CLINICAL BLOG ARTICLE

By Yoon Hang “John” Kim, MD, MPH  |  Board-Certified in Preventive Medicine | Fellowship trained in Integrative Medicine | Institute of Functional Medicine Scholarship Recipient

Published February 2026  |  Estimated reading time: 18 minutes

Introduction: Why the Textbook 5R Falls Short

The Institute for Functional Medicine (www.ifm.org) is credited with the original 5R protocol.

If you’ve been in the functional medicine space for any length of time, you know the 5R protocol. It’s elegant, logical, and for many patients, it works. Remove the offending agents. Replace what’s missing. Reinoculate with beneficial organisms. Repair the mucosal lining. Rebalance lifestyle factors.

But here’s what I’ve learned over two decades of clinical practice: the patients who find their way to an integrative medicine physician have usually already tried the straightforward approach. They’ve done the elimination diets, taken the probiotics, swallowed the L-glutamine. And they’re still suffering.

These are the complex patients—the ones with SIBO that recurs within months of treatment, environmental mold exposure layered on top of gut dysfunction, immune systems stuck in a chronic inflammatory loop. For these patients, we need something more than the standard playbook.

Over the past several years, I’ve developed an advanced clinical framework that integrates three powerful therapeutic strategies into the 5R model: targeted SIBO treatment algorithms, mycotoxin detoxification protocols, and low-dose naltrexone (LDN) therapy. This isn’t about replacing the 5R—it’s about making it adaptive enough to handle real-world complexity.

Patient Assessment: Phenotyping Before Protocol

Before prescribing a single supplement, I spend time understanding who the patient is biologically. The same set of symptoms—bloating, fatigue, brain fog, food reactivity—can arise from fundamentally different root causes. Jumping to a protocol without phenotyping is like prescribing antibiotics before identifying the organism.

The Four Clinical Phenotypes

In my practice, I’ve found that complex gut patients generally cluster into four overlapping phenotypes. Recognizing these patterns early shapes the entire treatment trajectory.

A thorough intake should include environmental exposure history (water-damaged buildings, occupational exposures), a timeline of symptom evolution, prior treatment responses, and objective testing including organic acids, mycotoxin panels, breath testing, and comprehensive stool analysis. I’m not ordering all of these on every patient—I’m letting the clinical picture guide which tests will yield the most actionable information.

The Modified 5R Protocol: Phase by Phase

What follows is the framework I use in clinical practice. It’s not a rigid recipe—it’s a decision architecture that adapts based on what the patient’s body is telling us at each stage.

Phase 1: Remove — Strategic Elimination

The Remove phase in a standard 5R focuses on eliminating dietary triggers, pathogens, and irritants. In the advanced protocol, this phase expands to address three distinct removal targets simultaneously.

Dietary Removal

I typically begin with a modified low-FODMAP approach for SIBO-dominant patients, or a low-histamine/low-mold diet for those with mycotoxin or mast cell features. The goal isn’t lifelong restriction—it’s reducing the inflammatory noise so we can hear what the body is actually telling us.

SIBO Antimicrobial Treatment

For SIBO, I use both herbal and pharmaceutical approaches depending on the patient’s history, preferences, and severity. Here’s the clinical decision framework:

A critical point I emphasize with patients: antimicrobial therapy without addressing the underlying cause of SIBO is a recipe for recurrence. The migrating motor complex must be restored. Adhesions, structural issues, and hypothyroidism must be evaluated. This is where the “Rebalance” phase connects back to “Remove.”

Mycotoxin Removal

For patients with confirmed or suspected mycotoxin burden, removal happens at two levels: environmental and internal. The environmental piece is non-negotiable—if a patient is still living or working in a water-damaged building, no amount of binders will resolve the issue.

Internal mycotoxin removal centers on binder therapy, which I introduce carefully and titrate based on tolerance:

I always initiate binder therapy at sub-therapeutic doses and increase gradually. Many mycotoxin-burdened patients have impaired detoxification pathways, and aggressive binding can mobilize toxins faster than the body can clear them—leading to a worsening of symptoms that erodes patient trust and compliance.

Phase 2: Replace — Restoring Digestive Capacity

Mycotoxin exposure and chronic SIBO both impair digestive enzyme production and gastric acid secretion. This phase addresses the mechanical and biochemical prerequisites for digestion.

• Digestive enzymes: Broad-spectrum pancreatic enzymes with meals, titrated to symptom response. For patients with fat malabsorption, lipase-heavy formulations are preferred.
• Betaine HCl: For patients with confirmed or suspected hypochlorhydria. I use the HCl challenge protocol to find the appropriate dose, recognizing that many complex patients underperform on acid production.
• Bile acid support: Particularly important in mycotoxin cases where hepatobiliary function is compromised. Ox bile supplementation or cholagogue herbs (dandelion, artichoke) can be transformative.

Timing matters here. If a patient is still actively on binder therapy, we separate binders from enzyme supplementation by at least two hours to avoid binding the very nutrients we’re trying to deliver.

Phase 3: Reinoculate — Strategic Microbial Restoration

This is where I see the most clinical error in standard protocols. The reflexive move is to throw a high-dose, multi-strain probiotic at every gut patient. In complex cases, that approach can be counterproductive.

Probiotic Selection by Phenotype

• SIBO patients: I am cautious with Lactobacillus-heavy formulations early on, as these D-lactate producers can exacerbate symptoms in susceptible individuals. Soil-based organisms (Bacillus species) and Saccharomyces boulardii are better tolerated initially.
• Post-mycotoxin: Saccharomyces boulardii has evidence for mycotoxin binding and is my first-line probiotic in this population. I layer in spore-based probiotics as tolerance allows.
• Immune-dysregulated: Specific strains with evidence for immune modulation (L. rhamnosus GG, B. infantis 35624) are introduced once acute inflammation is controlled.

Prebiotic fiber is introduced only after the antimicrobial phase is complete and symptoms are trending in the right direction. Premature introduction of fermentable substrates feeds the very organisms we’ve worked to remove.

Phase 4: Repair — Mucosal Healing and Barrier Restoration

Intestinal permeability (“leaky gut”) is both a cause and consequence of the conditions we’re treating. The Repair phase uses targeted nutrients and, critically, LDN to restore mucosal integrity.

Core Repair Nutrients

• L-Glutamine (3–5g BID): The workhorse of mucosal repair. Primary fuel source for enterocytes.
• Zinc carnosine (75mg BID): Evidence for reducing gut permeability and supporting mucosal integrity, particularly in the stomach and upper small intestine.
• Immunoglobulins (SBI Protect or equivalent): Serum-derived bovine immunoglobulins provide passive immune support to a depleted mucosal immune system.
• Butyrate: Short-chain fatty acid that nourishes colonocytes and supports tight junction assembly. Supplemental forms bridge the gap until endogenous production recovers.

The Role of Low-Dose Naltrexone in Gut Restoration

This is where the protocol takes a decisive turn from standard functional medicine approaches. LDN has become one of the most versatile tools in my clinical toolkit, and its application in complex gut cases deserves its own discussion.

For those unfamiliar with LDN: naltrexone at standard doses (50mg) blocks opioid receptors continuously and is used for addiction management. At low doses (typically 0.5–4.5mg taken at bedtime), it produces a brief, transient receptor blockade that triggers an upregulation of endogenous endorphin and enkephalin production. The downstream effects include immune modulation, reduced neuroinflammation, and—critically for our purposes—improved mucosal healing and visceral pain management.

When to Introduce LDN in the 5R Protocol

The timing of LDN introduction depends on the clinical phenotype:

I want to be clear about something: LDN is not a gut-specific therapy. It’s a systemic immune modulator that happens to have profound effects on gut function. In my experience with over 7,000 LDN patients through my support group, the patients who respond best are those with identifiable immune dysregulation—elevated inflammatory markers, autoimmune features, mast cell activation patterns, or visceral hypersensitivity.

LDN Dosing and Titration

I start low and go slow—particularly in mycotoxin-burdened patients whose detox pathways are already taxed. The standard titration in my practice:

1. Week 1–2: 0.5mg at bedtime
2. Week 3–4: 1.0mg at bedtime
3. Week 5–6: 1.5mg at bedtime
4. Increase by 0.5–1.0mg every 2–4 weeks as tolerated to target dose (usually 3.0–4.5mg)

Common early side effects include vivid dreams and mild sleep disruption, which typically resolve within one to two weeks. If sleep disruption persists, I shift the dose to morning administration. About 10–15% of my patients require dose adjustments below the standard 4.5mg target—and that’s perfectly fine. More is not always better with LDN.

Phase 5: Rebalance — Sustaining the Gains

The Rebalance phase is where good protocols become great outcomes—or where hard-won progress quietly erodes. This phase addresses the upstream drivers that created the problem in the first place.

Motility and Structural Support

For SIBO patients, prokinetic therapy is non-negotiable for prevention of recurrence. Options include low-dose erythromycin (50mg at bedtime), prucalopride, or herbal prokinetics such as ginger extract and 5-HTP. I typically maintain prokinetic support for a minimum of three months post-antimicrobial treatment, often longer.

Stress Physiology and the Gut-Brain Axis

The vagus nerve is the superhighway connecting emotional stress to gut dysfunction. I discuss this with every complex gut patient—not as a dismissal of their physical symptoms, but as a recognition that the nervous system and the digestive system are in constant bidirectional communication.

Practical interventions I recommend: vagal toning exercises (gargling, cold water face immersion, humming), structured stress management (I’m partial to mindfulness-based approaches given the evidence base), sleep optimization, and when indicated, targeted HPA-axis support with adaptogenic herbs.

Environmental Maintenance

For mycotoxin patients, ongoing environmental vigilance is essential. This means regular ERMI or HERTSMI-2 testing of living spaces, proper HVAC maintenance, and humidity control below 50%. I’ve seen too many patients go through successful detoxification protocols only to relapse because of ongoing low-level environmental exposure.

Long-Term LDN Maintenance

In my experience, most patients who respond well to LDN benefit from long-term maintenance therapy. LDN has an excellent long-term safety profile, and I have patients who have been on stable doses for years with sustained benefit. I reassess annually, and some patients can eventually taper or discontinue—particularly those who’ve successfully resolved the underlying triggers.

Clinical Decision Pathways: Putting It All Together

Theory is useful, but clinical medicine lives in the specific. Here are four real-world scenarios that illustrate how this framework adapts to different presentations. (Patient details have been modified to protect privacy.)

Pathway 1: Recurrent SIBO with Failed Prior Treatment

Presentation: 

45-year-old female with hydrogen-dominant SIBO, third recurrence in 18 months despite two courses of Rifaximin. Persistent bloating, food reactivity expanding, low ferritin.

Approach: 

Evaluate motility (gastric emptying study, consider small bowel imaging for adhesions). Initiate herbal antimicrobial protocol with concurrent prokinetic therapy. Begin LDN at 1.0mg during Repair phase for visceral hypersensitivity. Maintain prokinetic support for minimum six months. Address iron status and optimize thyroid function.

Pathway 2: Post-Mold Exposure with GI Dysfunction

Presentation: 

38-year-old male, 18 months after confirmed water-damaged building exposure. Elevated urinary ochratoxin A and gliotoxin. New-onset food sensitivities, chronic fatigue, brain fog, intermittent diarrhea.

Approach: 

Confirm environmental remediation is complete. Begin gentle binder protocol (cholestyramine, start at quarter dose). Support drainage pathways with liver-supportive nutrients. Introduce LDN early (Phase 1) at 0.5mg for immune modulation. Layer in gut repair nutrients once binder therapy is established and tolerated. Postpone probiotic introduction until binder phase is well-tolerated.

Pathway 3: Autoimmune Features with SIBO

Presentation: 

52-year-old female with Hashimoto’s thyroiditis, methane-dominant SIBO, constipation, and expanding food reactivity panel. Elevated anti-vinculin antibodies suggesting autoimmune SIBO mechanism.

Approach: 

Start LDN immediately (Phase 1) at 0.5mg for autoimmune modulation. Begin methane-targeted antimicrobial protocol (herbal allicin + berberine combination). Aggressive prokinetic support given autoimmune motility component. Consider immunoglobulin therapy for mucosal immune restoration. Long-term LDN maintenance likely given autoimmune etiology.

Pathway 4: The Complex Multi-System Patient

Presentation: 

41-year-old female with mast cell activation syndrome features, SIBO (hydrogen sulfide pattern), mycotoxin exposure history, and multiple chemical sensitivity. Failed four prior functional medicine protocols.

Approach: 

This patient requires the most careful sequencing. Phase 1: Stabilize mast cell activation (DAO enzyme support, quercetin, mast cell stabilizers) and introduce LDN at ultra-low dose (0.5mg). Phase 2: Begin gentle mycotoxin binder protocol once mast cells are more stable. Phase 3: SIBO treatment with careful bismuth-based protocol. Phase 4: Extended Repair phase with immunoglobulins and mucosal support. Phase 5: Long-term maintenance with LDN, prokinetics, and environmental monitoring. Expect 6–12 months for meaningful progress.

Monitoring Success: What to Track and When

I tell my patients that objective monitoring protects us both—it keeps us honest about what’s working and prevents the sunk-cost fallacy of continuing a protocol that isn’t yielding results.

Managing the Non-Responder

Despite our best efforts, some patients don’t respond as expected. Before concluding that a protocol has failed, I systematically evaluate:

1. Compliance: Is the patient actually following the protocol? Binder timing, supplement adherence, and dietary compliance are the most common failure points.
2. Missed diagnosis: Have we overlooked structural pathology (adhesions, Crohn’s stricture), an undiagnosed motility disorder, pancreatic insufficiency, or bile acid malabsorption?
3. Ongoing exposure: Is there continued environmental mold exposure, hidden dietary triggers (cross-reactive foods, mold in foods), or medication interactions?
4. LDN non-response: Not every patient is an LDN responder. In my experience, approximately 60–70% of appropriately selected patients achieve meaningful benefit. For non-responders, I ensure adequate trial duration (minimum 12 weeks at target dose) before concluding inefficacy.
5. Psychological factors: Unresolved trauma, chronic stress activation, and limbic system dysfunction (as described in DNRS and Gupta programs) can maintain gut dysfunction independent of the biochemical pathology we’re treating.

Conclusion: Adaptive Protocols for Complex Patients

The advanced 5R protocol I’ve outlined here isn’t meant to replace clinical judgment—it’s meant to scaffold it. Every complex patient is unique, and the art of integrative medicine lies in knowing when to follow the protocol and when to adapt.

What I’ve found consistently is that the patients who struggle most are the ones caught between disconnected treatment strategies—a gastroenterologist managing SIBO without considering mycotoxins, an environmental medicine doctor addressing mold without addressing the gut, or a functional medicine provider running protocols without incorporating the immune modulation that LDN provides.

The integration is the therapy.

If you’re a clinician looking for the full clinical reference document with detailed protocols, decision trees, and complete citations, I’ve made it available for download below. If you’re a patient navigating these complex issues, know that there are evidence-based approaches that go beyond the standard playbook—and you deserve a provider who understands how to use them.

Selected References

1. Pimentel, M., et al. (2020). ACG Clinical Guideline: Small intestinal bacterial overgrowth. American Journal of Gastroenterology, 115(2), 165–178.

2. Shoemaker, R. C., & House, D. E. (2006). Sick building syndrome and exposure to water-damaged buildings. Neurotoxicology and Teratology, 28(5), 573–588.

3. Younger, J., et al. (2014). Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatology, 65(2), 529–538.

4. Reznikov, L. R., et al. (2008). Bhattacharya A. Opioid receptor–mediated immune modulation in the gut. Immunology Letters, 116(1), 1–7.

5. Siebecker, A. (2019). SIBO: Dysbiosis has a new name. Townsend Letter, 427, 49–55.

6. Hope, J. (2013). A review of the mechanism of injury and treatment approaches for illness resulting from exposure to water-damaged buildings. The Scientific World Journal, 2013, 767482.

7. Chedid, V., et al. (2014). Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Global Advances in Health and Medicine, 3(3), 16–24.

8. Brewer, J. H., et al. (2013). Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins, 5(4), 605–617.

9. Kim, Y. H. (2024). Low-Dose Naltrexone: A Comprehensive Clinical Guide. Direct Integrative Care Publishing.

10. Li, Z., et al. (2021). Naltrexone’s effect on mucosal healing in inflammatory bowel disease. Journal of Clinical Gastroenterology, 55(1), 45–52.

About the Author

Yoon Hang “John” Kim, MD, MPH is a board-certified integrative medicine physician and founder of Direct Integrative Care, a membership-based telemedicine practice. He completed his integrative medicine fellowship under Dr. Andrew Weil at the University of Arizona and holds certifications in preventive medicine, medical acupuncture, and integrative/holistic medicine. Dr. Kim is the author of three books on low-dose naltrexone therapy and leads an LDN support community of over 8,500 members. He can be reached at www.DirectIntegrativeCare.com.