Research Briefs for Practitioners – October 2022 - Dr. Michael Ruscio, DNM, DC

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Future of Functional Medicine Review Clinical Newsletter

Research Briefs for Practitioners – October 2022

by the Ruscio Institute for Functional Medicine Clinical Team

Medically reviewed & fact checked by a
board-certified doctor
Medically reviewed & fact checked by a
board-certified doctor
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Episode 69

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Podcast Summary


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Featured Study

  • Nasal-spraying Bacillus spores as an effective symptomatic treatment for children with acute respiratory syncytial virus infection
    • 86 children (4 months to 5 years old) hospitalized with RSV infection, randomized to:
      • Placebo nasal spray (saline) 
      • Bacillus probiotic nasal spray 
    • After 6 days of treatment, probiotic nasal spray led to quicker resolution of:
      • Runny nose (4 days probiotics vs 5 days placebo) 
      • Difficulty breathing (2 days vs 3 days) 
      • Chest depression (2 days vs 3 days) 
      • Abnormal lung sounds (4 days vs 5 days) 
    • Probiotic nasal spray also led to: 
      • Reduced RSV nasopharyngeal load by 630x
      • Greater clearance of nasal co-infections like strep pneumoniae and haemophilus influenzae (90% probiotic vs 30% placebo
    • Commentary: RSV, an infection in young children, was improved with a spore-based probiotic nasal spray.

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Gastrointestinal Studies

  • Small Intestinal Bacterial Overgrowth In Various Functional Gastrointestinal Disorders: A Case-Control Study
    • 186 patients with functional GI disorders (FGIDs), 58 healthy controls (HC)
    • All were tested with glucose breath test
    • Compared to HC, SIBO prevalence was: 
      • Greater in IBS-D (24% vs 10% HC) 
      • Similar in functional dyspepsia (14% vs 10% HC)
      • Similar in overall IBS (18% vs 10% HC) 
      • Similar in functional constipation (17% vs 10% HC) 
    • IBS-D was associated with:
      • 2.8x increased risk of SIBO
      • Greater prevalence of elevated H2 (≥20 ppm) gas (18% vs 3% HC)  
    • Chronic constipation patients had  NO difference in methane-positive SIBO compared to healthy controls(9% vs 7%) 
    • Commentary: While SIBO was more prevalent in patients with IBS-D, there was no significant difference in SIBO prevalence when comparing various functional GI disorders and healthy controls.
  • Factors Associated with Circulating Zonulin in Inflammatory Bowel Disease
    • 117 IBD patients, 32 healthy controls (HC) 
      • 58% of IBD patients were in remission 
    • There was NO difference in serum zonulin between:
      • IBD patients and healthy controls (95 vs 97 ng/ml) 
      • UC vs CD patients (80 vs 106 ng/ml) 
    • Zonulin did correlate with disease severity in those with UC, but NOT in CD. 
    • Commentary: This study did NOT find a significant difference in zonulin levels in those with IBD compared to healthy controls. However, it’s important to keep in mind that more than half of IBD p
    • Patients were in remission.
  • Relationship between untreated obstructive sleep apnea and breath hydrogen and methane after glucose load
    • 52 patients with sleep apnea, all tested with a SIBO glucose breath test
    • Compared to healthy controls, patients with sleep apnea had: 
      • NO significant difference in SIBO positivity (31% vs 13% healthy control) 
      • Higher levels of hydrogen (26 ppm vs 6 ppm) 
      • Higher levels of methane (16 ppm vs 6 ppm) 
      • Increased flatulence
    • Commentary: While there was no overall difference in SIBO positivity between groups, those with sleep apnea had worse GI symptoms and higher levels of gas production.
  • Comparing probiotic and drug interventions in irritable bowel syndrome: a meta-analysis of randomised controlled trials
    • 32 RCTs on patients with IBS, randomized to:
      • Placebo vs probiotics (e.g. lacto/bifido, saccharomyces boulardii) 
      • Placebo vs medications (e.g.mesalazine, linaclotide, ramosetron, plecanatide, eluxadoline, rifaximin
    • Compared to placebo, both medications and probiotics led to:
      • Reduced persistence of IBS symptoms (32% probiotic vs 13% medication
      • Improved abdominal pain (small effect size for both) 
    • Only medications led to statistically significant improvements in bloating
    • Commentary: While probiotics led to greater reduction in persistence of IBS symptoms, medications were overall more effective for improving bloating.
  • Probiotics in Critical Illness: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
    • 65 RCTs, 8,483 critically-ill patients 
    • Probiotics led to:
      • 28% reduced risk of ventilator associated pneumonia 
      • 30% reduced risk of health-care associated pneumonia
      • Shorter ICU stay (-1.4 days) 
      • Shorter hospital stay (-2.2 days) 
      • Shorter duration of mechanical ventilation (-2.5 days) 
      • NO impact on mortality 
    • However, when the study eliminated the studies that had a high risk of bias, these benefits were negated
    • Commentary: This large study found probiotics may lead to better health outcomes in critically-ill patients. Because they are very safe and may have significant benefits, it is likely worthwhile for critically-ill patients to take them.

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Thyroid & Hormones Studies

  • Suboptimal Thyroid Hormone Replacement Is Associated With Worse Hospital Outcomes
    • 34,605 healthy controls, 8,873 patients with hypothyroidism, categorized by pre-hospitalization TSH status:
      • Low (<0.40 mIU/L) 
      • Normal (0.40-4.5 mIU/L) 
      • Subclinical (4.51-10 mIU/L) 
      • High (>10 mIU/L) 
    • All patients admitted to hospital for various reasons
    • Compared to those with a normal TSH pre-hospitalization, those with a high TSH experienced: 
      • Longer hospital stay (+1.2 days)
      • Higher likelihood of readmission 1 month later (49% vs -54%) 
      • Higher likelihood of readmission 3 months later (43% vs -8%) 
    • Commentary: Higher TSH levels were associated with worse outcomes if one was hospitalized.

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Diet & Lifestyle Studies

  • Comorbid insomnia and sleep apnoea is associated with all-cause mortality
    • 5,236 participants, categorized by: 
      • Healthy controls (52%) 
      • Insomnia (3%) 
      • Sleep apnea (42%) 
      • Sleep apnea + insomnia (3%) 
    • Compared to healthy controls, patients with both sleep apnea and insomnia experienced: 
      • 2x increased risk of hypertension
      • 1.7x increased risk of cardiovascular disease
      • 47% increased risk of mortality 
    • Compared to healthy controls, those with just sleep apnea or insomnia had an increased risk of hypertension (but NOT cardiovascular disease)
    • Commentary: The presence of insomnia and sleep apnea may lead to worse cardiovascular outcomes and increased risk of overall mortality.

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Episode 70

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Podcast Summary


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Featured Study

  • Metagenomic Changes of Gut Microbiota following Treatment of Helicobacter pylori Infection with a Simplified Low-Dose Quadruple Therapy with Bismuth or Lactobacillus reuteri
    • 46 patients with H. pylori infection (+ urea breath test), randomized to
      • Bismuth + triple therapy (PPI, metronidazole and tetracycline)
      • Lactobacillus reuteri + triple therapy 
    • After 1 month, compared to the bismuth group, the probiotic group experienced:
      • Identical eradication rates between groups (18/23 vs 18/23)  
      • NO significant difference in side effects (9.5% probiotic vs 26% bismuth) 
      • NO significant difference in GI symptom improvement (68% vs 53%) 
      • Fewer dropouts (2 vs 4) 
      • NO difference in dysbiosis post antibiotics 
    • After accounting for those that dropped out of the study, the bismuth group ended up being more effective in eradicating H. pylori (18/19 vs 18/21)  
    • Commentary: This study found overall that the addition of bismuth vs probiotics was more effective for eradicating H. pylori. It’s important to note that the amount of patients that dropped out of the study in the bismuth group led to a higher overall eradication rate. When those people are included in the study, the eradication rates are equal in both groups. 

Commentary: S. boulardii monotherapy led to a 30% eradication in H. pylori infection. This highlights the ability of probiotics to act as antimicrobials.


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Gastrointestinal Studies

  • A meta-analysis on randomized controlled trials of treating eosinophilic esophagitis with budesonide
    • 10 studies, 712 patients with eosinophilic esophagitis (EoE), randomized to:
      • Placebo
      • Oral Budesonide 
    • Compared to placebo, oral budesonide led to:
      • 23x higher histological remission
      • Reduced eosinophil count (large effect size) 
      • Improved dysphagia and swallowing symptoms (large effect size)  
      • 3.8x increased side effects (oral candida, nausea, dizziness) 
    • Commentary: Budesonide is an effective treatment for patients with EoE, however the benefits need to be balanced with the increased side effect profile.
  • Probiotics/Synbiotics to Reduce Infectious Complications after Colorectal Surgery: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
    • 21 studies on perioperative colorectal surgical patients, randomized to: 
      • Placebo
      • Synbiotics (lacto/bifido, streptococcus, inulin, FOS, GOS)
      • Probiotics (lacto/bifido, enterococcus, streptococcus, S. boulardii)
    • Probiotics and synbiotics led to: 
      • 41% reduced risk of infectious complications
      • 30% fewer surgical site infections
      • 65% reduced pulmonary infections
      • 59% reduced urinary infections 
    • Overall, there was NO difference between synbiotics or probiotics in reducing postoperative infections (-45% probiotic vs -31% synbiotic)
    • Commentary: This is another large study showing probiotics and synbiotics are effective in reducing infection risk after surgery.

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Thyroid & Hormones Studies


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Diet & Lifestyle Studies

  • Resistance Training and Mortality Risk: A Systematic Review and Meta-Analysis
    • 10 studies
    • Resistance training led to reductions in: 
      • All cause mortality by 15%
      • Cardiovascular disease by 19% 
      • Cancer mortality by 14%
    • 1-hour of resistance training per week led to a 27% reduction in all-cause mortality
    • Commentary: This study found that about 10 minutes per day of resistance training can provide health benefits.

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Episode 71

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Podcast Summary


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Featured Study

  • Effect of Levothyroxine on Older Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis
    • 13 studies, 5,000 older adults (≥60 years old) with subclinical hypothyroidism (SCH), randomized to:
      • Control (placebo, no intervention)
      • Levothyroxine (LT4)
    • Average follow up was about 16 months (6-60 months) 
    • Treatment with LT4 led to NO improvements in: 
      • Fatigue
      • Quality of life
      • Weight loss
      • Cognitive function
      • Depression
      • HDL-C or Apo-A
      • Fasting blood glucose 
      • Blood pressure
      • Bone mass 
    • LT4 did have a positive effect on: 
      • Total cholesterol (large effect size) 
      • Triglycerides (small effect size) 
      • LDL-C (moderate effect size) 
      • Apo-B (small effect size) 
    • LT4 did NOT lead to any adverse events, including: 
      • Cardiovascular events
      • All-cause death 
      • Atrial fibrillation
      • Heart failure 
      • Fracture 
    • Commentary: This large and long-term study found LT4 treatment in older adults with SCH led to 1) NO improvement in numerous hypothyroid symptoms, 2) NO adverse events and 3) improvement in lipids.

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Gastrointestinal Studies

  • Efficacy and Safety of Vitamin D Adjuvant Therapy for Ulcerative Colitis: A Meta-Analysis
    • 10 studies, 1,077 ulcerative colitis patients randomized to:
      • Mesalazine alone
      • Mesalazine + vitamin D 
    • Compared to mesalazine alone, mesalazine + Vitamin D supplementation led to: 
      • 4x increased clinical efficacy
      • Reduced disease activity (small effect size) 
      • Improved intestinal barrier function (moderate to large effect size) 
      • Reduced inflammatory markers ( IL-6, TNF-α, and CRP) (large effect size) 
      • NO difference in adverse events 
    • Commentary: Vitamin D may enhance the effects of other ulcerative colitis treatments by further reducing inflammation, improving leaky gut and reducing symptoms.  
  • Abdominal Massage in Functional Chronic Constipation: A Randomized Placebo-Controlled Trial
    • 74 patients with functional constipation, randomized to:
      • Placebo abdominal ultrasound + lifestyle advice 
      • Abdominal massage + lifestyle advice
    • After 1 month, compared to placebo group, abdominal massage led to:
      • Reduced constipation severity (70% massage vs 28% placebo) 
      • Improved quality of life (56% vs 38%) 
      • Increased stool frequency (70% vs 43%)
    • Commentary: Abdominal massage is a cheap and effective therapy for improving functional constipation. Consider using this as a first-line therapy in those with constipation. 
  • Antibiotic exposure and adverse long-term health outcomes in children: A systematic review and meta-analysis
    • 160 observational studies, 22 million children
    • Antibiotic exposure, especially in the first 2 years of life, was associated with an increased risk of: 
      • Asthma (2x) 
      • Allergies (1.9x) 
      • Wheezing (1.8x) 
      • Psoriasis (1.7x) 
      • Arthritis (1.7x) 
      • Atopic dermatitis (1.4x) 
      • Food allergies (1.3x)
      • Neurodevelopmental disorders (1.3x) 
      • Obesity (1.2x) 
      • Autism (1.1x) 
    • NO association was found between antibiotics and IBD, celiac disease, type 1 diabetes or ADHD. 
    • Commentary: Antibiotics were associated with a near two-fold increased risk of developing asthma, allergies and wheezing in children, among other negative health outcomes. Keep in mind this is an observational study, so causation can’t be determined.

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Thyroid & Hormones Studies

  • Obstructive sleep apnea and serum total testosterone: a system review and meta-analysis
    • 24 studies, 1,389 sleep apnea patients, 845 healthy controls
    • Compared to healthy controls, sleep apnea was associated with lower serum testosterone levels (large effect size) 
    • This effect was ONLY seen in men, not women 
    • Commentary: This study found an association between sleep apnea and low testosterone. Keep in mind this is an observational study, so causation cannot be determined.
  • Update on subclinical thyroid dysfunction
    • 2022 Review in Endocrinology on Subclinical Hypothyroidism
    • “Prior to confirming a diagnosis of SCH, serum FT4 and TSH levels should be reassessed 1–3 months later in order to rule out a transient increase of serum TSH levels”
    • “LT4 supplementation is NOT recommended if TSH levels are less than 10 mIU/L AND no symptoms of hypothyroidism are present, including fatigue, constipation, dry skin, edema, weight gain, and hoarseness”
    • “LT4 supplementation may be considered in those less than 70 years old with a TSH between 7-10 mIU/L if the patient has:
      • Cardiovascular risk factors such as high cholesterol, atherosclerosis, angina, a medical history of ischemic heart disease
      • Positive TPO antibodies “
    • “Overall, there is no evidence that long-term LT4 supplementation against SCH can ameliorate the symptoms of hypothyroidism, such as:
      • General fatigue
      • Depression
      • Improved quality of the life
      • Lowering BMI
      • Reduction of cardiovascular events”
  • Cancer Risk in Hashimoto’s Thyroiditis: a Systematic Review and Meta-Analysis
    • 23 studies, 73,426 participants
    • Compared to healthy controls, those with Hashimoto’s thyroiditis (HT) had an increased risk of developing:
      • Thyroid cancer (1.7x) 
      • Breast cancer (1.7x) 
      • Digestive cancers (2.8x) 
      • Urogenital cancers (1.5x) 
      • Blood cancers (4x) 
    • Commentary: This study found associations between HT and various forms of cancer. Keep in mind this is an observational study, so causation cannot be determined.

Commentary: This 10 year follow-up study found 16% of participants with subclinical hypothyroidism developed overt hypothyroidism, which was associated with positive TPO antibodies and a TSH ≥10 mU/L.


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Diet & Lifestyle Studies

  • Effects of omega-3 fatty acid on major cardiovascular outcomes: A systematic review and meta-analysis
    • 28 RCTs, 136,965 participants 
    • Compared to control, omega 3 fatty acids led to: 
      • 6% reduced risk of major cardiovascular events
      • 8% reduced risk of cardiac death
      • NO difference in all-cause mortality, heart attacks and strokes
    • Commentary: While omega 3 fatty acids slightly reduced the risk of cardiovascular events and cardiac death, there were no reductions in other important outcomes like all-cause mortality, heart attacks and strokes.
  • A double-blinded, randomized, parallel intervention to evaluate biomarker-based nutrition plans for weight loss: The PREVENTOMICS study
    • 82 overweight adults, randomized to:
      • Control diet 
      • Personalized diet
    • Personalized diets were based on lab results (genetics, blood, urine, saliva) to determine their optimal diet
    • After 2.5 months, both groups experienced similar:
      • Fat loss (-4.6 personalized vs -4.4 lbs control)
      • Weight loss (-6.8 vs -7.3 lbs) 
      • Improvements in insulin resistance and lipids
    • Commentary: This double blinded and randomized study found NO difference in weight loss results between a highly personalized and a generic diet. This beautifully illustrates why we at the clinic primarily focus on treating people, not lab results.

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Episode 72

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Podcast Summary


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Featured Study

  • Oral Fluconazole Therapy in Patients With Active Ulcerative Colitis Who Have Detectable Candida in the Stool : A Double-Blind Randomized Placebo-controlled Trial
    • 242 active UC patients assessed for candida via stool culture 
    • 28% of the UC patients were positive for candida, and were randomized to:
      • Placebo
      • Oral fluconazole (200 mg/day) 
    • After 3 weeks, compared to placebo, fluconazole led to:
      • Reduced UC severity score 
      • Higher # patients with reduced fecal calprotectin (84% vs 37%)
      • Higher # patients with reduced histological scores (74% vs 33%) 
      • NO serious side effects
    • Risk factors for the presence of candida included: 
      • Higher UC severity 
      • Steroid use
    • Commentary: This study found around 1/3rd of UC patients were positive for fecal candida, and anti-fungal medication led to significant improvements in symptoms, histology and inflammation.

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Gastrointestinal Studies

  • Association between irritable bowel syndrome and micronutrients: A systematic review
    • 26 studies on patients with IBS
    • Compared to healthy controls, patients with IBS were more likely to be deficient in:
      • Vitamin B2 (riboflavin) 
      • Vitamin D
      • Calcium
      • Iron 
    • IBS patients on various exclusion diets (SCD, low FODMAP) were associated with lower intake of: 
      • B1 (thiamine) 
      • B2
      • Folate
      • Magnesium
      • Calcium
      • Iron 
      • Zinc
    • Commentary: While diets like low FODMAP may reduce the intake of various vitamins and minerals, it’s important to keep in mind that 1) exclusion diets are designed to be short term and 2) the diets should be used to heal the gut so patients can tolerate more food and expand their diets.

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Thyroid & Hormones Studies

  • Higher serum thyroid autoantibody value is a risk factor of hypothyroidism in children and young adults with chronic thyroiditis
    • Retrospective study, 133 children (~11 years old) with elevated thyroid antibodies 
    • Children were monitored for 2.5 years, then categorized by thyroid status:
      • Overt hypothyroidism (TSH >10 uIU/mL) 
      • Euthyroid (TSH <10 uIU/mL) 
    • The following levels of thyroid antibodies increased the risk of developing hypothyroidism by 10x: 
      • Tg antibodies >106 IU/mL
      • TPO antibodies >16 IU/mL
    • The sensitivity and specificity for the following antibodies were: 
      • +Tg antibodies (82% sensitivity, 62% specificity) 
      • +TPO antibodies (77% sensitivity, 68% specificity
      • TPO >16 and Tg >106 IU/mL (75% sensitivity, 78% specificity)
    • Commentary: This small study found specific cut off values for Tg and TPO antibodies that may predict the progression to hypothyroidism in children.
  • Effects of testosterone therapy in adult males with hypogonadism and T2DM: A meta-analysis and systematic review
    • 13 studies, 1,596 hypogonadal type-2 diabetic patients
    • Testosterone therapy led to improvements in: 
      • Free and total testosterone levels (large effect size) 
      • Insulin resistance (large effect size) 
      • Fasting insulin (large effect size)
      • Fasting glucose (small effect size) 
      • Cholesterol (small effect size) 
      • Triglycerides (small effect size) 
    • Commentary: In patients with low testosterone, testosterone replacement therapy led to significant improvements in metabolic function.

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Diet & Lifestyle Studies


Discussion

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