a condition known as subacute combined degeneration of the spinal cord, as B12 is essential for maintaining the integrity of the myelin sheath that surrounds nerve fibres. Without functional B12, the myelin sheath deteriorates, leading to neurological deficits associated with B12 deficiency.

Intestinal Permeability and Autoantibodies

In The International Journal of Molecular Sciences on the 15^th Nov 2023, the paper entitled “The Relationships between Intestinal Permeability and Target Antibodies for a Spectrum of Autoimmune Diseases” set out to further develop the understanding of the dynamic interrelationship between altered intestinal barrier function and autoimmune disease[2].  Building on prior works from the 2021 Frontiers in Immunology[3] and the 2012 Alessio Fasano paper ‘leaky gut and autoimmune diseases’[4] the authors present several key clinical insights with implications for the understanding and treatment of autoimmune diseases:

Generalised Role of Intestinal Permeability: The research suggests that intestinal permeability may have a widespread impact on autoimmune diseases, affecting various bodily systems. This highlights the gut’s significant role in autoimmune responses.

Link between Intestinal Permeability and Type 1 Diabetes: The study finds a correlation between increased levels of tight junction antibodies and higher mean insulin/islet cell antibodies. This finding indicates a possible connection between intestinal permeability and the development of type 1 diabetes.

Use of Autoantibodies as Biomarkers: Circulating autoantibodies, specifically serum occludin/zonulin antibodies, could be valuable biomarkers for identifying autoimmune diseases. This offers a potential pathway for earlier detection and diagnosis.

Future Research Directions: The paper underscores the need for further research into intestinal permeability as a target for autoimmune disease treatment. Exploring this avenue could lead to innovative therapeutic strategies, offering hope for improved management of these conditions.

This study unveils a pivotal discovery in the realm of autoimmune diseases: the broad-ranging impact of intestinal permeability. Their findings reveal that this condition extends its influence to various organs and systems, including the brain, endocrine glands, joints, smooth muscles, and the cardiovascular system. This significant insight supports the concept that a host of autoimmune diseases, regardless of their specific location in the body, may have a common underlying factor – the integrity of intestinal junctions. This breakthrough enhances our understanding of autoimmune pathologies and opens new avenues for exploring unified treatment strategies targeting intestinal permeability.

Increasingly research is highlighting the potential connection between the microbiota, the intestinal barrier’s integrity, and the onset and progression of autoimmune diseases. This evolving understanding suggests that the gut’s health and its microbial composition may be pivotal in the development of these diseases. Recognising these links can pave the way for a range of therapeutic and preventative strategies. These might include pharmaceutical interventions, lifestyle changes, nutraceuticals, and tailored dietary approaches, all aimed at mitigating or reversing the expression of autoimmune diseases.

The Potential Connections

The relationship between Vitamin B12 deficiency, autoimmunity, and increased intestinal permeability (often referred to as “leaky gut”) is intricate and multifaceted:

1. Autoimmune Gastritis and B12 Deficiency: Autoimmune gastritis, where the body’s immune system attacks stomach cells, impairs the production of intrinsic factors necessary for B12 absorption. This condition is a direct example of how autoimmunity can lead to B12 deficiency. It also often coexists with conditions like increased intestinal permeability.
2. Increased Intestinal Permeability and Autoimmunity: A “leaky gut” allows substances that are normally contained within the gut to pass into the bloodstream, potentially triggering an immune response. This immune reaction can lead to, or exacerbate, autoimmune conditions.
3. B12’s Role in Immune Regulation: Vitamin B12 is crucial for maintaining a healthy immune system[5]. Its deficiency can disrupt immune system balance, potentially contributing to the development or exacerbation of autoimmune diseases and conditions associated with increased intestinal permeability.
4. Homocysteine Levels: B12 deficiency leads to elevated homocysteine levels. High homocysteine can indicate increased inflammation, which may further contribute to the weakening of the intestinal barrier, exacerbating leaky gut issues[6].
5. Epigenetic Factors: B12 is important for DNA synthesis and repair. Its deficiency can lead to changes in gene expression that might predispose individuals to both autoimmunity and increased intestinal permeability[7].
6. Neurological Implications: B12 deficiency affects nerve health, and the nervous system plays a role in gut barrier integrity. Deficiency in B12 might indirectly contribute to increased intestinal permeability through its impact on the nervous system.

Summary

Vitamin B12 deficiency in the US and the UK is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60. B12[8] deficiency, profound and marginal, is more common than many understand and often poorly managed, and can exacerbate or contribute to increased intestinal permeability, which in turn can trigger or worsen autoimmune responses, creating a complex cycle of interaction between these elements[9].

As B12 only occurs in animal foods or fortified foods, oral supplementation of B12 and allied B vitamins should be a standard of care for those following a plant based or highly restrictive diet, as well as those over 60 with reduced capability for nutrient absorption. Vitamin B12 deficiency can be caused by malabsorption, dietary inadequacy, inadequate intrinsic factor production, atrophic gastritis, interference with ileal uptake, drug-nutrient interactions, and genetic defects. Vitamin B12 deficiency can also be masked by folate fortification, and high doses of folate can prevent megaloblastic anaemia but allow neurological damage to progress[10].

References

[1] Wolffenbuttel B H, Owen P J, Ward M, Green R. Vitamin B₁₂ BMJ 2023; 383 :e07172

[2] Kharrazian D, Herbert M, Lambert J. The Relationships between Intestinal Permeability and Target Antibodies for a Spectrum of Autoimmune Diseases. Int J Mol Sci. 2023 Nov 15;24(22):16352.

[3] Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021 Apr 22;12:673708.

[4] Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012 Feb;42(1):71-8.

[5] Mikkelsen, K., & Apostolopoulos, V. (2019). Vitamin B12, Folic Acid, and the Immune System. Nutrition and Immunity.

[6] Farré R, Fiorani M, Abdu Rahiman S, Matteoli G. Intestinal Permeability, Inflammation and the Role of Nutrients. Nutrients. 2020 Apr 23;12(4):1185

[7] Ge Y, Zadeh M, Mohamadzadeh M. Vitamin B12 Regulates the Transcriptional, Metabolic, and Epigenetic Programing in Human Ileal Epithelial Cells. Nutrients. 2022 Jul 9;14(14):2825

[8] Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician. 2017 Sep 15;96(6):384-389

[9] Wolffenbuttel BHR, Wouters HJCM, Heiner-Fokkema MR, van der Klauw MM. The Many Faces of Cobalamin (Vitamin B₁₂) Deficiency. Mayo Clin Proc Innov Qual Outcomes. 2019 May 27;3(2):200-214.

[10] Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10;368(2):149-60.