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Intestinal Permeability: the AutoImmune Connection

January 31, 2026 | 18 Comments | SAFM Team

 

Hashimoto’s, Multiple Sclerosis, Lupus, Rheumatoid Arthritis …. These types of disease in the body seem so different because they attack different parts of the body. However, they are all actually caused by dysfunction of the immune system – an overwrought, dysregulated immune system. The brain, the thyroid, the skin, the joints, etc. are just the various localized battlefields. 

Conventional care often focuses solely on AI disease suppression. That can be a tissue- or even life-saving blessing, but suppression is not the same as regression. If we don’t address the root causes, then follow-on additional autoimmune dynamics elsewhere in the body are a logical expectation. We have to do better.

The Functional Medicine lens compels us to ask and resolve: what is feeding immune dysregulation upstream from the autoimmunity in this unique person?

With the rapid increase in exposure to processed foods, chemicals, toxins, chronic stress, GMOs, medications, and many other foreign molecules – usually on a daily basis – it shouldn’t be a surprise that our immune system is challenged to maintain optimal tolerance! The gut is not only the digestive system.The gut is a primary immune interface where the body constantly decides what is safe, what is a threat, and how intensely to respond.  

To promote regression of autoimmune disease (AI), we have to discover why each person’s immune system is overwrought and resolve it. Each case is unique, and there are usually a handful of triggers and mediators. From intestinal yeast overgrowth, to lead or arsenic toxicity, undiagnosed food sensitivities, Vitamin A deficiency, high viral load, B vitamin insufficiency (such as can lead to poor toxin clearance capability), iron overload, HPA dysregulation, non-pathogenic bacterial overgrowth such as Clostridia, and more.  

A common mediator of immune dysregulation is loss of barrier function in the body. Where normal controls over what can pass into circulation are weakened. Often this dysfunction begins in the gut via the development of enhanced intestinal permeability (EIP). It’s a functional imbalance that people will seldom hear about from their primary care provider. However, it may make all the difference as to whether an AI dynamic is sustained long-term or can be dramatically improved or even fully resolved.

Genetics play a role in predisposition for certain AI disorders, but alone, genes are almost never enough to cause activation.  Environment determines which of our genes “turn on” through epigenetic mechanisms. The gut is a primary path by which our body senses and responds to our environment.  EIP offers a short-cut for inflammatory molecules and mediators there (including myriad microbial and ingested toxins and partially digested foods) to rapidly gain over-exposure to our immune system and then enter into systemic circulation. This is one of the easiest ways to understand why a gut-centered problem can be expressed downstream via brain inflammation, joint pain, skin flares, or autoimmune volatility. 

It is also well-understood that individuals may be more vulnerable to EIP.  For example, when some people consume gluten, a protein found in many common grains, especially wheat, they release large amounts of a protein in the human gut called zonulin, which actually promotes greater intestinal permeability.  This may be at play regardless of whether an individual tests positive for IgG or IgA mediated immune hypersensitivities to gluten or wheat. Full gluten elimination is thus often a key component of an autoimmune healing plan. Elimination of cross-reactive foods (usually due to protein similarity), such as dairy or gluten-free grains, is often layered in but ideally only after sustainable gluten elimination has been achieved.

Merely making a recommendation is not the same, however, as partnering with a unique patient to facilitate their lifestyle change! Well applied Functional Medicine is never just about Diagnosis and Treatment. Your expertise must expand to also include Education, Inspiration, and Empowerment. It’s where our role as practitioners can really shine. Help your clients to find convenient, whole-food, nutrient-dense alternatives.  Teach them how to read labels.  Prepare them for navigating family gatherings.  Practice what to say at a restaurant.  Give them a thorough list of common hidden sources of gluten. Cheer them on!  Provide accountability and celebrate their wins.  There is an art you must master to creating and maintaining a savvy clinical partnership. It can also make all of the difference as to whether a person is actually able to get well or not. 

Here is an excellent article by Dr. Joe Pizzorno summarizing the effect of zonulin, wheat, and other foods in the etiology of autoimmune disease.  Great reading if you want to explore this topic more in-depth or share information fodder with a savvy client. We also owe a great deal to Dr. Alessio Fasano’s pioneering work in helping define zonulin as a credible mechanistic pathway in barrier regulation.

Enjoy this clinical tip video!  Many other considerations are covered, including EIP testing considerations. 

Consider the following interventions that can help to reduce gut inflammation, heal intestinal mucosa, and restore barrier function. You can learn to master the order of operations and a customized approach to help each of your patients heal this gateway to immunoregulatory disease. 

  • Probiotic, twice daily, that includes Lactobacillus rhamnosus or L. plantarum to increase T regulatory cells and re-establish appropriate immune tolerance. Saccharomyces boulardii may also be helpful if there are excessive immune challenges (e.g., Lyme disease) or immunosuppression (e.g., low secretory IgA) enabling opportunistic microbial overgrowths. 
  • Full elimination of all gluten as a first dietary priority. Only after this is well achieved, consider also dairy foods and other grains. Use care, however, not to promote overwhelm by pushing for too much elimination too quickly. 
  • Mucilaginous herbs such as aloe, DGL, marshmallow, and slippery elm can help to restore mucosal integrity. 
  • The amino acid l-glutamine (e.g., 3-4g dose, 2-3x daily, taken on an empty stomach) is often effective for promoting tissue restoration of villi and enterocyte function. Note that supplemental l-glutamine is contraindicated in brain cancers and may also exacerbate hypervigilance in those with acute anxiety (add low’n’slow if this is a concern, to safely gauge response). Those with celiac disease or healing from other inflammatory bowel disease may benefit from appreciably higher doses. 
  • Begin to crowd out processed, chemical-laden foods with a colorful diversity of whole foods. Begin this habit with easy, early wins by increasing intake of foods a person already enjoys.
  • Anti-inflammatory herbs, such as quercetin and/or curcumin (e.g., 500mg twice daily), may help to calm gut inflammation, heal excess permeability, and also reduce systemic inflammation in order to minimize use of medications that exacerbate EIP (e.g., NSAIDs, steroids).  
  • Optimal levels of vitamin A, vitamin D, and zinc, all nutrients required for maintenance of tight junctions between enterocytes. 

Go beyond EIP. If you wish to learn more about the overall pattern of dysfunction and imbalance that typically creates the terrain for autoimmune disease development, I encourage you to check out this episode of SAFM’s podcast. 

 

P.S.  If you are passionate about transforming healthcare through the power of functional medicine, we encourage you to learn more about SAFM’s practitioner training programs. Enrollment for our next cohort is now open!

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18 Questions for “Intestinal Permeability: the AutoImmune Connection”

  1. 9
    Marie Harrison says:
    November 6, 2020 at 11:07 am

    I find that a daily dose of S.boulardii tends to result in constipation in clients and wonder how you get around this ‘side effect’? Thank you :o)

    Reply
    • 9.1
      SAFM Team says:
      January 15, 2021 at 3:21 pm

      My clinical experience is actually that S. boulardii is typically normalizing and can often improve loose stools or diarrhea. For each individual case, though, it’s important that we examine the aggregate effect of case details. It may be that a person’s “normal” is actually constipation given other factors, and the S. Boulardii is simply revealing that reality (and next opportunity to address a functional imbalance!). For example, clients can have underlying motility due to common factors such as unacknowledged lactose intolerance, high intake of stimulants, medications (e.g. metformin, SSRIs), and/or hydrogen-mediated SIBO. Others can have underlying sluggish motility due to common factors such as insufficient fiber intake, magnesium insufficiency, hypothyroid function, insufficient Vitamin B6 (required to synthesize serotonin – 95%+ of which is made in the gut), and/or methane-mediated SIBO. S. boulardi will effect microbiome composition and thus also directly affect enteric serotonin synthesis in response. I would keep peeling the onion layer by layer addressing other imbalances that are likely at play.

      Reply
  2. 8
    Sarah Campbell says:
    November 10, 2019 at 10:36 pm

    You mention an overgrowth (or increased presence of) Clostridia (even though toxin A and B are negative) being a cause of intestinal permeability. Can you give me more detail on addressing this type of overgrowth in a client that suffers from eczema and autoimmune activation? Thank you.

    Reply
  3. 7
    Jacki Veler says:
    May 15, 2019 at 3:11 pm

    Thank you for the great information!

    My question is to the extent of removing inflammatory foods, like gluten, dairy, etc. Should we advise, or hope to see, our clients treat these elimination diets like they would if it were an allergen? Vigilance about cross contamination, or is simple avoidance of clear sources enough? There are many gluten free options among processed food, (even simply processed food) but that may have been cross contaminated in the processing. Or in restaurants, preparing food is also a cross contamination risk.

    Thank you,
    Jacki

    Reply
    • 7.1
      SAFM Team says:
      May 31, 2019 at 2:57 pm

      Your question brings up the concept of the individuality as the approach here will heavily depend on the situation of a client – are they barely getting out of bed due to a full-on autoimmune condition or are they generally well and only complaining from occasional joint pain. In the first case, 100% elimination of potentially exacerbating foods is the most healing choice. In the second scenario, they may get away with a marked reduction vs 100% elimination and get their results a bit more slowly but have more ease and food options available. That’s from the perspective of the dis-ease advancement and the health results that a person would like achieve.
      In real life when choices are indeed sometimes limited it may be worth supporting the brush border digestive enzymes with a formula that assists with the breakdown of most common allergens – a few good examples here include ProtectZyme by DFH, Digest Spectrum by Enzymedica or GlutenManager by Integrative Therapeutics and many others. Those enzymes are a nice tool to use to give clients peace of mind while eating out so that they don’t have to worry about the cross contaminations that you are talking about. Those enzyme formulas are not designed to fully replace the food elimination, though.

      Reply
  4. 6
    sharon chud says:
    February 5, 2018 at 2:36 pm

    On top of the question above if a client has yeast overgrowth would you avoid Sac Boulardi? as a probiotic

    Reply
    • 6.1
      SAFM Team says:
      February 14, 2018 at 9:45 am

      S. Boulardi might be beneficial, actually, if there is an intestinal yeast overgrowth because it provides competition, stimulates immune response, and can change up the pH of the environment to be less hospitable to candida. I would not use S. Boulardi, however, if there is a known allergy or sensitivity to yeast or if a person is severely immunocompromised. You might appreciate this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868213/ .

      Reply
  5. 5
    Lisa Verdejo says:
    January 29, 2018 at 10:12 am

    To confirm my understanding here, I see that gluten is to be eliminated for AI dynamics to mitigate intestinal permeability a la the zonulin release. However, you mention the elimination of all grains due to potential molecular mimicry to gluten. So, therefore, the gluten elimination is also to address a potential IgG (and other potential immune system) response?.

    Reply
    • 5.1
      SAFM Team says:
      February 7, 2018 at 11:18 am

      Yes. But also… Molecular mimicry may not be via IgG reaction at all; it may be via IgA reaction (in the mucosal lining) or other immune reactivity modes. Specifically for AI, we are concerned about multiple pathways of exacerbation. A person also may or may not have an IgG sensitivity to gluten, but it needs to be eliminated regardless to the zonulin provocation and its role in IP.

      Reply
  6. 4
    Ana Paula Robledo Soto says:
    August 7, 2017 at 11:45 am

    Hi, what is the proper way to use zinc carnosine and DLG licorice in regards to doses and times per day to heal the gut lining?

    Reply
    • 4.1
      SAFM Team says:
      August 8, 2017 at 11:30 am

      Alas, this depends on the individual and the extent of the damage. If we are speaking of general IP associated with a chronic autoimmune activation, then I would recommend twice daily dosing on an empty stomach – at least an hour before food (perhaps at bedtime ~3 hrs after finishing dinner and then again late morning?). The bedtime dose is ideal because there will be no interference from any other oral intake (other than perhaps water) for several hours. Perhaps 300-500mg DGL and 100mg zinc carnosine (together) for each dose. You may wish to use zinc carnosine in particular if there is a need to support the *gastric* lining (e.g. gastritis). Otherwise, you might consider a multi-nutrient formula for ease that involves other mucilaginous herbs (with or without l-glutamine) e.g. Thorne’s GI Encap, Pure Encapsulations DGL Plus, or Designs for Health’s GI Revive.

      Reply
  7. 3
    Heather Green says:
    September 12, 2016 at 4:23 pm

    So zonulin is also released in those without auto-immune dynamics correct? What causes this from creating intestinal permeability in those folks?

    Reply
  8. 2
    Lisa says:
    February 6, 2016 at 11:30 am

    I’m reading blogs in which people recommend taking much higher doses of l-glutamine (e.g. 40g or 80g/day). Any thoughts about such megadoses?

    Reply
    • 2.1
      SAFM Team says:
      February 7, 2016 at 2:25 pm

      I personally have never recommended doses this high, and I am unaware of clinical research indicating they are necessary for healing IP. In fact, it’s important that the diet contain a balance of other key amino acids which also help to nourish enterocytes (e.g. arginine); l-glutamine is the primary fuel but not the only one for these cells. I also do not think that megadoses of intake have been studied for safety for ongoing use. This might be of interest to you: http://jn.nutrition.org/content/138/10/2025S.long . I would also be cautious in known IP to consider the potential neurological effects of high doses of l-glutamine, being cautious to increase dosage slowly, even at the lower levels I mention (https://schoolafm.com/ws_clinical_know/leaky-brains/). I did specify above a likely higher need specifically for those with celiac disease (which can be gauged given ongoing assessment for other food sensitivities), as the precious intestinal lining in that case is the site of both intestinal permeability and the autoimmune attack itself. I believe people will likely have the best results combining l-glutamine with other supportive agents to nourish and build-up the protective mucosal layer in the intestines as well e.g. http://www.naturalmedicinejournal.com/journal/2010-03/nutritional-protocol-treatment-intestinal-permeability-defects-and-related .

      Reply
  9. 1
    Kathleen says:
    November 18, 2015 at 6:27 pm

    Hmmm… So if there is a gluten cross reactivity to yeast, then one would want to avoid Sac Boulardi (as a probiotic)?

    Reply
    • 1.1
      SAFM Team says:
      November 18, 2015 at 10:16 pm

      Yes – good for you! An excellent connection to make, Kathleen. In my clients with active autoimmune dis-ease, I always recommend a food sensitivity test panel to try to identify foods their immune system is reacting to – either from cross-reactivity with gluten or a separate reaction simply mediated by the intestinal permeability. I wouldn’t say yeast is a particularly common cross-reactive food, but people can definitely have food sensitivities to it. We much more typically see other grains (e.g. corn, oats, quinoa) and dairy foods as cross-reactive.

      Reply

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