Transcript Microbiome Surawicz

UW MEDICINE │ MINI-MEDICAL SCHOOL
WHAT’S BUGGING YOUR GUT?
LET’S FOCUS ON THE BUGS!!
CHRISTINA SURAWICZ MD
PROFESSOR OF MEDICINE
DIVISION OF GASTROENTEROLOGY
TOPICS
• What does our gut do?
• What is the microbiome and what does
it do?
• What happens when the microbiome
becomes altered?
• What can we do to keep our gut
healthy?
OUR LUMINAL GI TRACT
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Esophagus
Stomach
Small intestine
Colon (large intestine)
THE ESOPHAGUS
Has 2 main jobs:
• Get food from the mouth to the stomach
and
• To keep it there
THE STOMACH
• Grinds the food into small particles
• Pass those small particles gradually into
the stomach
• Minor role in digesting food, producing
acid to fight infections
THE SMALL INTESTINE
Digestion and Absorption
• Digests food (carbohydrates, proteins,
fats) into small compounds that can be
absorbed (amino acids, small sugars
etc. )with the help of enzymes from the
pancreas and bile from the gall bladder
• Absorbs these nutrients, salt and water
chyme
COLON (LARGE INTESTINE)
• Receives a liter of chyme but puts out
200 grams of stool/day—liquid to solid
stool
• Absorbs salt and water
• Store until convenient to evacuate
• Anal sphincter is the smartest sphincter
• Normal: 3 BM/day to one BM every 3
days
• Salvages calories from food the small
intestine can’t digest like roughage
How does our colon salvage
undigested food?
Our microbiota does it!
What we used to call our gut flora….
WHAT IS THE MICROBIOTA?
• Microbes= bacteria, fungi, viruses,
Microbiome=microbes and their genes
• In our gut
• More microbes than any other part of
our body, even skin
• 10 x more cells than all the cells in our
body
• 100 trillion!
•
1000 species
OUR MICROBIOME—SKIN AND GUT
 Skin and gut each have
1,000 different bacterial
strains
 Encodes physiologic
abilities that our own
genome does not
 We and our Microbiome
= A Super-organism!
Washington University St Louis
Genome sciences Website
WHERE DOES OUR MICROBIOTA COME FROM?
• Our gut is sterile at birth
• Babies get bugs in:
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Birth canal, breast milk
Environment
Food
• Stable by age 3
• Changes again:
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Puberty
Pregnancy
Aging
WHAT DOES OUR MICROBIOTA DO?
• Carbohydrate metabolism
• Bacteria ferment unabsorbed carbs,
produce fatty acids that are fuel for our
colon but also gas
• Vitamin synthesis
• Important for immune system
development
• More on this later– Dr. Afzali
• Colonization resistance
• Protects us from all the germs we
ingest from the environment
Bacteroidetes
And
Firmicutes
What happens when our microbiome gets
perturbed?
• The biggest culprit: ANTIBIOTICS
• Antibiotics - change the bacteria in the colon
and cause diarrhea in 10-20%
•
Usually better when antibiotics are stopped
• A severe form of antibiotic diarrhea is due to
Clostridium difficile
•
A gram positive anaerobic bacteria that
infects the colon
CLOSTRIDIUM DIFFICILE INFECTION
• It produces toxins that
cause colon disease
• It forms spores that are
very hardy in the
environment
• Most of us don’t get sick
because our colon
microbiota protects us
CLOSTRIDIUM DIFFICILE INFECTION
• Since the year 2000 there has
been a dramatic increase in
cases – more severe, more
deaths
• Hypervirulent strain
• Half a million cases / year in
US
• 29,000 deaths / year in US
CDI CASES BY AGE
85 yo
85
+
75-84
yo
7584
COMMON RISK FACTORS
• Antibiotics –in prior 2 months,
especially broad spectrum and multiple
antibiotics
• Recent hospitalization or being in a
long term care facility
• Age over 65
• Co-morbid conditions
• Immunosuppression
SYMPTOMS OF C DIFFICILE INFECTION
• Diarrhea
• Can be mild or very severe
• Usually watery
• Crampy abdominal pain
• Severe cases: colitis, fever, tender
abdomen
• When severe may require surgery to
remove the sick colon
• May be fatal
SEVERE CLOSTRIDIUM DIFFICILE INFECTION
Normal colon
Pseudomembranous colitis
Pseudomembranes
TREATMENT OF C DIFFICILE INFECTION
• Oral Antibiotics: metronidazole or
vancomycin or fidaxomicin
• Severe cases: need IV antibiotics
• Very severe cases: may need surgery
(remove colon or temporary bypass of
colon)
RECURRENT C DIFFICILE INFECTION
• Most CDI responds to standard therapy
• 10-20% will have a recurrence
• After one recurrence, further recurrences are
even more likely
• These are hard to treat: using an antibiotic to
treat a disease that is usually the result of an
antibiotic
• Vicious cycle!
WHY DOES THIS HAPPEN?
TREATMENT OF RCDI
• Repeat antibiotics are needed---with
metronidazole or vancomycin, but
pulse suggesting that spores
germinate on off days, and bugs can
normalize on off days
• Probiotics sometimes work
WHAT IS A PROBIOTIC?
A substance that stimulates the
growth of beneficial bacteria in
the alimentary and
gastrointestinal tracts and that
thus benefits the host as well.
Russians in Caucasus lived a
long time and ate a lot of yogurt
SACCHAROMYCES BOULARDII
• A probiotic nonpathogenic yeast
• We studied in 1980’s
• It decreased antibiotic associated
diarrhea
• It treated some patients with recurrent
C difficile infection
• This is actually how I got interested in
C diff.
• But it didn’t work all the time….
RCDI THERAPY
• Fecal enemas successful – 1 case
• Schwan Lancet 1983
• Rectal instillate of a mixture of 10
aerobic and anaerobic bacteria – 6
patients
• Bacteroides restored
Tvede and Rask Madsen, Lancet 1989
PATIENT SW
42 year old woman
•Retained placenta after birth of first son
•Prolonged hospitalization plus antibiotics
•C. difficile – 3 episodes
•Rx Metronidazole x 2
•Final – Vancomycin taper and Saccharomyces
boulardii
•Got better
However, 10 months after 2nd son
•Diarrhea again
•Recurs in 1 week, bloody
•Almost continuously on Vancomycin for 9
months
3 recurrences
•Vancomycin taper / pulse
•Saccharomyces boulardii
•Recurs within 1 week
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Time for me to try stool transplant
2004
1990’s – my opinion: desperate
patients and desperate doctors
2004 – This case: no other options
Husband donor
Delivered stool by colonoscopy
She was cured and I was convinced
Fecal Microbiota Transplant
aka Stool Transplant
• Healthy donor stool to colon via enema,
colonoscopy or upper-tract
• Rationale: restore normal microbiome
When was stool transplant first
documented?
A. 1700 years ago in China?
B. 1958 in post op patients in Denver?
C. On Grey’s Anatomy in 2008?
Answer = A
1700 years ago in China, 4 th Century
used human feces to treat severe
diarrhea; 16th century used infant feces,
called “yellow soup”
Grey’s Anatomy – 2008 “In the Midnight
Hour”, done in emergency room
Zhang et al, Am J Gastroenterol 2012; 107:1755 (letter)
Where did this idea come from?
• In 1958, a surgeon in Denver treated patients
who got a severe pseudomembranous colitis
after surgery with enemas of stool
• They got better!
• We forgot about this strategy until decades
later when we started to see more severe C
diff infection and nothing else was working.
• We found out about the Chinese practice a
few years ago
HOW WELL DOES FMT WORK?
• 90% overall for recurrent CDI
• Several randomized trial prove it works
• Several routes for getting stool into the
colon
• Enemas
• Colonoscopy
• Upper GI route
•
NG tubes or tube into the small bowel
HOW DO I DO FMT?
• Choose the right patient
• Make sure it is recurrent CDI and that
there have been proper prior
treatments
• Explain it is investigational but
permitted by the FDA, that we cannot
guarantee it will work
• Find a donor
DONOR SELECTION
• Usually family, friend or stool bank
• Extensive initial questionnaire, like for
blood donation, including
• Cancer
• Autoimmune disorders
• Metabolic syndrome
• GI disease or GI symptoms
Test blood and stool for pathogens
OBESITY RELATED TO MICROBIOME
AND DIET– OF MICE AND MEN/WOMEN
• Microbiota from lean twin to obese mouse:
mouse lost weight
Identical
twins
• Microbiota from obese twin to lean mouse:
mouse gained weight
(Jeffrey Gordon’s work; Science Sept 6, 2013)
Did fecal transplant make woman obese?
• 32 y.o. woman gained 40 lbs. and rising
after FMT for RCDI
• Her BMI: 26 to 33 (thin to start)
• Not able to lose the weight
• Donor: 16 yo daughter was obese
Was the new colon bacteria
responsible???
Alang and Kelly, Open forum infectious diseases November 2014
A LOT OF INTEREST FMT
• Remarkable efficacy for recurrent C
difficile infection (90%)
• A “natural” approach, simple
• Special interest in inflammatory bowel
disease
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No immune suppression
Both C diff and IBD have dysbiosis so it
might work---research being done in
patients
PLEASE DON’T TRY THIS AT HOME
LONG TERM EFFECTS?
• We do not know
• Some short term complications
• Fever, infection rare, constipation,
bloating
• May have long term effects
• We need studies to know if FMT will be
effective in other diseases
HOW DO WE PREVENT CDI?
• Wise antibiotic policies
• Clindamycin, Cephalosporins,
Quinolones are highest risk
• Hand hygiene (soap and water), barrier
and isolation in the hospital
• Probiotics not ready for prime time in
my opinion
HOW CAN WE KEEP OUR GUT HEALTHY?
• Regular meals; gut likes predictability
• Avoid unnecessary medications,
especially antibiotics
• Exercise is good, improves transit
• Healthy people don’t need probiotics
• But fermented foods may be good
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Kimchee, yogurt and kefir, sauerkraut
HEALTHY FOODS
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More fruits and vegetables
Whole grains
Nonfat or low fat dairy
Seafood
Nuts
Legumes (beans, peas, lentils, etc.)
AVOID OR LIMIT
• Refined grains
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White bread
• Processed meat
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Hot dogs, ham, sausage,
bacon
• Sugary sweet drinks
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Soda
• Red meat---3/week max
• Chemicals---can’t pronounce it?
Don’t eat it.
SUMMARY
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What our gut does
What our microbiome does
C difficile infection
Keeping our gut healthy