IT TAKES GUTS TO BE MENTALLY ILL! - PowerPoint Presentation

1. IT TAKES GUTS TO BE MENTALLY ILL!Relationship of the Microbiome’s Trillions of Germs to Mental DisordersHenry A. Nasrallah, MDVice-Chair for faculty Development Professor of Psychiatry, Neurology and NeuroscienceDirector: Neuropsychiatry and Schizophrenia ProgramsUniversity of Cincinnati College of MedicineCincinnati, Ohio, USA

2. Learning ObjectivesTo identify gut-related pathologies that are comorbid to mood disorders and examine how these pathologies may be related to the brainTo enhance our understanding of the microbiome & factors that affect itTo apply knowledge of the microbiome when discussing GI health options with patients with mood disorders

3. Why does the gut matter?“All diseases begin in the gut.”Hippocrates, father of medicine, 460-370 BCGood health required a balance of:black bile (melancholy)yellow bile (choleric)phlegm (phlegmatic)blood (sanguine)(Galen, too, 129-210AD)(Bernstein et al 2019; Buscaino 1953; Gupta et al 1997; Severance et al 2012, 2016; Wei & Hemmings 2005)

4. The human body is host to TRILLIONS of microbesMicrobe cells vs cells in the human body:NOT 10:1 but actually 1:1 bacteria vs body cells39 trillion bacteria to 30 trillion human(Luckey et al 1972; Sender et al 2016)A community known as theMICROBIOTABACTERIA FUNGI VIRUSES PROTOZOA ARCHAEA

5. DO YOU KNOW HOW BIG A TRILLION IS??If you count 1 number per second, this is how long it takes to count:1 Million: 11.5 days !1 Billion: 31.7 years !!1 Trillion: 31,700 years !!!Thus it takes over 1 million years to count the germs of the microbiome in a person’s gut !!

6. The Micro-organisms of the MicrobiomeThe 5 “Kingdoms” 1) Bacteriome 2) Virome 3) Mycobiome 4) Archaeome 5) ParasitomeThey interact among themselves and with their human hosts and impact physical and mental health.

7. The microbiome & associated forcesStressDietFood sensitivitiesAntibioticsMaternal factorsMode of birth BreastfeedingMaternal gut floraChronic health conditionsObesity, diabetes, allergies,inflammationSleepPsychiatric disorders Mood disorders, anxiety, psychosisEnvironmental exposuresAgeToxinsPro- & Pre-bioticsPetsExerciseSex/GenderHost genes

8. Large-scale & small-scale variation in the microbiomeSong et al’s paper:Cohabitating human pairs, dog pairs and human-dog pairs shared the most microbiota (esp. skin) compared to people/dogs from different households.Unlike dramatic changes in gut microflora, skin and oral microbiota of infants & children were quite similar to adults.Genes vs the environment:Gut microflora are thought to be more similar in genetically related people than in those who are not related.Gut microflora are more similar among non-genetically related people living in the same household than those living in other households.PetsRelatednessTwins, SpousesGeographyAgeAnatomical site

9. How Humans Gets the MicrobiomeFetuses have no microbiota at all.The newborn baby acquires the microbiome from the mother’s vagina during normal birth.Babies continue to acquire microbiota from their mother’s nipples during breast-feeding.Microbial colonization also occurs from the environment (breathing, touching the skin of other people, or from pets).

10. Impediments to Acquiring a MicrobiomeC-Section delivery: by not passing through the vagina, the newborn baby acquires all the bad germs from hospital air. It is recommended that the OBGYN takes fluid from the mother’s vagina and wipe the body of the newborn with it.Feeding by formula only deprives the baby from acquiring the mother’s microbiota.Treatment with antibiotics can kill billions of microbes in the gut which disrupts the diversity of the microbiome.Indoor livingExcessive sanitationFood preservatives

11. The Microbiota Gut-brain CommunicationsSystemic Communications: Immune -Cytokines -Bacterial metabolitesNeural Communications -Vagus nerve -Sympathetic nervous systemSystemic Communications: Endocrine -HPA axis -Neurotransmitters -Bacterial metabolites

12. Physical Diseases Associated with Dysbiosis of the Gut MicrobiotaNeurodegenerative Disorders Multiple Sclerosis, Parkinson’s Disease, Alzheimer’s DiseaseCardiovascular Disease: Coronary artery disease, hypertension Intestinal Disorders Crohn’s Disease and Ulcerative Colitis, Irritable Bowel Syndrome, Celiac DiseaseMetabolic Disorders Metabolic Syndrome, Obesity, Types 1 and 2 diabetesPregnancy-related Conditions Gestational hypertension gestational diabetes

13. Psychiatric Disorders Associated with Dysbiosis of the Gut MicrobiotaAnxietyDepressionAutism Spectrum DisordersBipolar disorderSchizophrenia

14. A Person’s Gut Microbiome Composition is Impacted by-Vaginal Birth -Environment-Genetics -Stress-Age -Infections-Diet -Other diseases-Physical Activity -Antibiotic Use-Dysbiosis = Unhealthy ImbalanceAnd that leads to many psychiatric problems

15. A Healthy Microbiome Implies -Normal gut microbiota -Normal behavior and cognition -Healthy levels of inflammatory cells/mediators -Normal intestinal permeability

16. Dysbiosis Causes Consequences -Antibiotics - Inflammation -Poor diet -Altered Behavior & Cognition -Stress - Gut permeability

17. Leaky Gut, Inflammation and the BrainStress Disrupted Bacterial Immune Neuro-Infections Intestinal Translocation Activation inflammationAntibiotics Barrier and inPoor Diet (Leaky Gut) Cytokines -Neuroinflammation Cognitive Dysfunction Depression, Anxiety -Repairing the Leaky gut: Prebiotics Probiotics Good diet

18. Microbiota In Major Depression Microbiota Richness and Diversity Inflammatory Biomarkers Cortisol Levels-Rats with Depleted Microbiota: Anhedonia Behavior Anxiety Behavior Intestinal Transit Time Plasma CRP

19. Functions of the gut microbiomeDigestion of foodstuffs, energy harvest, metabolism & synthesis of vitaminsProduction of short-chain fatty acids (SCFAs) through fermentation of dietary fiberImmune system development & protection against pathogens & autoimmunityBalancing good vs bad microbial compositions & metabolic functionsHormone production/regulation (esp. cortisol), promotion of fat storage & hypothalamic-pituitary-adrenal axis(Dinan and Cryan 2017; El Aidy et al. 2013; El Aidy et al. 2016; Erny et al. 2015; Rowland et al. 2018; Taylor & Holscher 2018). Modulation of the CNS

20. CNS FunctionsMicrobiotaGUTLUMENBRAINNeurotransmittersGABANorepinephrineDopamineSerotoninTryptophanSCFAsImmune cellsCytokinesVagus nerveSpinal afferents & efferentsHPA axisCRHACTHCortisol

21. The microbiome & neurotransmittersIn germ-free mice:↑ Hippocampal Serotonin (Clarke et al 2013)↑ Plasma/Serum Tryptophan (Clarke et al 2013; Wickoff et al 2009)↓ Tryptophan metabolism to Kynurenine (Clarke et al 2013)↓ Serum Serotonin (Wickoff et al 2009; Yano et al 2015)Catecholamines predominate GI physiology (Mittal et al 2017):NorepinephrineEpinephrineDopamineAll impact gut motility, nutrient absorption, GI innate immune systemThe gut microbiome produces 90% of the body’s serotonin, a hormone and excitatory neurotransmitter that contributes to anxiety and depression (De Vadder et al 2018).

22. The gut-brain axis in mood disordersAssociation of serotonin with depression & anxietyDepression in humans shows distinct compositional changes in gut bacteria inventory.Leaky gut and inflammatory phenotype first characterized in depression Led to multitude of studies to quantify and describe changes in diversity & abundance of taxa in rodent tests of depression.Overall rationale is to harness the functional microbial community: Gut bacteria are easily accessed and can be altered through probiotics, prebiotics, diet and fecal transplant.In patients, Lactobacillus and Bifidobacterium combinations may improve mood, reduce anxiety and enhance cognitive function.

23. Evidence for dysbiosis in mood disordersLow-level inflammationLeaky gut pathologyDisease-associated shifts in microbial inventoriesEpidemiological studies of antibiotic useEffects of probiotics to treat depression

24. Antibiotic exposures as risk factors for mood disordersSchizophreniaAffective disordersHazardRateRatio# prescribed anti-infective agents: 0 1 2-4 5-9 10-12 20+

25. THE MICROBIOME AND THE SECOND BRAIN:Bidirectional Interactions in the gut

26. The Second BrainKnown as the “Back-up Brain”Also known as the “Abdominal Brain”Also known as the “Enteric Nervous System” or ENSLocated inside the wall of the GI tract from the esophagus to the rectum.

27. The Second BrainNeurologic disorders of this abdominal brain include:Abdominal epilepsyAbdominal migraineAutism with intestinal symptoms such as enterocolitis

28. The Enteric Nervous System (ENS) (2nd Brain)Contains 100 million neuron (equal to the spinal cord)Has glia-like support cellsContains over 30 neurotransmitters including those associated with psychiatric disorders: - Dopamine (DA) - Serotonin (5HT) - Gamma Amino Butyric Acid (GABA) - Acetyl Choline (ACH)It is not part of the autonomic nervous systemCommunicates with the brain via the vagus nerve

29. The Microbiota In The GutThe microbiota are an extensive universe of commensal (i.e. symbiotic) bacteriaIt is adjacent to the second brain and plays an important role in signaling with it.Comprised of an astonishing number of 33 TRILLION bacterial organisms, which is slightly more than the number of all cells in the human body

30. The Microbiota In The Gut1000 species of diverse bacterialContains 4 million bacterial genes known as The Microbiome (compared to only 22,000 genes in humansIncredible density of a trillion bacteria in a cubic milliliter

31. The Microbiota In The GutThe second brain contains 90% of the body’s serotonin and 50% of the body’s dopamineSSRI antidepressants increase serotonin are associated with GI symptoms like nausea and diarrheaAntipsychotics are dopamine antagonists and are known to exert anti -emetic effectsClozapine has potent anticholinergic effects which can cause ileus, a severe disorder that arrests the movements of the GI tract (peristalsis)

32. The Second Brain and the Microbiome Influence on Psychiatric DisordersGI Disorders are associated with many psychiatric conditions:Irritable Bowel SyndromeIs associated with panic disorder, generalized anxiety disorder, social anxiety, dysthyria and major depression.Inflammatory Bowel DiseaseCrohn’s Disease and Ulcerative Colitis, affecting 14% in the U.S. and 46% in Mexico, are associated with mood and anxiety disorders and personality changes.Celiac Disease (worsened with gluten)Is commonly associated with neuropsychiatric disorders such as ataxia, epilepsy, peripheral neuropathy, headache, anxiety, ADHD, autism spectrum disorders and schizophrenia.

33. Psycho-Neuro-GastroenterologyCan intestinal biopsy reveal neurotransmitter pathology in schizophrenia?Can Parkinson’s disease be diagnosed very early with a GI biopsy?Can Alzheimer’s disease be diagnosed early with a GI biopsy?Can pre- and pro-biotic supplements influence the microbiome and be used as treatments for mood and anxiety disorders?Can the ENS be used as a therapeutic target?

34. QuestionsWhat is the largest endocrine organ in the human body?What is the largest immune organ in the body?Answer: It’s the 30-foot long GI tract, which contains The (the huge DNA of the Microbiota) as well as the “other brain”.

35. QuestionsHow does a human get trillions of bacteria (microbiota) in the gut?Answer: From the mother’s vagina as the baby is born, and from the mother’s nipples during breast feeding.

36. Non-Digestive Functions of the GI TractThe gastro-intestinal tract secretes dozens of peptides and other signaling molecules that influence the brainThe microbiota interact with and are regulated by gut hormones such as: - oxytocin - ghrelin - neuropeptide y - Cholecystokinin - CRG (Corticotrophin releasing factor) - pancreatic polypeptide

37. The MicrobiotaModulate brain development, functions and behaviorMaintain the intestinal barrier, which, if disrupted, would result in a “leaky gut”, triggering low-grade inflammation that is associated with depressionDiet is a major factor in shaping the composition of the microbiota. The food we eat can have a preventative or reparative effect on neuroimmune or neuroinflammatory diseases.

38. Food Effects and MicrobiotaEvidence is emerging that the food we eat and its effects on the gut microbiota can modify a person’s genes by epigenetic mechanisms. - Methylation - HistonesProbiotics can exert epigenetic effects by: 1) Influencing cytokines 2) Producing short-chair fatty acids (SCFA) 3) Vitamin synthesis 4) Producing various neurotransmitters

39. Microbiome-Gut-Brain AxisThe bidirectional trafficking between the microbiome and the enteric brain has reciprocal effects: 1) The brain influences the microbiome composition by regulating satiety, the hypothalamic pituitary axis and with neuropeptides. 2) The microbiome conveys information to the brain about the intestinal status via infectious agents, intestinal neurotransmitters, cytokines, sensory vagal fibers, and various metabolites.

40. Microbiome-Gut-Brain AxisFailure of these normal interactions can lead to a variety of pathological processes, including: - Inflammatory - Auto-immune - Degenerative - Metabolic - Cognitive - Mood and behavioral changesTherapeutic interventions for these adverse consequences can be implemented through microbiome manipulations (such as fecal transplants), nutritional strategies, and reinforcement of the enteric and cephalic brain barriers

41. The Microbiome and Psychiatric DisordersAlterations in the microbiota, such as the intake of antibiotics or by intestinal inflammation can lead to various psychiatric disorders including: - Schizophrenia - Autism - Depression - ADHD - Alzheimer’s disease - Irritable bowel syndrome - Anxiety

42. The Microbiome in Psychiatric DisordersMDD: Significant compositional differences were found compared to health controls. Certain bacterial genera were depleted (Coprococcus and Dialista). Better quality of life was associated with Fecalibactrium and Coprococcus. Certain probiotics appear to be beneficial especially containing Bifidobacterium and Lactobacillus.Bipolar Disorder: Several studies reported. A replicated study showed decreased levels of Faecalibacterium. Another study reported, the genus Flavon; fractorm which induces oxidative stress to be associated with BD. Like MDD, the probiotics Lactobacillus and Bifidobacterium may be helpful.

43. The Microbiome in Psychiatric DisordersAnxiety Disorders: A wealth of preclinical studies show a role for the gut microbiome in stress response and anxiety behaviors in animals. Probiotics help animals but no strong data for humans yet.PTSD: The relative abundance of Actinobacteria, Leptosphaeria and Verrucoomicrobiota phyla were decreased in PTSD patients.Schizophrenia and Psychotic Disorders: The microbiome in patients with first-episode psychosis and schizophrenia has a distinctly different from healthy subjects. Treatment-resistant patients had the strongest differences in microbiota in diversity. Increased Ruminococcaceae was related to low negative symptoms while Bacteroides was associated with depression.

44. Perturbations in The Microbiome in Psychiatric DisordersA meta-analysis of 59 studies in various disorders showed: 1) Significant decrease in microbial richness in bipolar disorder versus controls 2) A decrease in phylogenetic diversity 3) Difference in beta diversity observed in MDD and psychosis 4) A trans-diagnostic pattern of microbiota signature was found in MDD, bipolar, schizophrenia and anxiety. This suggests that all those disorders have a reduction of anti-inflammatory butyrate-producing bacteria, while pro-inflammatory genera are enriched

45. Schizophrenia & MicrobiomeProdromal StageFecal bacteria show an increase in SCFAs which can activate microglia (and trigger psychosis)First-Episode StageLow number of certain fecal bacteria -Bifidobacterium -E Coli -LactobacillusHigh levels of other bacteria -Clostridium CoccoidesAfter 6 months of antipsychotic RX, the above pattern was reversedOther studies show differences between SZ and healthy individuals. The greater the difference, the more severe the psychosis and less response to treatment

46. Autism & MicrobiomeAutism has been linked to increased microbiotaFecal samples from children with autism have an increase in SCFAsA certain strain of lactobacillus can modulate oxytocin or reverse some symptoms of autism

47. Depression & MicrobiomeDepression is associated with increased diversity of microbiota alphaLow numbers of Bifidobacterium and lactobacillusCertain strains reduce depression and anxiety in animal studiesMediterranean diet, but not western diet, is microbiota-friendly, and has been reported to mitigate the risk of depressionCertain probiotics have been reported to increase resilience to stress

48. ADHD & MicrobiomeSome studies suggest that ADHD may be linked to factors that can alter gut microbiota, including: -Birthing mode: C-Section can be a problem! -Type of infant feeding (breast-feeding is better) -Maternal health (inflammatory disorders) -Early stressors (child abuse)Dietary influences on gut microbiota can modify ADHD symptoms for better or worse.

49. Alzheimer’s disease & MicrobiomeObesity and diabetes can inflame the gut microbiota and increase the risk of dementia

50. Aging and the Gut MicrobiomeAging in determined by complex interactions among genetic and environmental factorsEvidence suggests that the gut microbiome is at the core of many aging changes, including immune system dysregulation ad susceptibility to diseasesThe microbiome changes extensively across the lifespan and aging influences the microbiomes and its metabolic alterationsA review of 27 studies showed the following: 1) Alpha diversity of microbial taxa, functional pathway and metabolites was HIGHER in the oldest adults 2) Akkermmansia was consistently ore abundant with aging 3) Faecalibacterium, Bacteroidacene and Lachnospiraceae were relatively REDUCED

51. Irritable Bowel Syndrome & MicrobiomeFecal microbiota transplantation has been shown to improve IBS by increasing the diversity of gut microbiotaMood is also improved in IBS patients with fecal transplants

52. Alcohol Use& MicrobiomeBoth alcohol consumption and withdrawal can cause neuroinflammation and immune dysregulation in the brainAlcohol can cause dysbiosis (alteration in the composition of the microbiome), which has a negative effect on microbe-host homeostasis

53. SEXUAL CONTACT AND THE MICROBIOME

54. Sexual Activity and the MicrobiomeSexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis defined as a reduction inn microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria. Symptoms of dysbiosis include:-Brain “fog”, irritability, mood changes and anxiety-Bloating, loss of intestinal permeability and insufficient reclamation of nutrients-Congestions of certain organs such as the liver, gallbladder and pancreas-Production of antigen-antibody complexes in response to chemicals in partially digested food-Aggravation of inflammatory disorders such as migraine arthritis and auto-immune disorders

55. Bacterial Vaginosis (BV)Is the consequence of acquiring pathogenic microbiota in the vagina.It is not an “infection” but an ecological imbalance in the composition of the vaginal microbiota.It is cause by a significant decline in the beneficial vaginal lactobacillus + a marked increase in the non-lactobacillus taxa, especially Gardenrella and Atopobum.It can last a week after sexual intercourseBV is rare among virginsFor male partners the penile microbiota change significantly after unprotected sex

56. BV ConsequencesDecrease in hydrogen peroxide-producing bacilliPrevalence of anaerobic bacteriaAlkalinization, fishy odor and gray-white vaginal dischargeIncrease in the rate of pelvic inflammatory disease ectopic pregnancy, endometriosis, pre-term birth and tubal-factor infertility

57. BV and MalesCircumcision decreases the risk of BVMore BV in wife's of men with extramarital affairs and in women with multiple partnersBoth oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiotaGingivitis has been reported after oral sexBottom Line: Sexual activity (kissing, vaginal, oral or anal sex and extensive skin to skin contact), can lead to exchange of microbidia

58.

59. Are probiotics effective for treating depression?

60. What are probiotics & prebiotics?Probiotics are live bacteria taken to supplement the bacteria living in the gut.Prebiotics are dietary fiber that feed the gut’s beneficial bacteria.Found in yogurt and fermented foods such as sauerkraut and kimchiCan be single strains or a blend of microbesProbiotics represent a $37 billion market worldwide.There are over 120 species of Lactobacillus alone, of which many are used as probiotics.The organisms represented in commercial products can differ from batch to batch and from one product to the next.The effectiveness of any given strain also can differ from one individual to another.Found in fruits and vegetables Usually contain a complex carbohydrateAre fiber-rich and not digestible by the bodyAre less well-studied than probioticsProbiotics & prebiotics are generally unregulated.

61. Probiotics prevent rehospitalization in mania patientsProbiotic treatment with Bifidobacteria & Lactobacillus prevents relapse in people with mania. 3-fold decrease in relapse over 24 week period, p<0.008Rehospitalization ratePlacebo(n=33)Probiotic(n=33)Days in study

62. Probiotics may improve depression in carefully selected patient populations44 adults with IBS & mild to moderate anxiety and/or depression received 6 weeks of Bifidobacterium longum strain.Reduced depression scores with probiotic compared to placeboNo effect on anxiety or IBS symptomsFMRI showed probiotic improvements associated with reduction of limbic reactivity.

63. Selected literature - altered microbiomes in depressionAltered microbiome & behavior in rodent stress models:O’Mahony et al, Biological Psychiatry 2009Bailey et al, Brain, Behavior, & Immunity 2011Bendtsen et al, PLOS One 2012 McGaughey et al, Scientific Reports 2019Microbiome alterations in MDD & BPNaseribafrouei et al, Neurogastroenterology & Motility 2014Jiang et al, Brain, Behavior & Immunity 2015Aizawa et al, Journal of Affective Disorders 2016Zheng et al, Molecular Psychiatry 2016Evans et al, Journal of Psychiatric Research 2017Lin et al, Journal of Affective Disorders 2017Chen et al, NeuroReport 2018Aizawa et al, Frontiers in Psychiatry 2019Coello et al, Brain, Behavior & Immunity 2019Rong et al, Journal of Psychiatric Research 2019Valles-Colomer et al, Nature Microbiology 2019Review articles of microbiome in depressionCryan & Dinan, Nature Reviews 2012Collins et al, Nature Reviews 2012Dinan & Cryan, Brain, Behavior & Immunity 2019Cheung et al, Frontiers in Psychiatry 2019

64. Selected literature – probiotics & moodProbiotics in rodent modelsDesbonnet et al, Journal of Psychiatric Research 2008Ait-Belgnaoui et al, Psychoneuroendocrinology 2012Ait-Belgnaoui et al, Neurogastroenterology & Motility 2014Savignac et al, Neurogastroenterology & Motility 2014Probiotics in healthy humansBenton et al, European Journal of Clinical Nutrition 2006Messaoudi et al, British Journal of Nutrition 2011Tillisch et al, Gastroenterology 2013Steenbergen et al, Brain, Behavior & Immunity 2015Allen et al, Translational Psychiatry 2016Papalini et al, Neurobiology of Stress 2019Probiotics in humans with depression (or BPD)Akkasheh et al, Nutrition 2016Romijn et al, Australian & New Zealand Journal of Psychiatry 2017Painold et al, Bipolar Disorders 2018Reininghaus et al, Neuropsychobiology 2018Kazemi et al, Clinical Nutrition 2019Probiotics in humans with GI disordersPinto-Sanchez et al, Gastroenterology 2017Urita et al, Bioscience of Microbiota, Food and Health 2015

65. SummaryThe microbiota universe inside our gut can have good or bad effects on mental healthThis field of research is still in its very early stages but is growing very rapidlyManipulating the diversity of the microbiota promises to be a novel therapeutic strategy in several psychiatric disorders

66. ConclusionsThe microbiome is altered in individuals with mood disorders.Antibiotic exposure in early life is a risk factor for mood disorders in later life.Probiotics may be useful to prevent relapses in mania & improve symptoms of people with depression.An increased understanding of the neurobiology of the microbiome is required so that the benefit that these micro-organisms serve to human health can be fully harnessed.Clinicians should inquire about patient GI conditions and overall GI health.Dietary interventions and use of probiotics and their limitations should be discussed as a supplemental therapeutic options.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.