RESTORING A CHILD'S MICROBIOME TO IMPROVE FUTURE HEALTH: Vaginal Seeding and Other Strategies Suchi Hourigan, M.D. Director of Pediatric Research, Inova Children’s Hospital Pediatric Gastroenterologist, Pediatric Specialists of Virginia
Financial Disclosure • I have no relevant financial relationship in relation to this presentation
Goals • GI Microbiome Overview • Development of the gut microbiome in early life → shapes future health • Gut microbiome manipulation • Fecal transplant • Vaginal Seeding
“We are not alone!” Nature Cover. June 2012
Human Microbiome Project: NIH
Intestinal Microbiome • Human intestine: > 10 14 bacteria – 1000-2000 species – Highly variable between individuals • Variety – Fungi – Protozoa – Viruses – Bacteriophages Gill. Science. 2006 Qin. Nature. 2010 Image from Medscape 2017
The intestinal microbiome is our friend! • In Health: Stable community • Exists in symbiosis with host – Immune and metabolic system: Development and maturation – Synthesis: Vitamins – Fermentation: Dietary carbohydrates – Pathogens: Competitive exclusion
Imbalance = Dysbiosis Sommer. Nature Reviews. 2013
Dysbiosis and Disease States Non – GI Illnesses GI Illnesses Colorectal Cancer Autoimmune diseases Necrotizing Enterocolitis Asthma/Eczema/Atopy Inflammatory bowel disease Autism Irritable Bowel syndrome Type 2 diabetes Clostridium difficile infection Obesity Hepatic Encephalopathy Mood disorders Gastric carcinoma/lymphoma Chronic Fatigue Syndrome Idiopathic Constipation Fibromyalgia Adapted from Brandt . AJG. 2013
Development of the gut microbiome in early life → Shapes future health
Dynamic development infancy→ Relative stability age 3+ Yatsunenko T. Nature. 2012
Dynamic development infancy→ Relative stability age 3+ Yatsunenko T. Nature. 2012
Infant Intestinal Microbiome Not stable until 1-3 years of age Many factors affect development Faa. J Matern Fetal Neonatal Med. 2013.
Putigani. Ped Res. 2014
Putigani. Ped Res. 2014
Putigani. Ped Res. 2014
Peripartum Factors: Delivery mode • Microbiome: Caesarean Section differs from vaginal birth Dominguez-Bello . PNAS. 2010
Peripartum Factors: Delivery mode • Microbiome: Caesarean Section differs from vaginal birth • Differences can persist up to 4 years of age Dominguez-Bello . PNAS. 2010 Foughy. Nat Commun. 2019
Early years • Diet: Breast milk vs. Formula – Breast milk contains unique oligosaccharides – 700 species bacteria breast milk and colostrum – Different dominating species gut microbiome breast fed vs. formula fed infants • In general more bifidobacterium in breast fed Wang. JPGN. 2015 Jost. PLoS One.2012 Bezirtzoglou E. Anerobe. 2011
Early years • Antibiotic exposure – Profound effect gut microbiome – Childhood anti- anaerobe antibiotic → IBD development – Association with childhood obesity • Hygiene Hypothesis – Infectious agents/microbiome → Development immune system – Older siblings →increased diversity and richness of gut microbiome in early childhood – Amish vs Hutterite Farming Kronman. Pediatrics. 2012 Bailey. Jama Ped. 2014 Gerber. JAMA. 2016 Laursen. BMC. Microbiol. 2015
Microbiome imbalance→illness • • • Necrotizing Obesity Diabetes enterocolitis (NEC) • • Asthma, allergies Heart Disease • • Autism Metabolic Syndrome • IBD
Early life antibiotics → Obesity Early Life antibiotics : Prenatal Peripartum First years of life NICHD 5-year grant to Inova Children’s Hospital to investigate this in children Miller. Obes Review. 2018 Cox. Cell. 2014
Manipulation of the Microbiome → Improve Health Outcomes
Manipulation of the microbiome • Probiotics and Prebiotics • Diet • Antibiotics • Fecal Microbiota Transplantation (FMT) • Vaginal Seeding Wu. Science. 2011 DeFillipis. Gut. 2015
Probiotics “Viable microorganisms, sufficient amounts of which reach the intestine in an active state and thus exert positive health effects” • Decreased sepsis in neonates in India • Colic – some evidence for L. reuteri • No benefit for children with gastroenteritis • Possible Harm? → Delayed recovery after antibiotics • Future: Personalized probiotics Panigrahi. Nature. 2017 Schnadower. NEJM. 2017 Freedman. NEJM. 2017 Suez. Cell. 2018
Prebiotics “A selectively fermented ingredient (non -digestible carbohydrates) that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well being and health” • Inulin type fructans (ITF) best studied • Studies in variety of diseases: CRC, allergies, IBS • Obesity in children: – Liber et al, RCT, no difference BMI for age z-score. – Nicolucci et al, RCT, significant decrease body weight z score Liber. Br J Nutr. 2014 Nicolucci. Gastroenterology. 2017
Fecal Microbiota Transplantation (FMT) Donate Deliver Restore • Fecal bacteriotherapy • Stool/fecal transplant Image from Borody et al Nature 2012
C. difficile Infection Increasing: • Prevalence: Children and adults • Community acquisition • Resistance to standard treatment (abx) • Recurrence Role for FMT Now in IDSA guidelines McDonald. Clin Infec Dis. 2018
FMT is not new! Ge Hong. 4 th Century. Li Shizhen. 16 th Century.
FMT Image from Borody et al. Nature reviews. 2012
FMT Image from Borody et al. Nature reviews. 2012
FMT Image from Borody et al. Nature reviews. 2012
FMT Image from Borody et al. Nature reviews. 2012
Randomized Controlled Trial Van Nood. NEJM. 2013
Randomized Controlled Trial Van Nood. NEJM. 2013
Randomized Controlled Trial Van Nood. NEJM. 2013
FMT: Effective for CDI • Systematic review – 2 RCT, 28 case series and 5 case reports – Overall resolution 85% of cases • Indications – Recurring or relapsing CDI – Moderate-severe CDI unresponsive to standard therapy Drekonja et al. Ann Intern Med. 2015
Nuts and Bolts: Donor Selection • “Healthiest microbiome” • Low infection risk • Source: Courtesy of awkwardfamilyphotos.com – Donor known to recipient – Universal Donors • Stool banks Hamilton MJ. Am J Gastroenterol 2012.
Nuts and Bolts: Donor Screening Blood & Stool Tests Questionnaire, H&P Bakken. Clin Gastroenterol Hepatol. 2011. Image adapted from openbiome.org
Nuts and Bolts: Procedure Youngster et al. JAMA. 2014
Nuts and bolts All routes effective for treatment of recurrent CDI Brandt L. Am J Gastroenterol. 2013
FMT: For non-CDI diseases • Growing interest in diseases associated with microbiome changes • Ongoing trials: • IBD • Irritable Bowel syndrome • Obesity • MDR pathogen decolonization • Autism • Type 2 diabetes
Short term side effects • Tolerable • Reported short term side effects: – Abdominal discomfort/cramping – Diarrhea – Constipation – Belching Brandt L. Am J Gastroenterol. 2013
Risks: Infections • Proven transmission: none reported until 2019. FDA safety alert death of patient from MDRO. • Human Microbiome Project: – Potential pathogens: low level in “healthy” microbiome – Asymptomatic carriage – Pathogenic in different host?? Human Microbiome Project Consortium. Nature. 2012 Hourigan. OFID. 2019
Long Term Risks • Hypothetical: – Inadvertent transfer of disease propensity associated with intestinal microbiome • Follow up studies up to 68 months: – Few patients developed autoimmune disease – No clear association with FMT – Predisposing factors • Accelerated weight gain after FMT Brandt. Am J Gastro. 2012 Agrawal. J Clin Gastro. 2015 Alang. OFID.2014
Special Considerations in Children FMT – Rapidly developing gut microbiome in first few years of life – ↑ risk of immune ageing and immune related diseases? – Use of age matched donors? Image from Arrieta. Frontiers in Immunology. 2014 Sharon. Genome Research. 2013 Drewes. JCI Insight. 2019
FMT: Pitfalls • “Hot Topic”! Promoted in lay press • Clear medium term benefit: In CDI only • Long term outcome: Unknown • GI Microbiome manipulation: Potential implications for GI & non-GI sites • Need: Controlled, well designed trials with long term clinical and microbiome follow up Future: Lab grown “stool”, e.g. “ RePOOPulate ”
Manipulation of the microbiome • Probiotics and Prebiotics • Diet • Antibiotics • Fecal Microbiota Transplantation (FMT) • Vaginal Seeding
C- sections:↑adverse childhood health outcomes • Can be necessary and life saving • 32% births in USA by CS • CS infants increased risk of: – Obesity • 3 meta-analyses • Controlled for Maternal BMI, birth weight, diet, SES • Murine models suggest CS effect independent of antibiotics – Asthma – Allergies Kuhle. Obesity Reviews. 2015 Mueller. Int J Obes. 2018
C-section impairs transmission of the early maternal microbiome Vaginal C-section Dominguez-Bello et al. PNAS 2010
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