Autoimmune Diets - Ketosis - LDN Stacking
- John Kim
- 2 minutes ago
- 11 min read
A Layered Strategy for Immune Modulation
Yoon Hang Kim, MD, MPH
Board-Certified Preventive Medicine | Integrative & Functional Medicine
Root Cause Medicine
LDN Therapy Expert
Introduction
Autoimmune diseases affect an estimated 24 million Americans, and the incidence continues to rise across industrialized nations (1). Conventional management typically relies on immunosuppressive medications—effective but often accompanied by significant side effects and incomplete disease control. A growing body of evidence suggests that dietary modification, metabolic reprogramming, and targeted pharmacologic immune modulation can serve as meaningful adjuncts to conventional therapy. Three strategies, in particular, are converging on a shared therapeutic theme: calming an overactivated immune system without blunt immunosuppression.
This article reviews the clinical evidence for the Autoimmune Protocol (AIP) diet, the Wahls modified Paleolithic diet, nutritional ketosis, and low-dose naltrexone (LDN) as complementary tools in autoimmune care. Each is evaluated through the lens of available clinical trial data, mechanistic rationale, and practical integration.
Why Food and Metabolism Matter in Autoimmunity
Autoimmune diseases arise when the immune system misidentifies self-tissues as threats, driving chronic inflammation, tissue damage, and symptoms such as pain, fatigue, and organ dysfunction. Diet and metabolism shape gut barrier integrity, microbiome composition, and both innate and adaptive immune tone (2). Highly processed, hyperglycemic, and pro-inflammatory diets appear to worsen autoimmune activity, while targeted dietary patterns can reduce symptoms and markers of inflammation.
Two of the best-known food-based strategies for autoimmune conditions are the Autoimmune Protocol (AIP) and the Wahls Protocol, a modified Paleolithic dietary pattern developed by Dr. Terry Wahls for multiple sclerosis (MS). Both emerged from clinical observation and patient experimentation, and both now have early—but real—clinical trial data supporting their use.
The Autoimmune Protocol: Targeted Elimination and Reintroduction
The Autoimmune Protocol is a structured, time-limited elimination diet designed to identify food triggers and reduce gut-driven immune activation. It removes common antigens and irritants—including grains, legumes, dairy, eggs, nuts and seeds, nightshades, coffee, alcohol, processed sugars and oils, food additives, and often NSAIDs—then gradually reintroduces foods to map individual tolerance (3).
Clinical Trial Evidence
The most cited AIP trial is a prospective, uncontrolled 11-week study conducted at Scripps Clinic enrolling 15 adults with active Crohn’s disease and ulcerative colitis. After a 6-week AIP elimination phase followed by a 5-week maintenance phase, mean Harvey–Bradshaw Index scores in Crohn’s patients fell significantly (p<0.01), and patient-reported quality of life (SIBDQ) improved by week 3 and continued to improve through week 6 (4). A majority of participants met criteria for clinical remission by week 11, and some were able to reduce medications. Notably, the mean disease duration in this cohort was 19 years, and nearly half were on biologic therapy at enrollment—suggesting that AIP can benefit even refractory cases (5).
Subsequent work has demonstrated that AIP modifies intestinal RNA expression in IBD patients, with changes in gene pathways related to immune regulation and mucosal healing (6). For thyroid autoimmunity (e.g., Hashimoto’s), small clinical series note self-reported symptom improvement and modest CRP reductions, though changes in thyroid-specific antibodies have not been consistently demonstrated (7).
Strengths and Limitations
AIP uses a clear, time-bound structure (elimination → maintenance → reintroduction) that fits well with clinical coaching and shared decision-making. It has disease-specific human data in inflammatory bowel disease showing symptomatic and quality-of-life benefits. However, the core IBD study is small (n=15), single-arm, and short-term, and evidence outside IBD is mostly observational. AIP functions best as a diagnostic-therapeutic tool: it can uncover individual food triggers and demonstrate what happens when antigen and additive load in an inflamed gut is systematically reduced.
The Wahls Modified Paleo Diet: Mitochondria, Myelin, and Nutrients
The Wahls Protocol grew out of Dr. Wahls’s personal journey with progressive MS and focuses on mitochondrial health, nutrient density, and removal of potentially inflammatory foods. The diet emphasizes large quantities of non-starchy vegetables and fruits (often framed as nine cups per day across leafy greens, deeply colored plants, and sulfur-rich vegetables), high-quality meats, fish, and organ meats, seaweed, and exclusion of grains, legumes, dairy, eggs, and nightshades (8).
The WAVES Randomized Trial
The strongest Wahls evidence comes from the WAVES trial, a 24-week randomized parallel-group study comparing a modified Wahls elimination diet to the low-saturated-fat Swank diet in 87 individuals with relapsing-remitting MS and clinically significant fatigue. Both groups experienced statistically significant within-group reductions in fatigue (Fatigue Severity Scale and Modified Fatigue Impact Scale) at 12 and 24 weeks (9). At 24 weeks, the Wahls group demonstrated a significantly greater reduction in MFIS scores compared to Swank. Quality of life (MSQoL-54) improved in both groups; in per-protocol analyses, a greater percentage of Wahls participants achieved clinically meaningful improvement in mental quality of life at 12 weeks compared with Swank (74.2% vs. 45.5%, p=0.02). Adherence was notably high in both groups (79.5% Swank, 86.8% Wahls) (9).
Secondary analyses of the WAVES data have shown that both diets improve metabolic risk factors, with evidence that diet-induced changes in fatigue may be mediated through metabolic health improvements and body composition changes (10, 11).
AIP vs. Wahls: Comparative Summary
Feature | AIP | Wahls Modified Paleo |
Core Goal | Reduce gut and systemic immune activation; identify individual food triggers via elimination and reintroduction | Optimize mitochondrial and neurologic health; reduce immune activation with high nutrient density and elimination |
Structure | Time-limited elimination (~6 weeks) → maintenance → individualized reintroduction | Long-term dietary pattern with specific intake targets; not typically time-limited |
Major Exclusions | Grains, legumes, dairy, eggs, nuts/seeds, nightshades, coffee, alcohol, processed sugars/oils, additives | Grains, legumes, dairy, eggs, nightshades; strong emphasis on vegetables, organ meats, seaweed |
Best-Studied Disease | Crohn’s disease and ulcerative colitis (uncontrolled trial, n=15) | Relapsing-remitting MS (RCT, n=87 vs. Swank diet) |
Key Outcomes | ~73% clinical remission at 11 weeks; improved QOL; some medication reduction | Significant fatigue reduction and QOL improvement vs. baseline and vs. Swank at 24 weeks |
Best Fit | IBD and gut-dominant autoimmunity; patients willing to do structured reintroductions | MS and neurologic autoimmunity; patients ready for intensive, nutrient-dense lifestyle change |
From a clinical perspective, AIP can serve as a diagnostic-therapeutic phase (e.g., 8–12 weeks), after which a longer-term dietary pattern—possibly Wahls-like, Mediterranean, or individualized—is built from the reintroduced foods that test safe.
Ketosis: An Anti-Inflammatory Metabolic State
Ketosis is a metabolic state in which circulating ketone bodies (β-hydroxybutyrate, acetoacetate) are elevated due to carbohydrate restriction, fasting, or exogenous ketone supplementation. Beyond their role as alternative fuel, ketone bodies act as signaling molecules with significant immunometabolic effects (12).
Mechanistic Evidence: From NLRP3 to Microglia and the Gut
The landmark work by Youm et al. (2015) demonstrated that β-hydroxybutyrate (BHB) directly inhibits the NLRP3 inflammasome, reducing maturation and secretion of IL-1β and IL-18 in multiple cell types and disease models (12). This finding provided a mechanistic explanation for the anti-inflammatory effects of fasting and ketogenic diets. The inhibitory mechanism operates through prevention of potassium efflux and reduced ASC oligomerization, independent of classical starvation-related pathways such as AMPK, ROS, or autophagy.
In experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, ketogenic diets attenuate neuroinflammation by reducing NLRP3 activation in microglia through HDAC3 inhibition and enhanced mitophagy (13). Additionally, ketogenic diets alter gut microbiota composition, expanding beneficial species and microbial metabolites that dampen Th17 responses and support regulatory T-cell function (14).
Integration with Elimination Diets
Because ketosis and elimination diets exert overlapping but distinct effects, layering them can be attractive in select patients. AIP or Wahls define what to eat, while nutritional ketosis defines how much carbohydrate to allow and what metabolic state to target. In practice, a low-glycemic, vegetable-rich Wahls or AIP framework can be tightened into mild or cyclic ketosis by lowering starchy vegetables and adjusting fats, while preserving micronutrient density. For autoimmune patients with co-existing insulin resistance or metabolic syndrome, intermittent nutritional ketosis may provide an additional lever on inflammation and fatigue—but this remains an extrapolation from mechanistic and early clinical data (15).
Many Faces of Ketosis
Prolonged fasting 3 days = ketosis
Drink green vegetable juice with low carbs = ketosis
Eat many colored vegetables (low carb) + modest protein = ketosis
Eat DUKE Keto by Eric Westman MD (meat first + low carb vegetables) = ketosis
Carnivore = ketosis
Ketosis is a metabolic state with one commonality - burning fat.
Low-Dose Naltrexone: Immune Modulation, Not Suppression
Low-dose naltrexone (LDN) represents a fundamentally different approach to immune modulation. At doses of approximately 0.5–4.5 mg nightly—far below the standard 50 mg dose used for opioid use disorder—naltrexone transiently blocks opioid receptors and toll-like receptor 4 (TLR4) on microglia and macrophages. This brief blockade triggers a rebound increase in endogenous opioids (endorphins, enkephalins) and modulates the opioid growth factor (OGF) axis, while dampening pro-inflammatory microglial activation and cytokine release (16, 17).
Mechanistic Rationale
Mechanistic and translational studies suggest that LDN decreases microglial activation and pro-inflammatory cytokine production, shifts immune balance by modulating TLR4 signaling and potentially normalizing aberrant Th1/Th17 activity while supporting regulatory T-cell responses, and enhances endogenous opioid tone—improving pain perception, mood, and potentially immune competence, since many immune cells express opioid receptors (17, 18). Critically, LDN is best conceptualized as an immune modulator rather than an immunosuppressant: it aims to recalibrate dysregulated immune activity rather than globally suppress immune function.
Clinical Evidence by Condition
Inflammatory bowel disease. The randomized placebo-controlled trial by Smith et al. (2011) in adults with moderate-to-severe Crohn’s disease found that 12 weeks of naltrexone 4.5 mg/day resulted in significantly higher endoscopic response rates (78% LDN vs. 28% placebo) and a trend toward higher endoscopic remission rates (33% vs. 8%) (19). A subsequent pilot RCT in pediatric Crohn’s disease demonstrated significant reductions in disease activity (PCDAI) scores after 8 weeks, with 25% achieving remission and 67% showing clinical improvement (20). A Cochrane systematic review concluded that while results are promising, further large-scale RCTs are needed (21).
Multiple sclerosis. Pilot studies have reported improvements in spasticity, pain, and quality of life with LDN in MS, though results for MRI lesions and relapse rates remain mixed or underpowered. LDN is commonly used as a symptomatic and potentially disease-modifying adjunct rather than a standalone therapy (22, 23).
Fibromyalgia. The crossover RCT by Younger et al. (2013) demonstrated that LDN 4.5 mg/day reduced fibromyalgia pain by approximately 30% compared to placebo, with improvements in general satisfaction with life and mood (24). A systematic review confirmed LDN’s potential as a safe and modestly effective analgesic for fibromyalgia, with an ED95 of approximately 5.40 mg (25).
Other autoimmune conditions. For Sjögren’s syndrome, Hashimoto’s thyroiditis, systemic sclerosis, and other autoimmune diseases, evidence remains largely case reports and expert clinical experience, with improvements in pain, fatigue, and sometimes inflammatory markers (26).
A Layered Autoimmune Strategy: Integration in Practice
The emerging evidence suggests that no single dietary or pharmacologic intervention is likely sufficient for most autoimmune diseases. Instead, a layered approach offers the strongest mechanistic and early clinical rationale. In my clinical practice, this framework typically unfolds as follows:
Step 1: Foundation diet tailored to phenotype. For gut-dominant autoimmunity (e.g., IBD), I start with an AIP-style elimination for 8–12 weeks, closely tracking symptoms, disease activity indices, and labs, then reintroduce foods to identify personal triggers. For neurologic autoimmunity (e.g., MS), a Wahls-style nutrient-dense elimination diet is preferred, particularly in patients with prominent fatigue and quality-of-life concerns.
Step 2: Metabolic modulation with ketosis where appropriate. For patients with metabolic syndrome, obesity, or evidence of high inflammatory load, trialing mild or cyclical nutritional ketosis within the chosen food framework adds an NLRP3- and microglia-targeted anti-inflammatory signal.
Step 3: Immune modulation with LDN. In collaboration with a knowledgeable prescriber, LDN can be layered on to target microglial activation and maladaptive immune signaling, especially in MS, IBD, and systemic autoimmune conditions where fatigue, pain, and neuroinflammation are prominent.
Step 4: Conventional therapy and monitoring. None of these strategies replace disease-modifying therapies where indicated; they are best viewed as adjuncts that may improve symptom control, reduce inflammatory burden, and possibly allow for gentler pharmacologic regimens in some patients.
Conclusion
The convergence of dietary immunology, metabolic medicine, and targeted pharmacologic modulation represents one of the most promising frontiers in autoimmune care. While AIP, Wahls, ketosis, and LDN each carry different levels of clinical evidence—from small RCTs to robust mechanistic data—they share a common therapeutic philosophy: working with the body’s regulatory systems to recalibrate immune function, rather than simply suppressing it.
As the clinical trial landscape matures, we can expect more head-to-head and combination studies—particularly protocols testing ketogenic versions of Wahls or AIP frameworks, or explicitly evaluating diet-plus-LDN regimens in MS and IBD. Until then, the layered approach outlined here offers a clinically grounded, evidence-informed framework for practitioners and patients who seek to go beyond immunosuppression and toward true immune modulation.
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Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting or modifying any treatment regimen.
© 2025 Yoon Hang Kim, MD, MPH, Integrative
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