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A Functional Medicine Protocol for Leaky Gut Syndrome

Medically reviewed by 
A Functional Medicine Protocol for Leaky Gut Syndrome

While leaky gut syndrome has not been universally established as a distinct medical condition, its concept remains a topic of considerable interest and discussion within the scientific community. 

Mounting evidence suggests increased intestinal permeability can contribute to various chronic health issues. Therefore, a growing need exists to test for and address leaky gut in patients presenting with typical gastrointestinal dysfunction and systemic inflammation symptoms. 

This article will provide a comprehensive overview of leaky gut treatment protocols, offering insights into testing modalities, dietary and lifestyle interventions, and targeted therapeutic approaches to restore gut health.


What Is Leaky Gut?

Leaky gut is the loosening of the tight junctions between the cells that line the small intestine. 

Under typical conditions, the small intestinal barrier exhibits selective permeability. This means it permits the passage of small, digested proteins, nutrients, and water into the bloodstream while blocking the passage of larger, undigested molecules. 

Leaky gut is a state characterized by increased permeability. This is how it develops:

  • Small intestinal cells are linked together by proteins called tight junctions.
  • Inflammatory triggers can lead to the breakdown of these proteins, effectively creating larger holes between the small intestinal cells.
  • Once this happens, you have a leaky gut. A leaky gut allows large molecules (like undigested food particles, microbes, and toxins) to pass through the intestinal barrier, leading to problems in and beyond the digestive tract.

Leaky Gut Signs & Symptoms

Leaky gut can cause a wide array of symptoms across multiple body systems:

  • Digestive: abdominal pain, gas, bloating, constipation, diarrhea
  • Neurological: headache, anxiety, depression, brain fog, fatigue
  • Musculoskeletal: joint pain
  • Skin: acne, rashes, eczema, psoriasis

Research also shows that leaky gut plays a role in the development and progression of chronic diseases, including: 

  • Allergies
  • Alzheimer's disease
  • Arthritis
  • Asthma
  • Autism
  • Autoimmune disease: celiac disease, inflammatory bowel disease, lupus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes
  • Chronic fatigue syndrome
  • Fibromyalgia
  • Liver disease
  • Obesity (5, 8, 33, 45

Root Causes of Leaky Gut

Zonulin is a protein secreted by the intestinal tract and is currently the only known protein that reversibly regulates intestinal permeability by controlling the tight junctions between epithelial cells. Environmental triggers and lifestyle factors can stimulate the upregulation of zonulin, effectively increasing intestinal permeability. (32)


Medications: Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy agents, radiation therapy, oral contraceptive pills, and frequent antibiotic use can cause leaky gut by inducing intestinal inflammation and decreasing diversity within the gut microbiome. (23

Diet: Western diets, characterized by excessive inflammatory foods (i.e., refined sugars, saturated/trans fats, alcohol) and insufficient fiber, increase intestinal inflammation and dysbiosis (2). The wheat protein gliadin can directly upregulate zonulin and lead to leaky gut. This mechanism is suspected to contribute to the development of celiac disease.

Stress: Emotional and physical stress influence nervous system function and increase stress hormones, which can contribute to leaky gut. Chronic, unresolved stress induces intestinal dysbiotic patterns and prevents healing pathways, making it more difficult for the body to restore an intact intestinal barrier. (25, 42, 57

Poor Sleep: Sleep deprivation can adversely affect the gut microbiota, which can exacerbate gut barrier dysfunction and lead to the development of leaky gut syndrome.


Intestinal dysbiosis (an imbalance of microbes in the gut) increases zonulin production and stimulates intestinal permeability (32). Dysbiosis can negatively impact the neural, hormonal, and immune mechanisms influencing gut permeability (51). Dysbiosis is associated with intestinal dysmotility and gastrointestinal symptoms. 

Environmental Toxins

Exposure to environmental toxins, including bisphenols, phthalates, heavy metals, and pesticides, contributes to increased oxidative stress, inflammatory responses, disruptions in healthy hormonal signaling, and imbalances in the gut microbiome. Together, these interruptions contribute to the progression of leaky gut.

How to Diagnose Leaky Gut

Doctors may diagnose leaky gut through medical history assessment, symptom evaluation, and laboratory tests.

Step 1: Leaky Gut Testing

Lab tests for intestinal permeability measure zonulin or the lactulose-to-mannitol ratio (LMR).


Fecal zonulin is a direct measurement of the mucosal production of zonulin. However, due to notable intraday fluctuations, concerns arise regarding the accuracy of this collection method. To address this, researchers suggest assessing IgA and IgG antibodies against zonulin, which are more stable and potentially provide a more precise evaluation of intestinal permeability. (20

These zonulin tests are available to order through Rupa Health:


Lactulose and mannitol are two sugar molecules of different sizes. When ingested orally, they pass through the intestinal barrier. However, if the barrier is compromised, larger molecules like lactulose may pass through more easily, leading to an elevated LMR in urine samples collected after ingestion. This ratio serves as an indicator of increased intestinal permeability, suggesting potential issues with gut barrier function. (20

The Intestinal Permeability Assessment by Genova Diagnostics measures the urinary LMR. 

Step 2: Testing to Uncover Root Causes of Leaky Gut

Once the presence of leaky gut has been established, additional testing can be helpful to identify the underlying triggers for increased permeability. These labs help guide doctors in personalizing treatment plans and may include comprehensive gastrointestinal, stress, food sensitivity, and environmental toxin testing. The decision to order these various labs can be guided by patient history and the symptoms they present with. 

These panels can be an excellent starting point: 


Treatment Plan for Leaky Gut

Plenty can be done to heal leaky gut and improve overall gut health. The 5-R protocol is a framework used to restore gut health by identifying, eliminating, and healing gut-related issues. Strategies used in this protocol include dietary changes, lifestyle modifications, and gut-healing supplements.

1. Remove 

Here's Why This Is Important: 

This phase involves removing potential triggers such as inflammatory foods, pathogens, toxins, and stressors that may aggravate the gut lining. By addressing these underlying causes, the "remove phase" creates a favorable environment for the subsequent steps of the protocol, allowing for effective healing and restoration of gut health.

How Do You Do This?

Several steps can be taken to eliminate factors contributing to gut dysfunction. A thorough patient history and lab results help doctors make their recommendations.

  • Trigger Foods: Identify and eliminate foods that may be triggering inflammation or sensitivity reactions in the gut. Common culprits include wheat, milk, peanuts, soy, egg, corn, and processed foods
  • Address Gut Infections: Test for and treat gut infections, including bacterial overgrowth, parasites, or fungal overgrowth. This can involve using prescription medications or antimicrobial herbs, such as berberine, oregano, neem, and garlic. 
  • Reduce Toxin Exposure: Minimize exposure to environmental toxins and harmful substances that can disrupt gut health. This includes avoiding cigarette smoke, eating organic produce, drinking filtered water, and using air purifiers whenever possible.
  • Manage Stress: Implement stress-reducing techniques such as meditation, deep breathing exercises, yoga, or mindfulness practices. 

2. Replace

Here's Why This Is Important:

The "replace phase" of the 5-R gut healing protocol focuses on restoring optimal digestive function by replenishing beneficial substances that support gut health. This phase lays the foundation for effective healing and gut restoration, which are the focus of the next steps in the protocol.

How Do You Do This?

This step involves reintroducing essential enzymes required for proper digestion and nutrient absorption. Digestive enzyme supplements often include one or more of the following ingredients to enhance the digestion of carbohydrates, proteins, and fats:

  • Hydrochloric acid
  • Pepsin
  • Amylases
  • Proteases
  • Lactase
  • Lipase
  • Ox bile

Nutrient replacement can also be initiated during this phase for patients with nutrient deficiencies secondary to malabsorption or restricted diets. A high-quality multivitamin/mineral supplement provides essential micronutrients required by the body for healing, optimal gut health, and general well-being.

3. Reinoculate

Here's Why This Is Important:

The "reinoculate phase" replenishes and diversifies the beneficial bacteria in the gut microbiome to restore balance in the microbial community. A healthy gut microbiome is essential for optimal digestion, nutrient absorption, immune function, and overall health.

How Do You Do This?

Reinoculation can be achieved with probiotic supplements or fermented foods like yogurt, kimchi, sauerkraut, or pickles. Lactobacillus spp., Bifidobacterium spp., and Saccharomyces boulardii are commonly utilized probiotics to optimize digestive health and function. 

4. Repair

Here's Why This Is Important:

The "repair phase" focuses on rebuilding and restoring the integrity of the intestinal lining by supporting mucosal healing, reducing inflammation, and promoting tissue regeneration. 

How Do You Do This?

Repairing the gut lining takes time, but various gut-healing supplements have been shown to decrease intestinal permeability and inflammation to support the healing process. 

  • Vitamin D modulates the expression of tight junction proteins and the immune system, thereby regulating intestinal permeability. 2,000 IU daily has been shown to improve intestinal permeability. 
  • L-glutamine is an amino acid and the preferred fuel source for the cells lining the intestines. A substantial pool of evidence supports its intestinal healing properties. Doses can range from 15-45 grams daily. (37, 40
  • Omega-3 polyunsaturated fatty acids 1,000-3,000 mg daily
  • Zinc carnosine 50 mg twice daily

Just as inflammatory diets can perpetuate leaky gut, an anti-inflammatory diet rich in nutrient-dense foods can support mucosal healing and reduce inflammation. This includes:

  • Bone broth is rich in amino acids, collagen, and minerals that support gut health and repair
  • Omega-3-rich foods, including fatty fish, flaxseeds, chia seeds, and walnuts
  • Colorful fruits and vegetables are rich in antioxidants and phytonutrients that help reduce inflammation, support tissue repair, and nourish a healthy gut microbiome
  • Fiber-rich foods: soluble fiber from foods like oats, apples, and beans can help support a healthy gut microbiome

5. Rebalance

Here's Why This Is Important:

This phase aims to sustain the progress made during the protocol by promoting a balanced and supportive environment for ongoing gut health. By incorporating lifestyle modifications, dietary adjustments, stress management techniques, and regular monitoring, this final phase helps prevent relapse and maintains long-term intestinal wellness.

How Do You Do This?

This is an ongoing process that focuses on forming sustainable, gut-healthy habits:

  • Get sufficient, good-quality sleep every night. Implement habits that support optimal sleep, such as having a consistent bed- and wake-up time every day, avoiding caffeine in the afternoon/evening, and turning off screens at least one hour before bed. Patients who continue to experience sleep disturbances despite having good sleep hygiene should discuss diagnostic testing and treatment options for sleep disorders.
  • Continue to eat a well-balanced, anti-inflammatory diet
  • Exercise regularly. Evidence suggests that getting three hours of moderate-intensity weekly best supports gut health.
  • When possible, eliminate stressors from your life. Mind-body practices, such as yoga, deep breathing, and meditation, can help reorient to unavoidable stressors so that they have less of a negative impact on mental, emotional, and physical health.

The Risks of Untreated Leaky Gut

When the intestinal barrier becomes compromised, undigested food particles, toxins, and bacteria can leak into the bloodstream, triggering an immune response. This immune reaction results in the release of inflammatory molecules that initiate and sustain inflammation throughout the body. 

Chronic inflammation can damage tissues and organs, contributing to the development of numerous health conditions, including autoimmune diseases, metabolic disorders, cardiovascular diseases, neurodegenerative diseases, and cancer. (19, 49)


Key Takeaways:

  • Leaky gut involves the disruption of the intestinal barrier, leading to chronic inflammation and dysregulation of the immune system, which can contribute to the development of various chronic diseases. 
  • The good news is that the intestinal barrier can be regenerated by addressing underlying factors predisposing someone to leaky gut, including poor diet, chronic stress, and gut dysbiosis. Comprehensive testing, which identifies specific triggers, plays a role in effective treatment.
  • Healthcare practitioners can develop targeted interventions to restore gut health and mitigate the systemic effects of leaky gut. Ultimately, a multifaceted approach combining dietary modifications, lifestyle interventions, targeted supplementation, and personalized treatment strategies offers the best chance to address leaky gut and promote long-term health.
The information provided is not intended to be a substitute for professional medical advice. Always consult with your doctor or other qualified healthcare provider before taking any dietary supplement or making any changes to your diet or exercise routine.
Learn More

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