10/4/2016

1

Robynne

Chutkan,

MD, FASGE

GutBiome

Institute, LLC

Georgetown

Hospital

WHY YOUR MICROBES

MAY BE MORE

IMPORTANT THAN

YOUR GENES

WORKER BEES

C-section Vaginal

Allergies

Asthma

Autoimmune

diseases

Obesity

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2

THE DEVELOPING MICROBIOME

5 DAYS OF ANTIBIOTICS

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HYGIENE HYPOTHESIS

MULTIPLE SCLEROSIS

HELMINTHS INFESTATION

Inappropriate inflammatory

response to commensal

microbes in a genetically

susceptible host

INFLAMMATORY BOWEL DISEASE (IBD)

> 100 host

susceptibility loci

Familial

clustering

Racial and ethnic

differences

Family history in

10-20%

10-fold increased

risk in relatives

EVIDENCE OF A GENETIC BASIS FOR IBD

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4

7,208 patients diagnosed with IBD

Pooled odds ratio for IBD = 1.57

Risk of CD in children most markedly increased

All antibiotics except PCN associated with IBD

Metronidazole or fluoroquinolones highest risk

American Journal of Gastroenterology 2014

“ANTIBIOTICS ASSOCIATED WITH

INCREASED RISK OF NEW -ONSET CROHN'S

DISEASE:

A META-ANALYSIS”

DYSBIOSIS IN CROHN’S

Increase in mucosally associated bacteria

Decrease in microbial diversity

Decreased production of butyrate

Enterobacteriaceae

Adherent/invasive E. coli

Clostridial group

Protective faecalibacterium

Roseburia

Firmicutes

CELIAC DISEASE

1/4 European ancestry carry genes

Genes necessary but not sufficient

Immune system trigger

New onset celiac disease strongly associated

with antibiotic use

People with celiac disease 40% more likely

to have received antibiotics shortly before

diagnosis

“ANTIBIOTIC EXPOSURE & THE

DEVELOPMENT OF CELIAC DISEASE: A

NATIONWIDE CASE CONTROL STUDY”

Swedish Prescribed Drug Register

Histopathology from 2,933 people with celiac

Antibiotics and celiac: 1.4 OR (95%)

“INTESTINAL DYSBIOSIS MAY PLAY A ROLE IN

THE PATHOGENESIS OF CELIAC DISEASE”

BMC Gastroenterology 2013

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Alpha diversity

Bacteroides

Firmicutes

Actinobacteria

OBESE MICE

Alpha diversity

Bifidobacteria

Firmicutes

Staphylococcus

Enterobacteriaceae

OBESE CHILDREN PREDICTING OBESITY

58%

90%

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CHRISTENSENELLACEAE A TALE OF TWO CITIES

IMPACT OF DIET IN SHAPING GUT MICROBIOTA

REVEALED BY A COMPARATIVE STUDY IN

CHILDREN FROM EUROPE AND RURAL AFRICA

Italy versus Burkina Faso

European children consuming a Western diet: greater abundance of gram-positive bacteria (Firmicutes)

African children - high fiber, vegetarian diet: dominated by Prevotella enterotype

greater abundance of gram-negative bacteria (Bacteroidetes)

higher microbial richness

more species diversity

lower prevalence of pathogenic strains of Enterobacteriaceae

rich species diversity

high levels of SCFA

PNAS, August 2010

“Healthy bacterial populations living in the gut

may not just exclude disease-causing bugs; by

pumping out beneficial compounds, they may

actively help to suppress disease”

IMPACT OF DIET IN SHAPING GUT MICROBIOTA

“DIET RAPIDLY AND REPRODUCIBLY

ALTERS THE HUMAN GUT MICROBIOME”

Nature, January 2014

Robynne K. Chutkan MD, FASGE,

Eugenia R. Hamshaw, Farah Ashraf

GutBiome Institute, LLC

Medstar Georgetown Hospital

EFFECT OF A LOW-COMPLEX CARBOHYDRATE DIET ON IBD

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HISTORY OF THE SCD

• Created by Dr. Sidney V. Haas (1870-1964),

a pediatrician who specialized in celiac

disease

• Later popularized by Elaine Gottschall, the

mother of one of Hass's patients, in her

1987 book Breaking the Vicious Cycle

• Commonly employed by patients with IBD

and IBS to treat their symptoms

THE SPECIFIC CARBOHYDRATE DIET

• Limits disaccharides and polysaccharides

• Excludes grains, sugars, and starches

• Includes:

• eggs • poultry/meat/fish • most vegetables • most fruits • aged goat cheese • butter • nuts • legumes • spices

BACKGROUND & AIMS

• A retrospective review to assess the

effectiveness of the Specific Carbohydrate

Diet (SCD) in improving quality of life and

reducing frequency and severity of flare ups

in patients with Inflammatory Bowel

Disease (IBD)

METHODS: ASSESSMENT

• Modified version of the Inflammatory Bowel

Disease Questionnaire (IBDQ)

• Used to evaluate quality of life and disease

activity

• Employed before and after the diet in 12

patients with IBD

• Medication requirements

• Endoscopic mucosal healing

PATIENT CHARACTERISTICS

Age range 16-69 (mean = 39.25)

Gender 9 female / 3 male

Diagnosis Ulcerative colitis: 3

Crohn’s disease: 9

Average number of years

of disease

2-23 (mean = 10)

Past surgery 5 out of 12 patients had

undergone surgery

PATIENT COMPLIANCE

100% Compliance with Diet 8/12

90% Compliance with Diet 4/12

<90% Compliance with Diet 0/12

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METHODS: AVERAGE TIME ON DIET

0

500

1000

1500

2000

2500

1 2 3 4 5 6 7 8 9 10 11 12

Avera

ge T

ime o

n D

iet

in

Days

Patient

Average Time on Diet per Patient

Time on Diet (in days)

METHODS: TIME ON DIET BEFORE

IMPROVEMENT

0

20

40

60

80

100

120

140

1 2 3 4 5 6 7 8 9 10 11 12

Tim

e o

n D

iet

(in

Days)

Patient

Average Time on Diet Before Patient Detected Improvement

Average Time (in Days)

10

RESULTS: MEDICATION

Mean time on diet before

patient detected improvement

38 days

Total number of patients who

were able to stop or decrease

medication(s) after starting the

diet

7 out of 12 (58%)

Number of patients who were

able to stop medication(s) after

starting the diet

5 out of 12 (42%)

Number of patients who were

able to decrease medication(s)

after starting the diet

2/12 (17%)

RESULTS: ENDOSCOPY

• Endoscopic data (colonoscopy) available for 8 pts

• 6 out of 8 showed mucosal healing

CONCLUSIONS

• Our data confirms that the SCD is a viable therapeutic option for management of IBD

• SCD can result in improvement of symptoms, mucosal healing, and a reduction or discontinuation of medication

• Further studies are necessary to evaluate the overall efficacy of the diet and the mechanisms by which it may improve disease activity

MECHANISMS

• Alteration of gut microbiota

• Improvement in IgG-mediated inflammation

We believe the absence of processed carbohydrates, rather than the presence of

animal protein, is the likely mechanism for the improvement in inflammation

Direct correlation with the amount of fibrous plants consumed and improvement

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VEGAN MICROBIOME

Follows a continuum

Distinct from omnivores

Unique in several characteristics:

Fewer pathogens

More protective species

Reduced levels of inflammation

Unique gut microbiome may be the mechanism

by which a vegan diet protects against metabolic

and inflammatory disease states

1. Can a therapeutic vegan diet can be prescribed to alter the gut microflora for long-term health benefits?

1. Is there evidence that strict vegan diets confer protective benefits beyond that of vegetarian diets or overall healthy eating?

QUESTIONS

ENTEROTYPES

Three distinct enterotypes of the human gut:

(1) Bacteroides predominant

(2) Prevotella predominant

(3) Ruminococcus predominant

Two enterotypes strongly associated with diet:

Bacteroides enterotype adapted to diets high in

protein and animal fats (meat eaters)

Prevotella enterotype associated with a vegetarian

diet and carbohydrate metabolism (plant eaters)

VEGAN VERSUS LACTO-OVO VEGETARIAN

van Faassen et al study

20-day vegan diet

20-day lacto-ovo vegetarian diet

20-day Western diet

Vegan diet produced a significantly different

result than the lacto-ovo vegetarian diet

Focus on vegan diets in their own right is

warranted

FAECALIBACTERIUM PRAUSNITZII

More prevalent in vegans

Protective role in metabolic disease: low levels associated with intestinal disorders,

inflammation, obesity, and type 2 diabetes

Prevalence linked to inulin ingestion

Strong correlation with SCFA production

Associated with:

higher fiber intake

reduced risk for cardiovascular disease

reduced risk for colon cancer

reduced risk for diabetes and obesity

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VEGGIES AS MEDICINE

Kim et al

Role of a vegan diet in obesity & inflammation

6 obese subjects with diabetes/hypertension

Vegan diet for one month

improved blood glucose levels

reduced body weight

reduced triglycerides, total cholesterol, LDL

reduced HbA1c

Reduced Firmicutes

Increased Bacteroidetes

VEGAN GUT MICROBIOTA MAY BE PROTECTIVE

AGAINST INFLAMMATORY DISEASES

Peltonen et al study of 53 RA patients

Significant change in intestinal flora after a

1-year shift from conventional diet to vegan

Significant differences between fecal flora in

high and low improvement groups

Direct connection between gut profiles and

levels of disease activity

Br J Rheumatol 1997

Microbial metabolism of

dietary l-carnitine in red

meat produces TMAO

TMAO directly linked to

atherosclerosis

Production dependent

on intestinal microbiota

Capacity to produce

TMAO negligible in

vegans

TMAO CONCLUSIONS

The vegan gut profile unique in several

characteristics:

reduced pathogens

increased protective species (F. prausnitzii)

Vegans lack the intestinal microbiota for

converting dietary l -carnitine into pro-

atherosclerotic TMAO

Reduced levels of inflammation may be the

key feature linking the vegan gut microbiota

with protective health benefits

Worst species die-off since the dinosaurs

80% of the earth’s forests

70% of the world’s fish

50% of the wild animals

Losing species thousands of times faster

Drought, famine, global warming

LAST CENTURY ALONE

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PHARMAGEDDON?

Antibiotic use increased 35% last decade

India highest consumption worldwide

US highest per capita

18 courses of antibiotics by 18 th birthday

Wide range of prescribing habits

2/3 adults for cold/flu symptoms

100 million prescriptions (outpatient adults)

Difference in microbiota composition in PPI users versus

non-users

PPI use associated with a significant decrease in diversity

PPI use associated with changes in 20% of bacterial taxa

increase in Enterococcus , Streptococcus , Staphylococcus and

Escherichia coli.

Less healthy gut microbiome in PPI users

Predisposes to C. difficile infection

Predisposes to enteric infections

Effects of PPIs more prominent than effects of antibiotics

“PROTON PUMP INHIBITORS AFFECT THE

GUT MICROBIOME”

Gut 2015

HOW DO WE REWILD?

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THE CASE FOR FMT

4th century:

Oral remedy for food poisoning and diarrhea

Described by the Chinese writings of Ge Hong

16th century:

Fecal preparations coined "yellow soup“ given for diarrhea, abdominal pain

21st century:

91% cure rates for C. diff

54 patients

Ages 4-91

Most family donors, 21 stool bank

11 patients with inflammatory bowel disease

1 patient persistent symptoms and (+) C diff

3 recurrences within 1 year – resolved with

additional treatment

93% cure rate with one transplant

GEORGETOWN FMT EXPERIENCE

The real voyage of discovery consists

not in seeking new landscapes, but in

having new eyes

Marcel Proust