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  • The Gut Balance Revolution

    Gerard E. Mullin MD

    Associate Professor of Medicine

    www.thefoodmd.com

    Johns Hopkins University School of Medicine

    Integrative Healthcare Symposium 2016

    February 26, 2016

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Learning Objectives

    • Know the role of the gut microbiota in human health and disease

    • Become familiar with the pathophysiology of obesity and how alterations in the gut microflora lead to obesity

    • To understand how prebiotics and probiotics can promote a lean metabolism by fostering a healthy gut microbiome

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Case History

     79 yo gentleman presents with

    abdominal pain, gas, bloating,

    mixed bowel habits for months.

     Pertinent positives: diabesity, GERD, CVD,

    MI/stents/angioplasty, HTN, poor sleep,

    fatigue, melancholy.

     Lactulose breath test: SIBO

     Elimination phase - herbal protocol x 30

    days and Low FODMAP diet 8 weeks

  • Case History

     SIBO improved, lost 27 pounds, felt

    like a new person - GI symptoms

    improved, better energy/mood

     Probiotic-rich diet - lost 10 more

    pounds.

     Started putting his friends on “His”

    weight loss diet

  • Figure 2. Meta-analysis of SIBO risk with PPI use.

    Proton Pump Inhibitor Use and the Risk of Small Intestinal Bacterial Overgrowth: A Meta-analysis Clinical Gastroenterology and Hepatology, Volume 11, Issue 5, 2013, 483–490

    PPIs and SIBO

  • PPIs Delay Small Intestine Transit

    Am J Physiol Gastrointest Liver Physiol. 2015 May 1;308(9):G785-93

  • The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.

  • Introduction to the Gut Microbiome

  • Introduction to the gut microbiome

     We are composite of species: a ‘supra-organism’  Our microbial census exceeds the total number of our

    own human cells by ~10 fold  Our largest collection of microbes resides in the

    intestine (~10-100 trillion organisms)  The aggregate genomes of

    these gut species (microbiome) may contain >100 fold more genes than our ‘own’ genome

     The microbiome is an integral part of our genetic landscape (‘human metagenome’) and of our genetic evolution

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Techniques used to characterize the gut microbiome

    NIH HUMAN

    MICROBIOME

    PROJECT

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Energy

    Transport

    Defense

    and Repair

    Structural Integrity

    Communication

    Detoxification &

    Biotransformation

    Assimilation

    Properly

    Functioning

    Gastrointestinal

    MicroBiome

    BioFilm &

    Permeability

    Mast Cell

    Degranulation

    Phase III

    Detoxification

    n-Butyrate

    SCFA

    Production

    Oral Tolerance,

    NF-κB, IL-10, IL-17

    Obesity

    Nutrition &

    Metabolis m

    GI Motility

    Entero-Hepatic

    ReCirculaton

  • Ecosystems and Biodiversity

    • Increased species diversity increases the efficiency and productivity of an ecosystem

    • More diverse communities are functionally less susceptible to external stressors

    • In relative terms, increasing stress has a stronger negative effect on low-diverse communities

    Global Ecosystem Changes

    Natural Processes

    Biodiversity

    Stability

    Ecosystem Functioning

    Ecosystem Services

    Human Wellbeing

    Khanna S and Tosh PK. (2014).. Mayo Clin Proc. 89(1): 107-114. Copyright © 2015 [Gerard E. Mullin MD]. All Rights Reserved

  • J. Physiol Biochem DOI 10.1007/s13105-0390-3 In Press 2/2015.

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • J Physiol Biochem. 2015 Sep;71(3):509-25.

  • Exposures in early life, infant gut microbiota, & future health

    www.cmaj.ca/lookup/doi/10.1503/cmaj.130147

  • Multiple intrinsic and extrinsic factors can affect the microbiota.

    Bohm M et al. Nutr Clin Pract 2013;28:289-299

  • The Good The Bad and the Ugly

  • Kamada N et al. Nat Immunology. 2013;14(7):685-690

  • Disorders Associated with an Altered Gut Microbiome

    Gastrointestinal Gallstones, Colorectal Cancer, Hepatic Encephalopathy, *IBS, IBD, FMF, Gastric cancer and lymphoma, *Recurrent Clostridium difficle infection

    Non-GI Anxiety, Arthritis, Asthma, Autism, Autoimmune disorders, Cardiovascular*, Chronic fatigue, Chronic kidney disease, Depression, Diabetes, Eczema, *Fatty Liver, Fibromyalgia, Hypercholesterolemia, ITP, Metabolic Syndrome, Mood disorders, Multiple Sclerosis, Myoclonus dystonia, *Obesity, Oxalic kidney Stones, Parkinson’s Disease, Senile Dementia, etc.

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Non-alcoholic Steatohepatitis: a Microbiome-Driven Disease

  • 21

  • Gut Microbes 2012;3(4):366-373.

  • Proposed causes of dysbiosis of the gut microbiota.

    Nature Reviews Immunology Vol 9, May 2009| 313

  • Introduction to the gut microbiome and obesity

    Two phyla of (mainly anaerobic) bacteria linked to obesity:

    –Firmicutes (positively)

    –Bacteroidetes (negatively)

     Impact on metabolism results

    from an imbalance of these

    phyla.

    Cause or consequence?

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Obese mice have altered gut flora transfer of gut flora induces

    weight gain

    Ley, et al. PNAS 102(31):11070, 2005

    Turnbaugh, et al. Nature 444 (21/28):1027, 2006

    Copyright © 2015 [Gerard E. Mullin MD]. All Rights Reserved

  • Microbial community transplant experiments

    Measure total body fat content before and after 14- day colonization

    Ley, et al. PNAS 102(31):11070, 2005

    Turnbaugh, et al. Nature 444 (21/28):1027. 2006 2006

  • Comparison of energy extraction between obese and lean mice

    Turnbaugh, et al. Nature 444:1027, 2006

  • Functional interactions between the gut microbiota and host

    metabolism

    Nature 489, 242–249 (13 September 2012)

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Microbiota-transplantation studies transfer of microbes to germ free mice

    ob/ob Diet-induced obesity

    Humanized Mice Diet-induced obesity

    Nature 2006

    Cell Host Microbe 2008

    Nature Sci Transl 2009

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Host remodeling of the gut microbiome and metabolic changes in pregnancy

    Cell, 150: 470-480, 2012

  • The effects of intestinal microbiota and host physiology

    Physiol Rev 2010;90:859–904 Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Curr Atheroscler Rep. 2014 Nov;16(11):454

  • Probiotics Improve Outcomes After Roux-en-Y Gastric Bypass Surgery: A Prospective Randomized Trial

    J Gastrointest Surg 2009;13:1198-1204

    Copyright © 2016 [Gerard E. Mullin MD]. All Rights Reserved

  • Metabolic Improvement

    after Bariatric surgery

    Dietary Change

    Gut microbiota

    Systemic Inflammation

    Enteric hormones

  • Dietary Effect on the Gut Microbiota

    DeFilippo C et al. PNAS. 2010;107(33):14691-14696.

    Green = Bacteroidetes Red = Firmicutes

  • Obesity Related Changes in the Microbiome

    Angelakis et al Future Microbiol. 2012 Jan;7(1):91-109.

  • Nature 2013;500:538-539.

  • Mehal, WZ. Nat. Rev. Gastro Hep. 20 August 2013

  • How sweet it is!

    “We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS- induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage”...”

    http://www.google.com/url?sa=i&rct=j&q=jackie+gleason+how+sweet+it+is&amp