The Gut’s Role in Histamine Intolerance and MCAS
Socrates once said, “All disease begins in the gut.”
While that may be a bit of an overstatement, modern science continues to show he wasn’t entirely wrong. The gut isn’t just a site of digestion—it’s a densely connected, highly intelligent organ system with profound influence over the immune system, nervous system, hormones, and even inflammation.
Around 70% of the immune system is located in the gut. It’s often called the body’s second brain, not only because it communicates constantly with the central nervous system, but because it contains more than 500 million nerve cells—more than the spinal cord.
The gut also produces more than 20 different hormones, houses trillions of microbes that influence everything from mood to metabolism, and serves as the body’s first line of defense against pathogens and toxins.
So it’s no surprise that when gut function is disrupted through infection, inflammation, or barrier breakdown, it can have ripple effects across nearly every system in the body. Downstream effects may include immune dysregulation and chronic inflammation, which can contribute to issues like histamine intolerance and conditions such as mast cell activation syndrome (MCAS).
In this article, we’ll explore whether gut dysfunction through changes in barrier integrity, enzyme activity, dysbiosis, and inflammation could be an overlooked driver of histamine-related symptoms in long COVID and MCAS.
What Is Histamine and What Happens When It Builds Up?
Histamine is a chemical messenger that exists widely in nature—it’s found in bacteria, plants (including many foods), and in the human body. It plays roles in digestion, immune signaling, and cell-to-cell communication. In the body, histamine is stored mainly in two immune cell types: basophils (in the blood) and mast cells (in tissues like the skin, lungs, gut, and nervous system).
When mast cells detect a potential threat such as an allergen, toxin, virus, or injury, they release histamine along with other mediators to coordinate the immune response. This can trigger familiar allergy symptoms like runny nose, flushing, rashes, hives, and itchy eyes. But because mast cells are found throughout the body, histamine’s effects can extend further—into digestion (nausea, diarrhea, bloating, reflux), hormones (worsening PMS), the nervous system (migraines, anxiety, brain fog, insomnia), and even the cardiovascular system (tachycardia).
Histamine intolerance occurs when histamine—whether from foods, gut bacteria, or immune activation—accumulates faster than the body can break it down. This is often due to reduced activity of diamine oxidase (DAO), the primary enzyme for degrading histamine in the gut. It frequently presents with persistent gastrointestinal symptoms, especially those without a clear cause.
Mast cell activation syndrome (MCAS), on the other hand, involves mast cells releasing mediators (including but not limited to histamine) too easily or too often. Triggers might be things that wouldn’t normally cause a reaction like heat, stress, exercise, certain foods. In MCAS, the number of mast cells is usually normal, but their behavior is dysregulated. DAO deficiency can add fuel to the fire, allowing histamine to build up and potentially worsening symptoms or triggering flares. While histamine may be part of the problem, it’s not the whole story.
Several factors can act as triggers—and viral infections are a big one. Some people notice these issues start or worsen after viral illness, including COVID-19. Viruses can alter mast cell behavior directly, increase inflammatory signaling, and even shift the gut microbiome, setting the stage for both MCAS flares and histamine intolerance.
The Gut Connection
The gut isn’t just where food is digested, it’s also a major hub for immune activity and histamine regulation. The cells lining the small intestine produce the histamine busting enzyme we mentioned earlier, DAO.
This lining is only one cell layer thick so it can easily be disrupted by inflammation, infections, stress, and more. When it becomes more permeable (referred to as increased intestinal permeability), substances like bacterial fragments, food particles, toxins, and histamine can cross into the bloodstream, triggering immune activation, chronic inflammation, and even food intolerances.
Research has shown that inflammation and gut barrier integrity indirectly influence DAO activity. When the intestinal lining is damaged, DAO production can drop, reducing the breakdown of histamine. This can create a cycle: higher histamine levels trigger more immune activation, which further damages the gut barrier and can worsen symptoms.
By optimizing the health of the gut we can increase this enzyme’s ability to break down histamine. Managing histamine solely by lowering intake (via a low-histamine diet) is like mopping up water from an overflowing sink—it may help in the short term, but the faucet (inflammation, gut barrier damage, low DAO) is still running.
Nourishing the Gut: Nutrition Strategies to Manage Histamine Intolerance and MCAS
So how do we support gut health? The gut is a complex topic—one I’ll break down in more detail in a future article. But if we zoom in on specific gut-centered strategies to help manage MCAS and histamine intolerance, fiber deserves the spotlight.
Not all fiber is created equal. Here, we’ll focus on soluble fiber: as its name suggests, soluble fiber dissolves in water, forming a gel-like substance in the digestive tract. Beyond general benefits like improving satiety and helping to lower cholesterol, soluble fiber also acts as a food source for the beneficial bacteria living in the gut.
These microbes make up the gut microbiome—a living ecosystem of trillions of organisms residing in the large intestine. They play an astonishing range of roles: producing hormones, influencing weight management, supporting nutrient absorption, regulating the immune system, and more. And just like any ecosystem, balance is key here.
Think of your gut microbiome like Yellowstone National Park. Before wolves were reintroduced, elk populations exploded, overgrazing vegetation, disrupting riverbanks, and throwing the entire ecosystem off balance. When wolves were reintroduced, they acted as a keystone species—a small but crucial population that helped restore balance across the entire park. Their presence didn’t just control elk numbers. It triggered a chain reaction: vegetation regrew, beavers came back, riverbanks stabilized, and the entire system recovered.
Our microbiomes are like this as well. Your beneficial gut bacteria act like those wolves—keystone species in your internal ecosystem. If there is not enough beneficial bacteria to keep the not so beneficial ones in check, it can lead to an overpopulation of pathogenic or opportunistic bacteria in this community (some of which produce histamine). That’s like leaving the “histamine faucet” turned on. By maintaining balance in your microbiome, you’re helping turn that faucet down while supporting a healthier, more resilient gut ecosystem overall.
Like all living things, your gut microbes need to eat too. Most nutrients are absorbed before reaching the large intestine, so the bacteria need something that can make the journey down there intact. That’s where fiber comes in because it reaches the colon largely undigested. There, it becomes food for your beneficial bacteria. These microbes ferment the fiber, producing byproducts called short-chain fatty acids (SCFAs): acetate, propionate, and butyrate—with butyrate being especially important for supporting the integrity of the gut lining by serving as an energy source for colonocytes (the cells lining the colon). If you are eating a low-fiber diet, these beneficial gut bacteria can become starved for energy and may die off or start feeding on the gut lining, which can further contribute to intestinal permeability.
Additionally, butyrate has been shown to inhibit mast cell degranulation, the process by which the mast cells release histamine and other metabolites. This finding indicates dietary fiber, and subsequently SCFAs, may help modulate mast cell activity, reducing unnecessary histamine release that can trigger MCAS symptoms.
In short, fiber influences histamine intolerance and MCAS in three key ways:
Strengthening the gut lining – SCFAs (particularly butyrate) provide energy for colonocytes, helping maintain a strong barrier.
Feeding beneficial bacteria – A fiber-rich diet nourishes the keystone microbial species that maintain balance in the gut ecosystem (also preventing them from feeding on the gut lining and imparing DAO activity).
Calming mast cells – SCFAs act as signaling molecules that help reduce overactive mast cell responses, lowering histamine release.
⚠️ Important nuance: Not all fiber is helpful for everyone—especially individuals with SIBO, IBD, or severe gut dysbiosis. While fiber can serve as a foundational, first-line strategy to support gut health, it is rarely the only intervention needed and may not be the right first step for some conditions. Personalization is key: a comprehensive stool analysis, evaluation for nutritional deficiencies, or other functional testing may be indicated to guide the best approach. In some cases, functional providers may also recommend targeted supplementation, such as DAO or other nutrients, on a case-by-case basis.
Medical Disclaimer
This article is for informational purposes only and is not intended as medical advice. MCAS and histamine intolerance are complex conditions that require individualized care. Always consult your healthcare provider before making changes to your treatment or lifestyle.
Wrapping Up
Yet another road brings us back to the gut. The more we learn about histamine, mast cells, and gut health, the more we see how interconnected these systems are—and how much there still is to uncover.
How might the other roads in your own health journey connect to the gut? This is just one piece of a larger map, and understanding these connections can inspire us to keep asking questions and investigate further.
If you’re navigating the ups and downs of histamine intolerance or Mast Cell Activation Syndrome and are looking for a food-first, root-cause approach to managing and reducing symptoms, you don’t have to do it alone. As a functional dietitian, I work with clients to build the foundation for stability, and create nutrition and lifestyle plans tailored to their unique needs.
📞 Ready to take the next step? Schedule your free 15-minute discovery call to learn more about working together.
