NUTRITION, THE GUT AND MENTAL HEALTH

SCOTT SHANNON, MD FAACAP

MARY RONDEAU, ND, RH(AHG)

DISCLOSURES

•  Dr Shannon has published two textbooks on integrative mental health and two on parenting.

•  Dr. Shannon is a PI/researcher on The Phase III MDMA assisted psychotherapy in PTSD study and receives support for clinical work from Multidisciplinary Association for Psychedelic Studies (MAPS), a 501c3 non profit through MAPS Public Benefit Corp

•  Dr. Rondeau has no conflicts

2

OVERVIEW

•  Diet

•  Population studies

•  Gluten

•  Microbiome: communication and health

•  Dysbiosis and disease

•  Physical and Mood Symptoms

•  Laboratory considerations

•  Treatment considerations

JAMA Psychiatry. 2018;75(9):918-928.

BUILD A BRAIN

• Grain fortification with folic acid took effect 1/98

•  Rapidly doubled folic acids levels in pregnant women

•  Compared MRI scans of 1,370 youths (pre/post/during)

•  Exposure related cortical thickness changes found

•  Also correlated with reductions in psychosis risk

Eryilmaz H et al JAMA Psychiatry. 2018 Sep 1;75(9):918-928.

Date of download: 1/7/2019

From: Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths

JAMA Psychiatry. 2018;75(9):918-928. doi:10.1001/jamapsychiatry.2018.1381

NUTRITIONAL PSYCHIATRY

•  Consistent studies: diet quality related to risk of depression and other MH issues

•   Concurrently, data point to the utility of selected nutraceuticals as adjunctive treatments

•  New studies… are pointing to the immune system, oxidative biology, brain plasticity and the microbiome-gut-brain axis as key targets

•  Increased Western diet and decreased traditional diet are inversely and separately linked to MH

Jacka, F EBio Medicine 2017, Mar; 17: 24–29.

POPULATION STUDIES

DIET AND PEDS MH

•  Systemic Review: 12 relevant studies

• We found evidence of a significant, cross-sectional relationship between unhealthy dietary patterns and poorer mental health in children and adolescents.

• We observed a consistent trend for the relationship between good-quality diet and better mental health and some evidence for the reverse.

O’Neil, A AJ Public Health 2014 October; 104(10): e31–e42.

WE NEVER KNOW FOR SURE

DIET QUALITY & MOOD •  Traditional diet reduces:

•  Depression

•  Bipolar disease

•  Anxiety

•  Traditional diet includes:

•  High in veggies

•  Fruits

•  Whole grains

•  Fish

•  Meat

Jacka,FNPsychosomaticMedicine2011;73(6):483-90Jacka,FNJAffectiveDisorder2011;129(1):332-7

ADOLESCENTS AND MENTAL HEALTH

•  Prospective study of 3,040 Australian youth aged 11 to 18 over 3 years

•  Diet quality associated with better mental health

•  Improving diet: improved mental health

•  Deteriorating diet: worse mental health

•  Patterns do not support reverse causality

Jacka, FN PLoS 2011 ; 6 (9): e 24805.

DIET QUALITY AND PEDIATRIC MH

•  Prospective multi-national study of 7,675 children ages 2-9

Followed 2 years

Fruit and veg intake: improved well-being

Fish intake: imp self-esteem and fewer peer problems

“Children’s physical and mental development is dependent on nutritional quality”

Arvidsson, L BMC Public Health 2017 Dec 17(1):926

CHANGING FATTY ACID RATIO: OMEGA 6 TO OMEGA 3

•  Prehistoric ~ 1900 ~ 2000

•  1:1 4:1 25:1

n-6 fatsn-3 fats

FATTY ACIDS AND MOOD

Pilot study: 38 children (11-17 yrs old) treated with emulsified omega-3. •  Significant reductions in Children’s depressive

inventory after 12 weeks. Trebaticka, JChild Adolesc Psychiatry Ment Health. 2017; 11: 30

Randomized, double-masked, crossover trial: 38 children. •  High palmitic acid (SAD diet) vs high oleic acid diet (Med diet). •  HOA group- more physically active and less angry •  High fat diet (palmitate) more mood disorders and correlates

positively with high serum palmitate

Kien, C American J Clin Nutrition 2013 97 (4): 689

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CRUCIAL FOR MEMBRANE FLUIDITY

PRACTICAL: AVOID OMEGA 6 INTAKE

•  However, the higher consumption of Linoleic acid, as now seen in the Western diet, shows an increase in the preference of these enzymes to metabolize n-6 PUFA, leading to AA synthesis, despite the fact that these enzymes show higher affinity for n-3 PUFA.

Patterson E et al. J Nutr Metab. 2012: 539426

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Mayer, A B. Historical Changes in the Mineral Content of Fruit and Vegetables. British Food Journal 99(6). 1997. 207- 211.

Decrease in Mineral Content In Vegetables Over 50 Years

BLOOD SUGAR

• Up and down rollercoaster

• High intake refined carbohydrates -->blood sugar increases--> quickly metabolized--> sharp decline in available glucose for brain = symptoms

Wenzel K-G: Orthomolecular Treatment for Mental Health: The Roles of Hypoglycemia, Pyrroluria and Histamine Disturbances. 2000 Apr. Nutritional Medicine Today 29th Annual Conference. Vancouver, BC. Rao J, Oz G, Seaquist ER: Regulation of cerebral glucose metabolism. Minerva Endocrinol, 2006 Jun; 31(2): 149-158. Hoffer A: Orthomolecular Medicine for Physicians. New Canaan, CT. Keats Publishing. 1989.

FOOD SENSITIVITY SYMPTOMS

•  Allergic shiners

•  Hx of colic

•  Hx of eczema

•  Hx of reflux

•  Bad breath

•  Foot odor

•  Hx of otitis

•  Acne

•  Family hx atopy

• Runny nose

•  Insomnia

• Abdominal pain, IBS

•  Joint pain

• Migraine/ headache

• Congestion

•  Flushed cheeks/ears

ELIMINATION DIET AND ADHD

• Open label phase followed by RCT crossover challenge phase

•  100 children, 4-8 yrs with ADHD

•  Elimination diet (based on IgG) vs healthy diet

• Responders challenged with high IgG foods. 63% relapsed

• Conclusion: strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food

Pelsser LM et al Lancet, 2011; 5:377(9764): 494-503.

DIET AND ADHD

Meta analyses: ADHD and diet

•  Artificial food coloring = More studies needed

•  Food elimination = The effect size is substantial, offering treatment opportunities in subgroups of children with ADHD

PLoS One. 2017 Jan 25;12(1)p-; Diet and ADHD, Reviewing the Evidence: A Systematic Review of Meta-Analyses of Double-Blind Placebo-Controlled Trials Evaluating the Efficacy of Diet Interventions on the Behavior of Children with ADHD.

GLUTEN: FRIEND OR FOE?

GLUTEN •  Celiac Disease linked to increased rates of:

•  CNS Disease-ataxia, dementia, vasculitis, encephalitis, epilepsy, migraine

•  Psych Disease-ADHD, depression, anxiety, suicide, eating d/o, schizophrenia and autism

•  Linked to increased risk for infertility, osteoporosis, Lupus, RLS, anemia

•  30% of population genetically vulnerable: HLA DQ2 and DQ8

Cascella NG Schizophr Bull 2011 37 (1): 94-100

GLUTEN SENSITIVITY

• Milder variation of CD

• CD represents tip of the iceberg

• Most CD is undiagnosed

• As we age more convert to sensitivity or CD

• Rates of CD rising rapidly? Now close to 1%

• Rates of GS? 10% of population or more???

• Tests not very good for GS: Elimination diet!

Ann Nutr Metab. 2015;67 Suppl 2:16-26. doi: 10.1159/000440990. Epub 2015 Nov 26. Gluten Sensitivity.

FIVE FOLD RISE IN CD

• Followed 3,511 patients from 1974 to 1989

• During this 15 year period the rate of CD rose 5 fold in the followed patients

• Significant percentage of adults lost gluten tolerance over 15 year period

• Gluten sensitivity may be acquired and not just inherited/congenital

Catassi C, Ann Medicine 2010 42 (7): 530-8.

CNS MECHANISM FOR GLUTEN?

• Cerebral perfusion studied in 3 groups: CD on no diet, CD on gluten free diet and controls

• CD on no diet: 73% had one or more brain regions with marked hypoperfusion

• No differences between other two groups

Addolorato G, Am J Medicine 2004 116 (5): 312-7.

ANTI-GLIADIN AND AUTISM

•  57 children dx with Autism

•  Significantly higher IgG anti-gliadin than controls

• No difference in celiac markers

• More pronounced IgG anti-gliadin in children with GI symptoms

Lau, NM PLoS One 2013. 8(6): e66155

GLIADIN ANTIBODIES AND PSYCHOSIS

• Analyzed archival blood samples from newborns born 1975 to 1985.

•  Registry of patients with non-affective psychosis and matched controls.

• Assessed for IgG antibodies to gliadin and casein.

• Significance for gliadin but not for casein.

Karlsson H, Am J Psychiatry 2012 169 (6): 625-32.

POSSIBLE MECHANISMS

• Gut dysfunction: inflammation/malabsorption-gliadin triggers the release of zonulin (breaks down intestinal tight junctions)

• CNS perfusion

•  Immunological shift: TH1/TH2 balance

•  Immunological sensitization: gliadin and autoimmunity-cross reactivity

• Gliadin exorphins: partial breakdown products with CNS opiate activity

• Wheat, dairy and soy contain high levels of excitotoxins: glutamic acid and aspartic acid trigger NMDA and other receptors

THE MICROBIOME

MICROBIOME

•  The body has approximately

•  10 trillion human cells

•  100 trillion bacteria

•  1,000 trillion virus

• Outnumber human cells 10:1 and genes 100:1

J Transl Med. 2017; 15: 73.

DEFINITION

•  Gut-Brain Axis

•  “an interaction that consists of bidirectional communication between the central and enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal function. This interaction occurs through signaling to and from gut-microbiota and brain, by means of neural, endocrine, immune and humoral connections.

Ann. Gastroenterol. 2016; 29(2):240

THE GUT AND BRAIN INFLUENCES ONE ANOTHER

•  Intestinal bacteria change thoughts and mood AND...

•  Thoughts and mood change the composition of the gut microbiota

COMMUNICATION

Flux MC, Lowry CA, 2019, Finding intestinal fortitude: Neurobiology of Disease, 2020 Feb;135:104578.

GUT PHENOTYPES

Valles-Colomer et al. Nature Microbiology, 2019, 4: 623-632.

GUT AND PSYCH SYMPTOMS

•  111 adult inpatients admitted for psychiatric crisis assayed with 16S rRNA gene sequencing and whole genome shotgun sequencing 

•  Depression and anxiety severity: negatively associated with bacterial richness and alpha diversity. 

•  bacterial taxa associated with depression and anxiety severity.

•  Gut microbiota richness and alpha diversity: significant predictor of depression remission at discharge.

Madan, N et al J Affective DO 2020 Mar 1;264:98-106  

GUT MICROBIOTA CHANGES BRAIN DEVELOPMENT

• 5 different brain regions, found 40 genes that were affected by presence of gut bacteria. • These affected nerve cells and influenced

genes to be turned off or turned on • Germ free mice were hyperactive and

lower anxiety (disinhibited) • Life long changes from early alteration

Diaz Heijtz R, PNAS, 2011 108 (7): 3047-52

IMPORTANCE OF GUT MICROBES

• ASD population higher levels of Clostridria histolyticum . ASD children had 9 species of Clostridia not found in controls

• Altered gut microbes in chronic fatigue syndrome, supplemented with 24 B units lactobacillus for 2 months = significant decrease in anxiety

•  Bifidobacteria infantis could modulate tryptophan metabolism and influence the pool for serotonin

• GI symptoms were strongly correlated with severity of autism…lower levels of bifidobacter and higher levels of lactobacillius were found

J Med Microbiology 2005; Gut Pathog 2009 March; Br J Nutr 2011; J Psychiatr Res 43: 164-174; BMC Gastroenterol 2011; Clin Infect Dis. 2002

LIPOPOLYSACCHARIDE ENDOTOXIN (LPS)

•  Structural portion of the external membrane of gram-negative bacteria.

•  LPS creates anxiety, cognitive deficits, depressive symptoms at extremely low levels (0.4 ng/kg)

• Most people carry a gram or more of LPS in intestinal lumen.

•  LPS can create limbic system/amygdala excitotoxicity

Haba R et al Brain Behavior Research 2012 ; 228: 423-431

PSYCHOBIOTICS • Live organism that offer benefit to psychiatric illness.

• Depression associated with shift in range of organisms

• Healthy aging relates to diversity of microbiota

• Mechanisms: anti-inflammatory, neurochemical, calm HPA axis, dietary mediation

Dinan, T et al Biological Psychiatry 2013 74 (10): 720-726.

PSYCHOBIOTICS

• RCT of 132 pts. Significant improvements in mood with Lactobacillus casei

•  Placebo controlled trial of 39 pts with CFS. Significant improvements in anxiety with Lactobacillus casei

•  44 pts with IBS noted significant improvements in anxiety with Bifidobacteria

•  42 non-clinical adults given Lactobacillus helveticus and Bifidobacterium longum in RCT noted reductions in anxiety and free cortisol.

Bested A et al Gut Pathology 2013 5(4): 1 -22

PHYSICAL SYMPTOMS OF GUT DYSBIOSIS

•  Abdominal Pain •  Abnormal stools •  Anorexia •  Belching •  Constipation •  Diarrhea •  Distention

•  Dysphagia •  Flatulence •  Hemorrhoids •  Nausea •  Reflux •  Ulcers •  Vomiting

CANDIDA

•  Randomized, placebo-controlled longitudinal pilot study 56 pts w schizophrenia

•  Probiotic treatment significantly reduced C. albicans antibodies over 14 weeks in males. Trend of improving psychiatric sx in males

•  Results: association of C. albicans seropositivity with worse positive psychiatric symptoms (confirmed with larger cohort 384 males w schizophrenia)

Brain Behav Immun. 2017 May;62:41-45. doi: 10.1016/j.bbi.2016.11.019. Epub 2016 Nov 18.

Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study.

CANDIDA

•  Case study: ADHD and Depression 3 year following

•  Deterioration in psychiatric sx when infected with Candida sx improvement with anti fungal tx (Olive leaf) and probiotics

•  Micronutrient treatment might be severely compromised by infections such as Candida and may highlight importance of gut health when treating psychiatric disorders with nutrients

Rucklidge, J Adv Mind Body Med. 2013, 27(3):14-8.

PROPOSED MECHANISMS GUT: BRAIN EFFECTS

• Reduction in lipid peroxidates

• Direct microbial neurochemical production

• Direct activation of neural link: gut/brain-vagus nerve

•  Limitation of cytokine production

•  Improvement of nutritional absorption

• Modulation of neurotrophic chemicals-BDNF, etc.

•  Indirect influence on NT/neuropeptide production

• Direct protection of intestinal barrier

• Reduction of amine/uremic burden

•  Limitation of intestinal pathogens

• Analgesic properties

Logan AC et al Medical Hypothesis 2005 64: 533-538.

LABORATORY

•  Blood work: ferritin, Vit D, homocysteine, CRP, GGT

•  Organic Acid Test (OAT)

•  Food Sensitivity/ Food Allergy-serum (IgG and IgE)

•  Comprehensive Stool Analysis

•  Celiac/gluten sensitivity

•  Microbiome assays

•  Genetic SNPs

TREATMENT: GI DYSBIOSIS

•  Identify all factors in health imbalance

•  Reactions: food, supplements, environment, medicine, body care products etc

•  Microbial imbalance

•  Chemical burdens

•  Genetic predispositions/ vulnerabilities

•  Stress (physical, mental, emotional etc.)

TREATMENT: GI DYSBIOSIS

•  Yeast vs Bacteria

•  Antifungals Rx vs Antibiotics

•  Herbals- olive leaf extract, caprylic acid, berberine plants, oil of oregano, garlic etc.

•  Probiotics

•  Gut healing nutrients

•  Digestive support

•  herbal or enzymes

•  DIET!!!

CLINICAL ADVICE

•  Avoid processed food

•  Diet diversity is critical

•  Think traditional patterns.

•  Cook together and eat together

•  Sugar craving/severe illness: Anti-fungals

•  Supplementation: omegas and probiotics

CLINICAL ADVICE

• No soda; reduce chips and fries

•  Add one fruit per day and one veggie per day

•  Reduce sugar load

•  High protein breakfast

•  If allergic: consider elimination diet or gluten free, dairy free trial

•  Hypoglycemia: protein bars, nuts, etc…

SUMMARY

•  Diet plays a role in mental health

•  Diet should be incorporated into treatment plans

•  Elimination diets can be useful for numerous conditions

•  The microbiome affects mental health

•  Mental health status affects microbiome

•  Assessment of gut health/microbiome can be a useful adjunct treatment in mental health

CASE: PEDIATRIC BIPOLAR

•  5 yo Male, presents for “medications” to help with behaviors at risk of being kicked out of kindergarten. Described as “completely out of control”, sensory concerns, poor sleep, encoporesis/constipation

•  Past Medical: Numerous abx for chronic ear infections, tonsils out at 3 yrs old, constipation, eczema

•  PE:Dark circles, erythematous cheeks and ears, bloated abdomen

CASE : PEDIATRIC BIPOLAR

•  Labs: OAT:++yeast markers

• Tx: Fluconazole: x 10 days, digestive enzymes, diet: GFCF, corn free and no sugar (yeast free diet)

CASE : PEDIATRIC BIPOLAR

•  1 month post treatment: Continues to do well in school. Sleep 11-12 hrs Encoporesis still issues- (However no pain with defecation), Erythematous cheeks and ears resolved

•  2 month post tx: Dietary changes continued. Continues to do well. Encoporesis resolved

•  3 months post tx: Diet associations with constipation, behaviors, repeat yeast tx and reenforced diet.

MARY RONDEAU, NDSCOTT SHANNON, MD

• Wholeness Center• 2620 E Prospect Rd. #190 • Fort Collins, Colorado 80525• 970.221.1106• scott@wholeness.com• www.wholeness.com