NATURE|Vol 453|29 May 2008
HUMAN MICROBIOME NEWS FEATURE
STRAIGHT FROM THE GUT
tephanie is the first to admit that she never had the guts for life. She was born with familial adenomatous polyposis, a genetic disorder in which thousands of polyps form in the colon. By the age of 22, much of the organ had to be removed. Four years later, a massive benign tumour choked off the blood supply to her small intestine, so doctors cut out all but a metre of it. For the next six years, she was fed by a t
Dirty business: gut transplants give bacteria and scientists new choices.
S
tephanie is the first to admit that she
never had the guts for life. She was born
with familial adenomatous polyposis,a genetic disorder in which thousandsof polyps form in the colon. By the age of 22,much of the organ had to be removed. Fouryears later, a massive benign tumour chokedoff the blood supply to her small intestine, sodoctors cut out all but a metre of it. For the
next six years, she was fed by a tube every nightuntil the feeding left her liver badly scarred and
fighting recurring infections. “I was given a
month to live,” she says.
That’s when doctors referred Stephanie toGeorgetown University Hospital in Washing-
ton DC. There, on 17 April 2006 , surgeons cut
out her stomach and what was left of her small
and large intestine and replaced it with new
organs from a donor who had died days earlier
in Tennessee. “Oesophagus to anus, her entire
gastrointestinal tract was in the garbage can,”says Tom Fishbein, who directed the surgery.
“She got a brand new one.”
All organ transplants are complicated,but there are only a handful of centres in theUnited States that have theexpertise to transplanta small intestine, theseven metres of coiled tissue connected up to
the stomach at one end and the large intestine
at the other. The technique is complicated
because the gut is teeming with trillions of bac-
teria and other microbes, plus the bulk of thebody’s lymphocytes. Before such transplants,
the donor’s intestine has normally been flushed
with antibiotics. But rates of infection andrejection from such transplants are very high
because, it is thought, some for-eign bacteria and immune cells
survive the cleaning process
and are thrust into an immuno-
suppressed recipient.
The idea that these intes-tinal bacteria are a menace isnow under review. By team-ing up with microbiologists, the surgeons aretaking advantage of a rare chance to study microbes as they colonize the walls of the gutafter transplanting an intestine: which onesarrive first, and how they restore the ravaged
microbial communities. “An all new ecosystem
of organisms had to populate that bowel from
scratch,” says Fishbein. Their new appreciationof that ecosystem, along with their grow-
ing surgical experience, suggeststhat the populations mightbe better left intact before a
transplant.
The same studies may
also offer insight into
how the gut is first populated by microbes afterbirth, how it recovers from the damage done by a heavy course of antibiotics and, perhaps, how
to minimize that damage. “Most people study
this in animal models, but this is a real-person
model,” says Brett Finlay, a microbiologist at
the University of British Columbia in Vancou-
ver, Canada. “It’s an artificial system in some
sense, but it’s a neat model.”
How the moist, pink intesti-
nal tubing lives in such harmo-nious contact with bacteria has
puzzled scientists for decades.But “it’s hard to get in there,especially in a healthy person”,
says David Relman, who studiesmicrobiology and immunology
at Stanford University, California. “And to do
it in a way that doesn’t perturb the system, and
to do it every week or every day, well, forget
it.” For this reason, most researchers interested
in the contents of human innards have had to
collect and filter faeces.
Beautiful opportunity
The transplant scenario is a unique and attrac-
tive alternative. For the first few months afteran operation, the end of the gut that wouldnormally go into the rectum is left poking
out of the abdomen
so that doctors can check
the transplant is stable. As often as necessary,doctors can probe this stoma, or opening,
STRAIGHT FROM THE GUT
T . F I S H B E I N
“Oesophagus to anus,her entire gastro-intestinal tract was inthe garbage can.”
— Tom Fishbein
581
NATURE
|
Vol 453
|
29 May 2008
HUMAN MICROBIOME
NEWS FEATURE
with an endoscope to pinch off biopsies of the
intestinal wall with its microbial community
intact. Yellow faeces and glistening, pink skin
are signs that the new intestine has success-
fully taken. “That is beautiful stuff,” says Stuart
Kaufman, medical director of the intestinal-transplantation programme at Georgetown.
“We live for poop like this.”The adult samples are also beautiful stuff for
researchers who want to chart the arrivals of the
different bacterial species. The material is put
on ice and shipped to the lab of Jonathan Eisen,
a microbial geneticist at the University of Cali-
fornia, Davis. There, graduate student Amber
Hartman identifies the inhabitants by analysingdistinguishing gene sequences that vary slightly
between different species of bacteria.
It’s far too early to draw firm conclusions from
their data; Fishbein and his collaborators haveonly studied 15 patients over the past 2 years.But what they have found suggests that the gutis populated first by enterobacteriaceae, a large
family of facultative anaerobes, which can grow
with or without oxygen. This suggests that thetransplanted tissue has higher oxygen levelsthan the normal gut, where anaerobic bacteria
dominate. Inflammation may boost oxygen lev-
els, giving enterobacteria the advantage.
Hartman and Eisen have also found thateach person studied so far has had differentproportions of the various microbial species,and that these oscillate rapidly in the first fewmonths after a transplant. Their preliminary
observations suggest that the more chaotic the
variations over time, the worse the outcome of
the transplant. “One thing that becomes very
obvious is that the amount or degree of fluctua-tion is much greater in the sicker patient,” Hart-man says. They now want to know whether the
microbiota becomes more stable and reachesequilibrium as a patient recovers, but thatrequires following more patientsover longer times, and intestinal
transplants are rare.
A different bloody, messy procedure arrives all toooften though: a birth. Here,too, researchers see a fascinat-ing opportunity to explore howmicrobes colonize a gut, onethought to be sterile inside thewomb. During birth and in the hours
after, babies can swallow bacteria from
the mother’s birth canal, faeces and fromwhatever environment they arrive in.
No one knows yet whether bacteria move
into a baby’s spanking new innards in the sameway they grab a foothold in a used, adult trans-
plant. Much of what scientists know about theformer process has been learned from a study
of Relman’s, in which he and his colleagues col-
lected used nappies from 14 babies beginningwith the first stool after birth and at regular
intervals throughout the first year of life
1
. What
they found mirrored some of the discoveriesin the transplanted intestines: every baby’s
microbiota is unique but dynamic, with differ-
ent populations of bacterial species shifting in
abundance. And as in the transplant study, the
babies showed a succession of colonization, with
facultative bacteria settling in first, followed by
a more complex and diverse population.
Nice and dirty
Whatever parallels may emerge from thesestudies, there is one obvious difference: the
transplanted gut has already been soiled by the
faeces, microbes and immune cells it hosted
before. And, until recently, doctors did all they
could to scour away the muck.
Paradoxically, the surgeons at Georgetownbegan to notice that the more antibiotics they used to keep the microbes to a minimum, themore intestinal infections they saw after thetransplant. At first, the alterna-
tive seemed too fantastic to con-
template: taking an essentially infected organ and placing it in
a body crippled by immunosup-
pressant drugs. But about a yearago, Georgetown and other centres began
shifting their practice to do exactly that. Early
evidence indicates that those who receive a gut
replete with its native microbiota have fewer
chaotic fluctuations.
That makes sense in retrospect, notes Eisen,
because people who need transplants may do
so precisely because they had trouble coloniz-
ing their bowels properly to begin with. Insome patients — those with Crohn’s diseaseor ulcerative colitis, for example — the nativebacteria may turn on the body, inflaming thegut and scarring the intestinal walls. So the
new intestine might be more likely to help if it
comes with its own set of inhabitants. “To take
out all the microbes seems completely inane,”
Eisen says.
The Georgetown researchers have nowstarted to investigate how those bacterialfluctuations during colonization are control-led. They suspect that a gene called
NOD2
,which is expressed in some immune cells, is
essential for keeping the chaos to a minimum.
The NOD2 protein recognizes components of
bacterial cell walls and controls the production
of defensins, small proteins that kill particularbacterial species.
The team has found that about 35% of theirtransplant patients carry mutations in
NOD2
,regardless of the intestinal disorder, and thatthose with mutations are 100-fold more likely to have a failed transplant compared with con-trols
2
. The hypothesis is that this mutation
somehow lowers production of defensins, so theimmune system is unable to maintain the appro-
priate proportions of bacterial species. Perhaps
patients with a mutant
NOD2
gene might benefitfrom doses of the bacteria that they are missing.
In one patient with a
NOD2
mutation who later
died, “the proportions of normalness were very,
very off”, Hartman says.
Quite what ‘off’ is, is hard to define. Theteam still has only a cursory understandingof what the microbiota looks like in healthy
people, compared with their subjects. “It’s like
watching colonization of a disturbed ecosys-tem without knowing what was srcinally inthe forest,” says Eisen. That may be helpedby the National Institutes of Health’s HumanMicrobiome Project and other new researchefforts that aim to catalogue the microbes in
the human body (see page 578). “We need that
field guide to microbes to understand when
something is not normal,” Eisen says.
In the meantime, clinical signs are still thebest predictors of a transplant’ssuccess. Two years after a newgut was slotted into Stephanie’sbody, she still has scars criss-
crossing her abdomen but she is a
healthy weight and eats whatever
she wants. It is still not clear which microbesto thank: the donor’s bugs that survived frombefore the transplantation, or new microbesthat settled there afterwards. “Whoever’smicrobes have prevailed, they’re probably
good ones,” says Fishbein, “because she’s doneexceptionally well.”
I
Apoorva Mandavilli is a freelance writerbased in New York.
1. Palmer, C.
et al. PLoS Biol.
5,
e177 (2007).2. Fishbein, T.
et al. Gut
57,
323–330 (2008).
See Editorial, page 563, and News Feature, page 578.
C A M E R O N / C O R B I S
An opportunity to track gut colonization.
“We live for pooplike this.”
—Stuart Kaufman
582
NATURE
|
Vol 453
|
29 May 2008
NEWS FEATURE
HUMAN MICROBIOME