Landmark Study Suggests Efficacy of Autoimmune Paleo Protocol

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Many people following the autoimmune paleo (AIP) protocol witness objective measures of improvement, but now we have a bonafide clinical trial revealing its efficacy in inflammatory bowel disease (IBD). These results may be applicable to all autoimmune disorders, since these conditions share common etiological origins.

Diminished Antigenic Burden: A Tenet of the Time-Honored Elimination Diet

Until now, most of the evidence for the efficacy of the autoimmune paleo (AIP) diet in inducing remission of autoimmune disorders has been anecdotal. An extension of the paleolithic diet, the autoimmune paleo diet not only excludes grains, dairy, and legumes, but it also removes other potentially immunogenic substances including eggs, nuts, seeds, refined sugar, alcohol, food additives, and nightshade vegetables such as sweet and hot peppers, tomatoes, potatoes, eggplant, and goji berries (1).

This represents an adaptation of the gold standard oligoantigenic elimination diet that nutritional professionals have long implemented to produce abatement in symptoms recalcitrant to other interventions. Allergenic and immunogenic foods are removed from the diet for a trial period of a month or longer, and then sequentially re-introduced in a systematic manner to gauge tolerance. Not only does this enable the identification of food reactions, but it also decreases the burden of antigenic foods capable of producing an immune response and imparts opportunities for gut repair and correction of micronutrient deficiencies. Notably, however, most functional medicine practitioners agree that the autoimmune protocol should constitute a short-term intervention and that food re-introductions should commence as soon as significant symptomatic reduction has occurred.

Nutrient Density: A Pillar of the Autoimmune Paleo Diet

Some argue that the therapeutic potential of the autoimmune protocol lies in its exclusion of potentially antigenic foods and its minimization of anti-nutrients, as I previously touched on in my article “Lectins and Autoimmune Disease: Separating Fact from Fiction”. However, the principal strength of the autoimmune protocol is its inclusion of the most nutrient-dense foods—namely, wild-caught seafood, grass-fed meat and offal, roots and tubers, herbs and spices, and fruits and vegetables. The value of eliminating grains and beans, therefore, may actually lie in the fact that they commonly displace these more nutrient-dense foods.

Although the original inception of the paleo diet had its roots in evolutionary biology as well as in anthropological ethnographic studies of contemporary hunter-gatherers and ancient foraging populations, the newfound rationale for adopting a paleo template lies in its emphasis on those foodstuffs delineated in the peer-reviewed literature to have the most nutritive value. Moreover, the autoimmune protocol addresses many of the underlying root causes of aberrant immune responses.

Healing and Sealing the Gut Barrier

The one cell thick lining of the gastrointestinal tract is normally tightly regulated by conformational changes in tight junctions, which supervise the paracellular trafficking of molecules from the intestinal lumen to the submucosa and into systemic circulation (2). Dynamic proteinaceous structures between cells change shape to allow the selective passage of nutrients and water while excluding deleterious foreign elements which exceed a particular molecular radius (2). However, in autoimmune disease, various environmental insults cause the tight junctions to become excessively permeable, enabling undigested food proteins, toxicants, and microbial products to navigate across the gut barrier where they elicit immune reactions that can culminate in autoimmunity (2).

Liver, fatty fish, and shellfish, regarded as nutrient powerhouses on the autoimmune protocol, are particularly essential as they provide nutrients such as vitamins A and D which support regeneration of the gut lining that is compromised in autoimmune disease (3, 4). These fat-soluble vitamins are quintessential for maintenance of mucosal integrity, the violation of which is the precursor to every autoimmune disease in which it has been studied, including multiple sclerosis, celiac disease, ulcerative colitis, Crohn’s disease, type one diabetes, rheumatoid arthritis, ankylosing spondylitis, as well as allergic disorders such as asthma (2, 5, 6, 7, 8, 9, 10, 11).

Vitamin A prevents inappropriate activation of T cells in the immune tissues known as the gut-associated lymphoid tissue (GALT) and Peyer’s patches encircling the digestive tract, therefore reducing risk of chronic gut inflammation (4). It is also instrumental in orchestrating oral tolerance, or the ability to consume an array of foods without adverse reaction (4). Lastly, vitamin A promotes the synthesis of immunoglobulin A (IgA), an antibody in mucosal tissues which confers protection against infection and helps engender healthy gut flora (12). Contrary to popular belief, over half of people do not convert any beta carotene from orange and leafy green vegetables into active vitamin A at all, so consuming preformed vitamin A is essential (13).

Restoration of Immune Homeostasis

It was formerly hypothesized that polarization of the immune system towards dominance of either the Th1 (cellular immunity) or Th2 (humoral or antibody-mediated immunity) pathways was responsible for autoimmune disorders (14). This was later recognized to be an oversimplification, as this paradigm not only failed to elucidate the role of Th17 cells, but it was also discordant with data demonstrating that autoimmune diseases do not always fall into these neat categorical distinctions (14). However, this view still has utility in that regulatory T cells (Tregs) represent an overarching control mechanism that maintains balance between divergent classes of immune cells.

Vitamins A and D, which feature prominent on the autoimmune protocol, display immunomodulatory properties, restoring harmony between the different branches of the immune system. Not only are vitamin D levels commonly deficient in autoimmune disease, but lower levels of vitamin D are directly related to severity of autoimmune manifestations (15, 16, 17). Both vitamin A and D up-regulate expression of a population of immune cells known as toleragenic FoxP3+ regulatory T cells (Tregs), which engender balance between the Th1, Th2, or Th17 arms of the immune system, all of which can perpetuate autoimmunity when their exquisitely fine-tuned balance is disrupted. Likewise, vitamins A and D suppress activation and differentiation of pathogenic interleukin-17 producing Th17 cells, which appear to be the principal mediators of tissue destruction in a host of autoimmune disorders (18).

Balancing Omega-6 to Omega-3 Ratio

As a corollary, the autoimmune protocol emphasizes inclusion of preformed long-chain omega-3s, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), from wild-caught fatty fish such as salmon, mackerel, herring, and sardines, while excluding omega-6 seed oils from corn, canola, cottonseed, soybean, safflower, and sunflower. Compared to dietary omega-6 fatty acids, which generally give rise to more inflammatory thromboxanes, prostaglandins, and leukotrienes, omega-3 fatty acids are metabolized into less inflammatory eicosanoid signaling molecules. Although plant-based sources such as flax, hemp, chia, and walnuts are touted as sources of omega-3s, less than 5-10% of the alpha-linolenic acid (ALA) these foods contain is converted into EPA and less than 2-5% is converted into DHA (19).

Traditional hunter-gatherer populations consuming an ancestral paleolithic diet had the most optimal dietary omega-6 to omega-3 ratio, of 1:1, and were virtually free from the chronic and degenerative diseases of modernity (20, 21, 22). In comparison, the Standard American Diet to which contemporary Western populations are accustomed, where populations are plagued by chronic illness at epidemic proportions, has a dismal omega-6 to omega-3 ratio ranging from 10:1 to 25:1 (21). Incorporating fatty fish, as well as grass-fed meat, the latter of which has been demonstrated to predictably raise plasma and platelet long chain omega-3 status (23), may particularly benefit autoimmune cohorts since omega-3s inhibit multiplication of pathogenic T cell subsets and prevent the synthesis of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-2 (IL-2) (24).

Neutralization of Oxidative Stress

The pathophysiological conditions that give rise to autoimmune disorders entail an imbalance between oxidants and antioxidants, the latter of which neutralize oxidative stress. Generation of reactive oxygen species, or free radicals such as superoxide and hydrogen peroxide, is a normal byproduct of metabolism, but can damage cellular machinery when excessive and impair the production of cellular energy, which becomes a vicious cycle as energy-intensive repair processes become untenable (25, 26).

Including an array of colorful plant foods is tantamount to increasing antioxidant intake. Because they function in redox reactions and defend against reactive oxygen and nitrogen species, bioactive constituents in plants known as phytochemicals are categorized as antioxidants (27). Deeply pigmented fruits and vegetables which are staples on the autoimmune protocol include constituents such as stilbenoids, lignans, tannins, carotenoids, phenolic acids, and flavonoids which ensure integrity of genetic material, facilitate cellular repair, and regulate genetic expression in a favorable direction (28, 29, 30). The autoimmune diet is likewise rich in fat-soluble antioxidants such as tocopherols, carotenes, vitamin A and ubiquinol, as well as water-soluble antioxidants such as ascorbate and glutathione (31).

Optimization of Detoxification and Hormone Balance

Many of the fruits, vegetables, herbs and spices included on the autoimmune protocol up-regulate phase II detoxification enzymes, which are required to convert phase I intermediates into their water-soluble counterparts so that they can be excreted. This is important to correct the bottleneck that often occurs in autoimmunity whereby phase I outpaces phase II, creating an accumulation of toxic phase I metabolites and leading to an over-burdening of the liver (32). Many herbs, spices, and phytonutrients, emphasized on the autoimmune protocol, such as ginger (33), curcumin from turmeric (34), cinnamaldehyde from cinnamon (35), resveratrol from grapes, blueberries, and cranberries (36), quercetin concentrated in apples and onions (37) and countless others significantly up-regulate expression of phase II enzymes to enhance excretion of toxins implicated in autoimmunity.

Similarly, an isothiocyanate compound called sulforaphane in cruciferous vegetables, which are often staples of the autoimmune protocol, is the most potent inducer of phase II enzymes identified to date (32, 38). Arugula, broccoli, Brussel sprouts, red, green, Chinese, and savoy cabbage, cauliflower, chard, collard greens, radish, rapini, rutabaga, turnip and turnip greens, wasabi, and watercress are all sources of this compound within the autoimmune protocol.  Another benefit of these vegetables is that they contain indole-3-carbinole (I3C), the biological effects of which are attributed to its oligomeric products, such as 3,3'-diindolylmethane (DIM). Both of these compounds can support healthy estrogen metabolism in the case of estrogen dominance, which is common in autoimmune cohorts.

I3C in particular increases metabolism of estradiol down the 2-hydroxyestrone pathway at the expense of the unfavorable 16-hydroxyestrone pathway (39, 40). In general, 2-hydroxyestrone metabolites have the weakest estrogenic effect, whereas 16-hydroxyestrones are considered proliferative, cancer-promoting estrogen species (41, 42). In addition, I3C inhibits formation of 4-hydroxyestrogen, another potent estrogen possessing growth-promoting effects that has a strong affinity for estrogen receptors (43).

Enrichment of Microbiota Diversity and Inhibition of Pathogens

There is an element of dysbiosis, or bacterial imbalance, in most autoimmune conditions given the inextricable connection between the microbiota and the immune system. Ample substrate to nourish commensal flora, in the form of microbiota-accessible carbohydrates (MACs) or prebiotics, is required to restore a healthy ecosystem. Paleo diets confer a decisive advantage in terms of fiber intake, which is associated with bacterial richness due to prebiotic effects (44).

Prebiotics, or foods that escape digestion and are instead selectively fermented by beneficial bacteria in the colon, are a viable strategy for encouraging microbial diversity and in turn enhance the health of the host (45). Barring any small intestinal bacterial overgrowth (SIBO), liberal use of prebiotics such as asparagus, garlic, onion, artichoke, chicory root, jicama, green bananas, plantain, beetroot, asparagus, leeks, jicama, yacon, and burdock are all permitted on the autoimmune protocol and help to engender a harmonious gut ecology which translates into better immune balance. Studies have shown that changes in the microbiome can materialize in as few as one to two days with increased consumption of plants (46).

In addition, lacto-fermented foods included on the autoimmune protocol such as sauerkraut and coconut kefir are reservoirs of both beneficial bacteria and polyamine compounds, which increase the rate of cellular renewal and regeneration when absorbed by enterocytes and can contribute to gut healing. Re-establishment of healthy gut flora will in turn competitively inhibit attachment of pathogens (47) which can trigger or perpetuate autoimmunity (48).

Improved Cardiometabolic Parameters

Endothelial cell activation, vascular smooth muscle dysfunction, oxidative stress, and inflammation, mechanisms which underlie heart disease, diabetes, and hypertension, are all variables which can precipitate or perpetuate immune imbalances in autoimmune disease. The paleo template has been proven to be superior to the lower fat, higher carbohydrate American Diabetes Association (ADA) diet in correcting these metabolic derangements in type two diabetes (49). For instance, subjects on the paleo diet exhibited improvements in glucose control, as indicated by hemoglobin A1c (HbA1c) (49). The researchers attribute the decrease in blood sugar spikes in subjects on the paleo diet to the greater fiber content they consumed, which was 35 grams per 2500 kcal compared to 12 g per 2500 kcal with the ADA diet (49).

This is complemented by other studies of subjects with hypercholesterolemia, where the paleo diet was found to significantly lower total cholesterol, LDL cholesterol, and triglycerides and to significantly increase HDL cholesterol relative to the traditional grain-based “heart-healthy” diet recommendations (50). Studies have also illuminated that individuals who were most insulin resistant at baseline had the greatest improvement in insulin sensitivity on the paleo diet, which can lower inflammatory burden (51). The paleo diet likewise was more effective than a reference healthy diet for lowering systolic and diastolic blood pressure and other cardiovascular risk factors which often accompany autoimmunity (52).

Repair of Mitochondrial Dysfunction

Malfunctioning mitochondria, the energy powerhouses of the cell, are implicated in almost all pathologic conditions, including most autoimmune disorders (53). Mitochondrial restoration is compatible with the autoimmune protocol since repair of these organelles requires a diet that is nutrient-dense and anti-inflammatory in nature, excluding immunogenic foods and emphasizing micronutrients that sustain aerobic respiration and “facilitate efficient functioning of the biochemical pathways to extract and transform energy into a biological useful form” (54).

Because mitochondrial matrix enzymes function best in an alkaline medium, metabolic processes can be optimized by eating a primarily plant-based autoimmune paleo diet (54). Removing acidic processed foods, sugar, flour, high-glycemic foods, coffee, and alcohol can prevent alterations in membrane potential which compromises mitochondrial function by interfering with the electron transport chain integral to oxygen-based oxidative phosphorylation (55, 56). The autoimmune protocol is likewise rich in cofactors for the citric acid cycle, the process which produces high-energy reduced coenzymes that donate electrons into the electron transport chain in order to generate cellular energy.

For instance, heme molecules required for the complexes of this electron shuttling system are dependent on iron and zinc, both of which are more abundant and bioavailable in organ meats compared to plant sources. By comparison, "The bioavailability of iron and zinc in vegetarian diets is poor because of their higher content of absorption inhibitors such as phytate and polyphenols and the absence of flesh foods" (57, p. 459S). Vegetarian diets have been demonstrated to reduce non-heme iron absorption by 70% and total iron absorption by 85% (58). Similarly, vegetarian diets reduce zinc absorption by 35% compared to omnivorous diets due to phytate content, such that vegetarians may require up to 50% more zinc than omnivores (58). Therefore, the autoimmune protocol is advantageous both in its omission of anti-nutrients which impede mineral absorption and its inclusion of bioavailable vitamins and minerals.

Proven Efficacy in Inflammatory Bowel Disease

A single-center, open-label, uncontrolled study was conducted to assess the efficacy of the autoimmune paleo protocol in inflammatory bowel disease (IBD). The cohort included 9 patients with symptomatic Crohn's disease (CD) and 6 with ulcerative colitis (UC), half of whom were on biologic therapy, with an average disease duration of 19 years (1). Individuals were advised to continue medication therapy during the study duration, with the exception of corticosteroid tapers. Further, a certified health coach and registered dietician were recruited to provide dietary counseling and education on lifestyle facets of the protocol.

73% of subjects were classified as achieving remission by the sixth week of the diet, which persisted through the five-week maintenance phase (1). By week six, fecal bleeding had significantly reduced in patients with UC (1). Not only were endoscopic improvements observed in mucosal appearance, but significant improvements in disease scales such as the mean partial Mayo score for UC and the mean Harvey-Bradshaw index for CD were witnessed (1). In addition, average levels of fecal calprotectin decreased from 471 at week 1 to 112 at week 11 (1). Calprotectin is a marker of intestinal inflammation that is predictive of relapse in quiescent IBD patients when it appears at higher levels (59, 60).

The authors cite, "We did not hypothesize, a priori, that clinical remission would be achieved so early (week 6). Indeed, this proportion of participants with active IBD…achieving clinical remission by week 6 rivals that of most drug therapies for IBD” (1, p. 2058). As a result of the dramatic results produced in the study, the researchers suggest that AIP is a viable adjunctive therapy in IBD, “even among those with moderate-to-severe disease” (1, p. 2056). Despite the significant improvements observed, two Crohn’s subjects with native or anastomotic ileal strictures exhibited partial small bowel obstruction or exacerbation of disease activity with the autoimmune protocol, highlighting the need for physician supervision.

Practical Applications

Although this preliminary study is demonstrative of the efficacy of the autoimmune protocol, it is limited by its design. Not only does it use a small sample size, but it is a non-randomized, non-blinded, prospective observational study that may also be confounded by selection bias—in other words, the subjects may not be representative of the population of individuals with IBD. Therefore, more clinical trials are necessary to reproduce results and extrapolate to other autoimmune conditions. Of course, funding clinical trials is often cost-prohibitive and pharmaceutical industry investors, with legally-binding fiduciary obligations to shareholder interests, have little fiscal incentive to devote resources to dietary protocols for which market exclusivity is an impossibility.

As discussed in my previous installment, some of the dogmatism within the paleo realm does not hold up to scientific scrutiny, and the scientific literature on anti-nutrients is deficient in high-quality human studies. However, many people do not have the luxury of time when it comes to arresting debilitating autoimmune condition, and the clinical experience of many integrative and functional practitioners is a direct testament to the potential efficacy of AIP whether or not biochemical mechanisms have been fully developed.

Moreover, there are many protective lifestyle elements embedded within the autoimmune protocol, such as mobilization of social support, stress management, disease-appropriate exercise, and restorative sleep, all of which are fundamental to healing. Therefore, given the benign, non-invasive nature of the autoimmune protocol and its quintessential nutrient-dense, anti-inflammatory nature, individuals with autoimmune disorders owe it to themselves to explore this regimen as therapeutic option.


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