I FEEL IT IN MY GUT: THE BRAIN AND MICROBIOME Learning Objectives - PowerPoint PPT Presentation

I FEEL IT IN MY GUT: THE BRAIN AND MICROBIOME

Learning Objectives •Provide an overview of the origins and importance of the gut-brain connection •Examine the relationship between the gut-brain- microbiome axis and chronic inflammation •Consider current evidence of the gut-brain connection’s impact on mental health •Consider potential implications of the gut-brain connection for the treatment of mental illness

Origins and Importance of the Gut-Brain Connection

The Gut-Brain Connection: A Topic of Much Interest In 2014 and 2015, NIMH offered a fund of $1 million to study the gut microbiota-brain axis In 2015, the US Navy Institute announced a fund of $14.5 million over the next 6–7 years to research the role of the gut in cognitive and stress disorders The European Union launched a 5-year “MyNewGut” project ($10.1 million US dollars) for research on brain development and related disorders In 2014, >$1 million was transferred to the Human Microbiome Project, supported by the NIH, which aims to understand microbiome diversity and determine roles of microorganisms in health and disease Wang HX, Wang YP. Chin Med J (Engl) 2016;129(19):2373-80; Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci 2015;13(3):239-44.

Origins and Colonization of the Gut Microbiota •The gut and brain originate from the same tissue during embryogenesis, the neural crest, and influence each other during development •Bacteria, mostly residing in the gut, outnumber the body’s cells 10:1 and are referred to as a • A microbiome comprises the entirety of microscopic organisms and their genetic material that inhabit a particular environment •Gut microbiota begin to colonize the gastrointestinal tract at birth; a complex microbiome forms after the first year Human brain Gut microbiota • Bacteria in the gut is estimated to consist of >1000 species and >7,000 subspecies ~1 kg •Microbiome bacteria have co-evolved with us and interact with our body in a bidirectional manner Chen X et al. Protein Cell 2013;4(6):403-14; Verdino J. Health Psychol Open 2017;4(2):2055102917724335; Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci 2015;13(3):239- 44; Petra AI et al. Clin Ther 2015;37(5):984-95; Dinan TG et al. J Psychiatr Res 2015;63:1-9.

Communication Along the Microbiota-Gut-Brain Axis O OH CORTISOL O H H O H Neural Communication Systemic Communication: Systemic Communication: Vagus nerve Endocrine Immune Sympathetic nervous Hypothalamic-pituitary-adrenal axis Cytokines system Neurotransmitters Bacterial metabolites Bacterial metabolites NH 2 SEROTONIN HO N H Mayer EA et al. J Neurosci 2014;34(46):15490-6; Kelly JR et al. Front Cell Neurosci 2015;9:392; Cryan JF, Dinan TG. Nat Rev Neurosci 2012;13(10):701-12.

Diseases Associated with Dysbiosis of Gut Microbiota Psychiatric and mood disorders Neurodegenerative disorders • Anxiety • Multiple sclerosis • Depression • Parkinson’s disease • Autism spectrum disorder • Bipolar disorder • Schizophrenia Cardiovascular disease • Coronary artery disease • Hypertension Metabolic disorders • Metabolic syndrome Intestinal disorders • Obesity • Inflammatory bowel • Types 1 and 2 diabetes disease • Crohn’s disease Pregnancy-related conditions • Ulcerative colitis • Gestational hypertension • Irritable bowel syndrome • Gestational diabetes • Celiac disease Cekanaviciute E et al. Proc Natl Acad Sci U S A 2017;114(40):10713-8; Sampson TR et al. Cell 2016;167(6):1469- 80.e12; Senthong V et al. J Am Heart Assoc 2016;5(6):e002816; Li J et al. Microbiome 2017;5(1):14; Carding S et al. Microb Ecol Health Dis 2015;26:26191; Fond G et al. Pathol Biol (Paris) 2015;63(1):35-42; Tai N et al. Rev Endocr Metab Disord 2015;16(1):55-65; Dunlop AL et al. Adv Neonatal Care 2015;15(6):377-85.

Gut-Brain Connection: A Conceptual Framework •Preclinical data and early clinical research support the gut-brain connection •Too soon to make therapeutic recommendations based on randomized clinical trials and best practices •Interesting and well-funded avenue of research with promising future

The Gut-Brain Connection and Inflammation

Early Life Adversity and the Microbiome •Negative in-utero and early life experiences alter initial gut colonization, which predisposes an individual to stress-induced inflammation later in life by: • Establishing a hyperactive hypothalamic-pituitary-adrenal (HPA) axis • Altering immune system activity • Increasing intestinal permeability • Influencing epigenetic regulation •Early life experiences, through modification of the gut ecology, magnify stressors, amplify the stress response, and inhibit corrective homeostatic mechanisms resulting in chronic sustained inflammation Sudo N et al. J Physiol 2004;558(Pt 1):263-75; Gur TL et al. Front Psychiatry 2015;6:5.

A Healthy Microbiome • Normal gut microbiota Healthy Microbiome • Normal behavior and cognition • Healthy levels of inflammatory cells/mediators • Normal intestinal permeability Kelly JR et al. Front Cell Neurosci 2015;9:392; Cryan JF, Dinan TG. Nat Rev Neurosci 2012;13(10):701-12.

Causes and Consequences of Dysbiosis Dysbiosis • Increased inflammation • Altered behavior and cognition • Increased gut permeability *Examples of potential causes of dysbiosis. Not an exhaustive list. Kelly JR et al. Front Cell Neurosci 2015;9:392; Cryan JF, Dinan TG. Nat Rev Neurosci 2012;13(10):701-12.

Impact of Ketogenic Diet on the Gut Microbiota is Distinct From a High-Fat Diet Fold change from baseline of genera whose abundances were significantly different between high-fat diet and ketogenic diet (false discovery rate < 0.1, DESeq2), in mice fed ketogenic diet for 3 weeks (n = 6 mice). Data are presented as mean ± standard error of the mean. Each data point represents an individual, singly housed animal. Ang QY et al. Cell 2020;181(6):1263-75.e16.

“Classic” vs. Chronic Inflammation • Described ~2000 years ago • Described in 1993 Chronic inflammation Classical inflammation • Pain (dolor) • Low-grade, causing only a small (“metaflammation”) rise in immune system markers • Redness (rubor) • Persistent, resulting in chronic, • Heat (calor) rather than acute, allostasis • Swelling (tumor) • Has systemic, rather than local, • Short-term response to effects infection and injury • Has antigens that are less apparent • Aims to remove infective as foreign (“inducers”) stimulus and allow repair of • Appears to perpetuate, rather than damaged tissue resolve, disease • Is associated with reduced, rather than increased, metabolism Egger G. Prev Chronic Dis 2012;9:E95.

Leaky Gut, Inflammation, and the Brain Infection Antibiotics Stress Poor diet Immune activation Proinflammatory cytokines HPA Disrupted activation Bacteria intestinal barrier translocation “leaky gut” Neuroinflammation Intact intestinal Cognitive dysfunction barrier Depression Anxiety Prebiotics Probiotics Decreased social function Good diet Kelly JR et al. Front Cell Neurosci 2015;9:392.

Proinflammatory Cytokine Entry Pathways From the Periphery Into the Central Nervous System CNS =central nervous system DAMP =damage-associated molecular patterns IFN =interferon IL =interleukin PAMP =pathogen-associated molecular patterns TNF =tumor necrosis factor Park C et al. Brain Behav Immun 2018; 73:115-24.

The Role of the Gut-Brain Connection in Mental Health

Clinical Observations Suggestive of Gut-Brain Connection •Common co-occurrence of gastrointestinal (GI)-related comorbidities with a variety of psychiatric conditions (e.g., anxiety, depression, schizophrenia) •GI problems can create stress and anxiety; conversely, stress and anxiety can make GI problems worse •Experiencing emotion, such as excitement or nervousness, may impact the digestive system, causing the “butterflies in the stomach” feeling Prinsloo S, Lyle RR. NeuroRegulation 2015;2(4):158-61; Schnorr SL, Bachner HA. Yale J Biol Med 2016;89(3):397-422; The Cleveland Clinic 2017;https://my.clevelandclinic.org/health/treatments/16358-gut-brain-connection.

Evidence of the Gut-Brain Connection Preclinical Clinical (limited) •Stress in rats has been reported to lead to •A double-blind, placebo-controlled trial of a reduction in diversity of the 66 subjects who ingested a fruit bar gastrointestinal microbiome containing a probiotic formula for 30 days reported significantly lower levels of •The naturally exaggerated physiological anxiety, anger, depression, and response to stress in germ-free mice was somatization, as well as lower cortisol reversed when they were colonized with a levels particular strain of bacteria •A placebo-controlled study assessing the •Rats given a strain of bacteria for 28 days effect of a fermented milk product showed a decline in both anxiety and containing probiotics on the brain activity depression scores of healthy women reported significant impact on the regions controlling emotional and sensory processing Verdino J. Health Psychol Open 2017;4(2):2055102917724335; Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci 2015;13(3):239-44.