Brain-Gut Connection: An Example of When Limbic Retraining Can Yield Substantial Improvements

Treating Clinician: Dr. Michael Ruscio, DNM, DC

Patient Info:

• Rebecca, 38 y/o, Female
• Previous Dx
  • Pan Ulcerative Colitis, 1998.
• Rx
  • n/a
• Chief Complaints
  • Urgent Diarrhea (4-16/day), 10-Constant
  • Bloody Stools, 4-Occasional
  • Fatigue, 8-Intermittent
• Other Symptoms
  • Female, moderate – pain/cramps, PMS, heavy flow

Visit 1 (Day 1) – History and Exam:

Initial Impression

• Rebecca is a 38 y/o female, on a very restricted diet, quite fearful, and in need of support and reframing.
• Notes:
  • Rebecca’s paperwork is partially revealing of 2 things; 1) the waste in functional medicine and 2) subtle early indicators of limbic imbalance
  • 1) using stem cell therapy for someone with IBD, instead of recommending something like an elemental diet (with actual evidence) is an example of extreme waste and a-scientific practice.
  • 2) Her answer to the timeline question in the screenshot below is overly long and detailed – not the longest you’ll see but longer than normal.
    • Food appears to be blamed a few times for how she is feeling. She has done Paleo, SCD, low FODMAP, and SCD…. she does not eat poorly, but seems to have an unrealistic standard and propensity to blame food.
    • She is motivated (perhaps scared) enough to spend what I am assuming was a LOT of money for stem cells.
  • With all this in mind, I will have “Limbic imbalance” in my ddx and be listening carefully during our exam/history visit to affirm or deny this differential. I will also be careful not to allow her to vent and monologue, which is one way in which this patient type makes it hard for the clinician to help them. It’s our responsibility as a clinician to focus them and not allow them to waste their time with us just because it feels good to vent. Be firm but supportive.
    
• Dx/Rx:
  • Dx: Pan Ulcerative Colitis
  • Rx: n/a
• Previous Testing:
  • n/a
• Onset:
  • Diagnosed with Pan UC in 1998, treated with 5-ASA, then only diet. Flared last year and harder to get into remission. Flared caused by stress/death.
  • From the patient: I worry that the inflammation is just depleting me overall and sucking any amount of life from every part of me.
    • Note: another flag for limbic/emotional imbalance
  • Family History:
    • Uncle and cousins: Crohn’s
    • Grandmother: colitis
    • Uncle: diverticulitis
  • Prior Treatments:
    • Has responded well to diet, 5-ASA, probiotics, ED, herbal anti-inflammatories, but over time is regressing and stress is very impactful.
  • Notes/DDx:
    • Personalized GI/IBD plan plus limbic retraining should work very well.
    • Female hormones may need support as well.
  • Prognosis:
    • Good to excellent.

Previous Diets

• Fasting – helpful
• Low FODMAP – best
• Paleo – helpful
• AIP – helpful

Visit 2 (a few days later) – Initial Recommendations

Testing

• We will consider tests at a later date
• Rationale
  • We already know the primary diagnosis. Could there be SIBO? Yes. Would this demonstrably impact how I treated her right now? No. Would the testing delay her initiation of treatment? Yes. Would the test results likely stress Rebecca? Yes.
  • In short, we need to quell her symptoms (including emotional) quickly and not further her worry or fear.

Recommendations

• Diet:
  • Start on the elemental diet. Use exclusively for 2-4 days. Then, use in the “Hybrid” application; roughly 1/2 food and 1/2 elemental.
  • Please start on either the Standard low FODMAP Diet or the LOFFLEX Diet. Do your best to be compliant, but you do not need to be perfect.
  • Intermittent fast, 1-2 days per week, for 14-18 hours
• NRT: Vit D/K, Curcumin, EPA/DHA
• GI: continue your previous probiotics
• Lifestyle: Please start on the DNRS program (very important)
• Follow Up: 4 weeks
• Rationale:
  • We see signals from her history that elemental dieting helps, so we will revisit that.
  • She had also reported that low FODMAP might have been best of all the prior diets, and that most vegetables flared her. Low FODMAP combined with lower vegetables is somewhat expressed by the LOFFLEX combined with standard low FODMAP.
  • Some basic anti-inflammatory support with the NRT.
  • And the much-needed DNRS for limbic retraining.
  • Standard functional medicine may have really harmed this patient; a stool test followed by feeding the gut bacteria, lots of worry due to all the ‘findings’, etc…

Visit 3 – Treatment Evaluation

Subjective Assessment:

• Standard low FODMAP + LOFFLEX – higher carbs helps, eating more LOFFLEX-like, DNRS is allowing her to think about food less
• DNRS – hugely helpful; mood, stress, GI

 Improved:

• Urgency, bloody stools, fatigue, mood, female: spotting

Same:

• n/a

Worse:

• n/a

Impression:

• Diets were a slight help but DNRS was a game-changer. All chief complaints have improved, most markedly. Today, I will continue the plan and add in probiotics (had been using prior). Then f/u in 2-3 months.

Recommendations:

New:

• GI: Lacto-Biff, S. boulardii, Soil-Based probiotic

Follow up: 2-3 months

Dr. Ruscio’s Comments

This is a great example of how crucial the correct diagnosis is. She needed less dietary restriction with a bit of direction as to which foods to broaden to. Combining this with limbic retraining and this somewhat obsessive and fearful individual was back to normal in weeks.

You can’t ‘test’ for any of these. They require the clinician to listen and note what is required. This type of patient can make it challenging because they provide superfluous details and vent, but with caring but firm direction and the correct tools to refer to, you can help these individuals get their lives back. Sadly, this type of patient I also fear is the type we in functional medicine may disserve the most.

GI-MAP: To Use or Not to Use?

Review of a recent study on and the evidence for the GI-MAP stool test & functional medicine stool pathogen testing in general

Performance of a new molecular assay for the detection of gastrointestinal pathogens Open Access

What this study concluded 

• Diagnostic Solutions Lab’s (DSL) GI-MAP test is inaccurate for stool pathogens.
• Why?
• It suffers from unacceptably low specificity 27% for detecting stool pathogens. This is when compared to an FDA-approved test, the BioFire by Meridian labs.
  • Note: poor specificity means more false positives.
• So, the test is inaccurate due to high false positives.

Is this a fair and truthful conclusion?

• Maybe…
• The debate over the detection limit
• Potential funding conflict, funded by Doctor’s Data
• Let’s expand

The main point of contention / The key question

• The main critique from DSL/GI-MAP is regarding different detection limits. DSL claims their detection limits are better than the FDA-endorsed ranges used by BioFire (BF). When spiking a sample with pathogens, DSL correctly detects them but the issue is their reporting a positive when the amount is less than FDA-determined detection limit. Thus, risking a false positive.
• Analogy: a radio receiver that was able to detect even the faintest signal, might sound great, but you also risk having lots of background noise and thus not being able to hear the music you want. This is the challenge, if the instrument picks up too much noise, we lose the signal.

A review of the evidence finds

• While DSL’s GI-MAP has not produced data to support their claims (as we covered in a prior issue of FFMR) there IS ample evidence supporting the use of other tests following FDA guidelines, including the comparator test in this study, the BioFire assay (BF).
• Again, DSL’s claim; a lower level detection limit indicating a positive for PCR probes is better. However, nothing to support this has been published.
• The tests with the best-published evidence (for PCR pathogen detection) are BioFire (much more data) and a few other similar tests from Luminex, Verigene, and BD Technologies.
• Funding conflict: Doctor’s Data (a competitor of DSL’s GI-MAP) funded this study, yet Doctor’s Data did not use their test as the comparator…
• Doctor’s Data testing (and their GI360 test) has a CE mark validation study for their ‘dysbiosis’ assay, but NONE for PCR pathogens, so they are in the same boat as DSL’s GI-MAP (claiming that their approach is better, without any supporting evidence)
  • This raises some serious questions, Doctor’s Data GI360 will criticize another lab for doing the same thing they are? And, hope people don’t fact check and catch this?
  • No data/studies are validating Doctor’s Data PCR pathogen detection approach, other than an internal validation which has not been published or even white papered.
  • Doctor’s Data GI360 has one study that validates their GA-map® Dysbiosis Test
    • Also, the test has been used in 20 clinical studies in numerous patient cohorts, published in peer-reviewed journals like
      • https://pubmed.ncbi.nlm.nih.gov/28416515/
      • https://pubmed.ncbi.nlm.nih.gov/26896085/
      • https://pubmed.ncbi.nlm.nih.gov/29302878/
      • https://pubmed.ncbi.nlm.nih.gov/27894337/
    • Doctor’s Data & their collaborator Genetic Analysis from Norway GA-map® test also have potential funding conflicts, but they have at least produced data to support their test.

Recap

• Doctor’s Data funded a study comparing their competitors’ labs, DSL’s GI-MAP, against another PCR pathogen test (BioFire) which uses FDA guidelines for PCR pathogen detection limits.
• The study found GI-MAP did not perform well.
• DSL’s GI-MAP has no data validating their PCR pathogen cutoffs, only a white paper where table “Bacteria & Bacterial Toxins in the GI-MAP Sensitivity Specificity” lists only the percentages, not CFU cut-offs compared to FDA cut-offs.
• DD’s GI360 also has no data published validating their PCR pathogen cutoffs
• Doctor’s Data GI360 has validated its GA-map® Dysbiosis Test

Who is correct? What is the best detection limit? 

• It has not yet been demonstrated that there is a clinical benefit to labeling lower quantities of pathogens than the FDA established ranges as a ‘positive’ finding. Not by DSL nor by DD. These labs make that claim, but provide zero evidence to support this.
• It seems to be a poor practice to make the claim ‘these lower detection limits are better’ and provide published evidence of the cut offs AND build a major lab company around said premise.
• I suspect that there is no benefit, perhaps detriment.
  • What are these lower detection limits allowing clinicians to do better? More readily use Habx/Abx?
  • My concern is that DSL will lead to over-treatment and lack of supportive treatment for non-pathogenic findings like dysbiosis. For which DD is using a research verified index borrowed from the body of research for the GA-map® Dysbiosis Test out of Norway.
  • For example, in a highly symptomatic individual, a mild SIBO finding is likely not the cause of sequelae.
  • Example 2, FFMR case study wherein overuse of Habx led to C. difficile.
  • In a recent conversation with Dr. Allison Siebecker, she expressed and I agree, how ‘tough cases’ often require other, non-Abx or Habx treatments. So, one could argue that for those who are most likely to use this test (tough/chronic cases), it could misdirect them to Abx/Habx treatment.
• Said simply:
  • For mild/moderate cases, these tests provide distracting noise
  • For complicated cases, empiric (trial therapy) and looking into other causes (limbic, EPI, etc…) might be key to success.
• DSL’s GI-MAP response statement
  • “A qualitative assay (reporting only Positive/Negative results) cannot be used to determine the sensitivity of a quantitative assay (which reports numbers of detected organisms at levels as low as 10 cells/gram of stool). 
  • The BioFire and Meridian assays are designed to detect only high levels of organisms, intended to correlate to acute disease states. They are not intended to report low levels of organisms and cannot do so. A negative result does not rule out that the organism is present at levels below disease levels.”
• I understand what they are after here, but their posit must be demonstrated. Its incumbent upon the lab to provide the evidence that their claims are true, and not merely to speculate.

Doctor’s Data conflict of interest and misleading study

• Why didn’t DD use THEIR test instead of BF? Perhaps because they were looking to use an FDA sanctioned test to compare to.

Recap

• The key question: Are clinicians any better equipped to treat patients with a lower limit of pathogens constituting a “positive” test finding.
• The evidence: none, by either DSL’s GI-MAP or DD’s GI360
• The misleading study funded by Doctor’s Data; showcasing that their competitor lab was inaccurate but not disclosing they are using the same/similar methodology.

A wakeup call for FM field

• Why are these two, prominent GI labs (Doctor’s Data and Diagnostics Solutions Laboratory), not producing data to validate their claims?
  • Clinicians too trusting
  • Labs not being fact-checked
  • No market pressure on the labs to spend resources on a peer-reviewed published validation study, thus funds go into marketing

Other limitations & critiques 

• Different or better probes could have been used in the study. This appears true, however, it doesn’t appear to negate the findings.

My recommendation for pathogens

• Consider using BioFire assay (or one of the other companies listed above) until DSL or DD demonstrates their approach (detection limits) are better than standard.
  • It should correlate symptoms to lab findings and they should demonstrate patients with a positive GI-MAP were more likely symptomatic than someone with a positive BF. And that + were not more common in healthy controls.
• Using GI-MAP or GI360 PCR for pathogens is permissible if, as we have discussed before, the clinician is aware of false positives and doesn’t overtreat ie they build a case and don’t look at the lab result literally.
• FM clinicians and patients should provide ‘market pressure’ to push the labs to prove their claims.
  • Labs are not omnipotent. If this test more closely correlates with symptomatic patients, that should be demonstrated in a ‘proof of concept’ peer-reviewed published study.
  • The fact that it has not been, that the main premise of this lab, has not been substantiated exposes a problem in the field.
• I realize this will create work for the clinician. Just ask yourself this question
  • ‘do I want to do what everyone else is doing, or do what is right, true, and likely the most accurate in the best interest of my patients.’

My recommendation for dysbiosis

• Use GI360, but understand validation evidence is preliminary.

My word of caution

• I recall 1-2 years ago, someone from our FFMR remarked something to the effect of,
  • I think the GI-MAP is the best test, I am seeing many more patients come back with infections…’
• This poses a real problem if the clinician assumes that more positives equal a better test.

In close 

• We, clinicians and patients, should be more cautious with claims from labs
• The utility of functional medicine stool testing is something to be questioned
• I encourage you to email or call DSL and DD asking for them to produce a peer-reviewed published validation study
• Consider no longer using these labs, or reducing your usage, and using a validated lab in their place.

Table 1. Summary of available GI pathogen panels.

Clinical Takeaways:

• Functional medicine stool testing companies are making claims that have not been supported.
• What to tell your patients:
  • Many stool tests have not been validated with peer-reviewed published studies and thus the report must be interpreted with caution or verified with a lab that has been validated.
  • What your previous lab results say, could be wrong.

Rapid-Fire Research: Ultra-Concise Summaries of Noteworthy Studies

Effects of a Paleolithic Diet on Cardiovascular Disease Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Adv Nutr. 2019 Jul 1;10(4):634-646.

Intervention:

• Meta-analysis of 8 eligible studies revealed that a PD significantly reduced
  • body weight [weighted mean difference (WMD) = -2.17 kg; 95% CI: -3.48, -0.87 kg],
  • waist circumference (WMD = -2.90 cm; 95% CI: -4.51, -1.28 cm),
  • body mass index (in kg/m2) (WMD = -1.15; 95% CI: -1.68, -0.62),
  • body fat percentage (WMD = -1.38%; 95% CI: -2.08%, -0.67%),
  • systolic (WMD = -4.24 mm Hg; 95% CI: -7.11, -1.38 mm Hg) and diastolic (WMD = -2.95 mm Hg; 95% CI: -4.72, -1.18 mm Hg) blood pressure, and
  • circulating concentrations of total cholesterol (WMD = -0.22 mg/dL; 95% CI: -0.42, -0.03 mg/dL),
  • TGs (WMD = -0.23 mg/dL; 95% CI: -0.46, -0.01 mg/dL),
  • LDL cholesterol (WMD = -0.13 mg/dL; 95% CI: -0.25, -0.01 mg/dL), and
  • C-reactive protein (CRP) (WMD = -0.41 mg/L; 95% CI: -0.81, -0.008 mg/L) and also
  • significantly increased HDL cholesterol (WMD = 0.05 mg/dL; 95% CI: 0.005, 0.10 mg/dL).
• However, sensitivity analysis revealed that the overall effects of a PD on lipid profile, blood pressure, and circulating CRP concentrations were significantly influenced by removing some studies, hence the results must be interpreted with caution. Although the present meta-analysis revealed that PD has favorable effects on cardiovascular disease risk factors, the evidence is not conclusive, and more well-designed trials are still needed.

Clinical Takeaways:

• Additional data suggesting an ancestral/paleo diet has cardiovascular benefits, but further replication work is needed.
• What to tell your patients:
  • The paleo diet is one healthy diet option, despite some media malignment.

Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training

Immunol Cell Biol, 2016 Feb;94(2):158-63. doi: 10.1038/icb.2015.108. Epub 2015 Dec 2.

• Emerging data from our laboratory show that different forms of exercise training differentially impact the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis) and may be jointly related to gut immune cell homeostasis and microbiota-immune interactions.
• It is now well established that exercise training initiates significant changes in the gut microbiome (genetic characterization of the microbiota) in animal models. A handful of studies indicate that exercise alters both the bacterial community structure and numerous taxa that are associated with host health. 35, 36, 37
• Future studies designed to understand exercise-induced changes in the gut microbiome must consider past studies that have employed various sequencing techniques (for example, temperature gradient gel electrophoresis, pyrosequencing, and Illumina platforms)
  • These differences in analysis platforms may be responsible for variability and sometimes lack of cohesive results between studies.
  • It is our opinion that future work examining the effects of exercise on the microbiota should incorporate targeted proteomic and metabolomic approaches along with whole community genomic sequencing.
  • These will ultimately provide more comparable data sets and help to establish a more complete dialogue regarding the relationship between exercise, the gut microbiota, and health.

Clinical Takeaways:

• Exercise impacts the gut microbiota, likely in a healthy way, but data here are still early.
• What to tell your patients:
  • Exercise has many health benefits, including gut health as described in the latest review.