Histamine, Migraines, and the Role of Gut and Microbiome Health: A Guide to Finding Food Freedom

I’m seeing more and more patients these days on restricted diets due to histamine intolerance.

Histamine intolerance is becoming increasingly recognised, with symptoms ranging from migraines and digestive discomfort to skin reactions and fatigue. Understanding the root mechanisms can provide more sustainable management strategies, beyond restrictive diets. Central to histamine regulation are the gut microbiome, intestinal health, and the activity of diamine oxidase (DAO), an enzyme responsible for breaking down histamine in the gut.

Understanding Histamine Intolerance

Histamine is a biogenic amine involved in immune responses, stomach acid regulation, and neurotransmission. However, elevated levels of histamine—due to high intake, excess production, or impaired breakdown - can result in symptoms like headaches, skin reactions, and digestive issues (Maintz & Novak, 2007).

However, it's important to distinguish histamine intolerance from related conditions like amine intolerance and tryptase intolerance, as they are not the same thing but are interconnected in certain ways.

1. Histamine Intolerance: This condition is caused by an imbalance between histamine levels and the body's ability to break it down, primarily due to impaired activity or deficiency of DAO. This can lead to histamine accumulation, resulting in symptoms such as headaches, digestive issues, skin reactions, and fatigue (Schnedl & Enko, 2021).

2. Amine Intolerance: A broader term encompassing not only histamine but also other biogenic amines like tyramine, putrescine, and cadaverine. These amines are found in various foods, and their metabolism can also depend on DAO and other enzymes. Amine intolerance shares many symptoms with histamine intolerance but is triggered by a wider range of biogenic amines.

3. Mast Cell Activation Disorders: Conditions like Mast Cell Activation Syndrome (MCAS) and systemic mastocytosis involve abnormal mast cell activation and the excessive release of mediators, including histamine. These disorders lead to symptoms similar to histamine intolerance, such as flushing, gastrointestinal issues, and allergic-like reactions. Although often confused with histamine intolerance, these conditions are better described as mast cell dysregulation disorders, where the improper release of histamine plays a central role in symptom development. However, they differ in that their underlying cause is related to mast cell activation rather than DAO deficiency or impaired histamine metabolism in the gut.

Mechanisms Behind Histamine Intolerance

1. Role of Diamine Oxidase (DAO)
   DAO is the primary enzyme for breaking down histamine in the gut. Reduced DAO activity or levels, which may be caused by genetic, pharmacological, or pathological factors, can lead to histamine accumulation and intolerance symptoms (Schnedl & Enko, 2021). DAO deficiency can result in headaches, gastrointestinal disturbances, and other symptoms mimicking allergies (Sánchez-Pérez et al., 2022). DAO activity may be compromised due to gut inflammation, intestinal permeability or nutrient deficiencies.

1. High Histamine Foods
   Foods rich in histamine, such as aged cheeses, processed meats, fermented products, alcohol, and certain vegetables (e.g., tomatoes, spinach), can worsen histamine intolerance (Matysiak, 2022). Consumption of these foods can lead to symptoms, especially in individuals with DAO deficiencies.

2. Histamine Liberators
   Some foods and substances don't contain histamine themselves but trigger the release of histamine stored in body cells. These include citrus fruits, strawberries, shellfish, and chocolate (Maintz & Novak, 2007). When consumed, they can prompt a rapid release of histamine, leading to symptoms even if the DAO is functioning normally.

3. Endogenous Histamine Production
   The body produces histamine as part of normal physiological processes, particularly in response to allergens, infections, or stress. Overactivity of immune cells like mast cells can lead to excess histamine production, overwhelming the body's ability to degrade it effectively (Sánchez-Pérez et al., 2022).

4. Gut Microbiome and Intestinal Health
   The gut microbiome significantly influences histamine metabolism. An imbalance in the microbiome (dysbiosis) can lead to an overgrowth of histamine-secreting bacteria, such as Bacteroides, Escherichia coli (E. coli), and Proteobacteria, contributing to increased histamine levels in the gut (Sánchez-Pérez et al., 2022). Furthermore, conditions like "leaky gut" or intestinal permeability can worsen histamine intolerance by promoting inflammation and reducing the activity of DAO, the key enzyme for histamine breakdown (Schink et al., 2018).

DAO: The Key to Histamine Degradation

Diamine oxidase (DAO) is the primary enzyme that breaks down dietary histamine in the gut. Produced by the cells lining the small intestine (enterocytes), DAO converts histamine into inactive metabolites, which are then safely excreted from the body. When DAO levels are insufficient or its activity is impaired, histamine from food is not broken down properly, leading to the symptoms associated with histamine intolerance.

Factors That Affect DAO Production and Activity

Many factors can influence DAO production and activity, ranging from genetics and gut health to lifestyle and environmental factors. Understanding these factors can help identify strategies to support DAO production and manage histamine intolerance more effectively.

1. Genetic Predisposition: Certain genetic variations can reduce DAO production or its activity. For example, variations in the ABP1 gene can lead to lower baseline DAO levels, increasing susceptibility to histamine intolerance (Garcia-Martin et al., 2015).

2. Gut Health and Intestinal Integrity:

• The health of the gut lining is crucial for DAO production. Intestinal damage from conditions like inflammatory bowel disease (IBD), coeliac disease, and non-coeliac gluten sensitivity (NCGS) can reduce the number of healthy enterocytes that produce DAO (Schwelberger, 2010).

• Small Intestinal Bacterial Overgrowth (SIBO) can decrease DAO levels by creating an inflammatory environment in the gut, damaging the intestinal lining, and impairing DAO production. Additionally, some bacteria directly degrade DAO, further reducing its effectiveness (Takakura & Pimentel, 2020).

• Increased Intestinal Permeability ("Leaky Gut") allows harmful substances to cross the gut lining, triggering immune responses that can damage enterocytes and reduce DAO production (Park et al., 2009).

3. Microbiome Influences: The gut microbiome significantly impacts gut health and DAO production. An imbalance in the gut flora can contribute to intestinal permeability and inflammation:

   • Pathogenic bacteria like Escherichia coli and Clostridium difficile can damage the gut lining and increase intestinal permeability, impairing DAO production.

   • Beneficial microbes, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Saccharomyces boulardii are known for their role in repairing the gut lining and reducing intestinal permeability, which helps maintain the health of the intestinal barrier and supports DAO production (Everard et al., 2013) (Kelesidis & Pothoulakis, 2012).

   • Butyrate, a short-chain fatty acid produced by bacteria like Faecalibacterium prausnitzii, Roseburia, and Eubacterium rectale, play a crucial role in maintaining gut health by reducing inflammation and supporting immune function. Butyrate has also been shown to reduce histamine levels by blocking mast cell degranulation, helping to alleviate symptoms of histamine intolerance (Di Pierro et al., 2020).

   • Bifidobacteria and Lactobacillus species help regulate the immune system, reduce gut inflammation, and maintain a balanced gut environment, which supports overall gut health and DAO productions

4. Medications That Inhibit DAO: Some medications can inhibit DAO activity or reduce its production, such as:

   • Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin, which can damage the gut lining and inhibit DAO production (Izquierdo-Casas et al., 2018).

   • Antidepressants and Antihistamines: Certain types can interfere with DAO activity.

   • Antibiotics: Long-term use can disrupt the gut microbiome, affecting DAO production.

   • Alcohol: Directly inhibits DAO activity and increases histamine release (Vlieg-Boerstra et al., 2005).

5. Nutritional Deficiencies: Vitamin B6, Copper, and Vitamin C are essential nutrients for DAO activity. Deficiencies in these can impair the enzyme’s function and lead to higher histamine levels:

   • Vitamin B6 acts as a cofactor for DAO.

   • Copper is critical for the enzyme’s catalytic activity.

   • Vitamin C helps reduce histamine levels in the body by supporting DAO activity (Maintz et al., 2011).

6. Hormonal Influences: Hormonal fluctuations can impact DAO levels. For example, DAO production increases during pregnancy to protect the foetus from histamine’s effects. Conversely, some women experience lower DAO levels during their menstrual cycle, which may exacerbate histamine-related symptoms like migraines (Manzotti et al., 2016).

7. Lifestyle Factors:

• Chronic stress and poor sleep can impair gut health and reduce DAO production. Stress can also trigger the release of histamine from mast cells, increasing the body’s histamine load.

• Dietary Choices and Alcohol Consumption: Regular alcohol intake can inhibit DAO activity and increase histamine levels.

8. Allergies and Immune Responses: Frequent allergic reactions can deplete DAO levels as the body continuously tries to break down histamine. The immune response to allergens triggers histamine release, increasing the body’s demand for DAO (Doeun et al., 2017).

Optimising Histamine Metabolism for Better Gut Health and Reduced Histamine Levels

Rather than relying on restrictive long-term diets to manage histamine intolerance, a more effective approach is to support DAO activity and overall gut health. This involves addressing multiple factors that influence histamine metabolism:

1. Improve Gut Health:

• Address Underlying Conditions: Conditions like SIBO (Small Intestinal Bacterial Overgrowth), IBD (Inflammatory Bowel Disease), and increased intestinal permeability ("leaky gut") can impair DAO production and histamine metabolism (Schink et al., 2018). Treating these issues and supporting gut health are vital for improving histamine tolerance.

• Incorporate Fibre and Prebiotics: Consuming fibre and prebiotic foods (e.g., vegetables, whole grains, legumes) helps nourish beneficial gut bacteria, maintains gut integrity, and creates an environment that supports DAO production.

2. Boost Butyrate Production:

• Encourage a Diverse Microbiome: Promoting a diverse gut microbiome enhances the production of butyrate, a short-chain fatty acid that is essential for gut health, reducing inflammation, and supporting DAO function (Sánchez-Pérez et al., 2022). Consuming a variety of fibre-rich foods, including fruits, vegetables, whole grains, and legumes, can increase butyrate production in the gut.

• Support the Gut Lining: Butyrate also helps maintain a healthy intestinal lining, which reduces inflammation and supports the breakdown of histamine.

3. Add Probiotics:

• Choose Beneficial Strains: Probiotics containing strains like Bifidobacteria and Lactobacillus can indirectly support DAO activity by improving gut health and modulating immune function.

• Use Targeted Probiotics: Consider probiotics such as Saccharomyces boulardii and strains that promote the growth of butyrate-producing bacteria to help repair the gut lining and reduce inflammation.

4. Address Nutritional Deficiencies:

• Nutrients for DAO Support: Adequate levels of vitamin B6, copper, and vitamin C are important for optimal DAO activity. These can be obtained through a balanced diet or supplemented as necessary.

5. Review Medications and Alcohol Consumption:

• Medications That Inhibit DAO: Some medications can inhibit DAO activity or affect histamine breakdown (e.g., NSAIDs, certain antidepressants). Speak to a healthcare provider about potential alternatives.

• Limit Alcohol: Reducing or avoiding alcohol intake can help maintain DAO activity and effectively manage histamine levels.

6. Manage Stress and Sleep:

• Stress Reduction: Practices like mindfulness, meditation, and regular exercise support gut health and help regulate histamine levels.

• Prioritise Good Sleep Hygiene: Quality sleep is crucial for maintaining a healthy gut and supporting DAO function.

If you're struggling to introduce new foods or supplements into your diet and feel overwhelmed by histamine intolerance, I can help you find a path to food freedom. By taking a comprehensive approach to your health, it’s possible to manage your symptoms sustainably while enjoying a balanced, unrestricted diet.