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Dirty business: gut transplants give bacteria and scientists new choices.

Stephanie is the first to admit that shenever had the guts for life. She was bornwith 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. Fouryears later, a massive benign tumour chokedoff the blood supply to her small intestine, sodoctors cut out all but a metre of it. For thenext six years, she was fed by a tube every nightuntil the feeding left her liver badly scarred andfighting recurring infections. I was given amonth to live, she says.

Thats when doctors referred Stephanie toGeorgetown University Hospital in Washing-ton DC. There, on 17 April 2006 , surgeons cutout her stomach and what was left of her smalland large intestine and replaced it with neworgans from a donor who had died days earlierin Tennessee. Oesophagus to anus, her entiregastrointestinal 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 transplant

a small intestine, the

seven metres of coiled tissue connected up tothe stomach at one end and the large intestineat the other. The technique is complicatedbecause the gut is teeming with trillions of bac-teria and other microbes, plus the bulk of thebodys lymphocytes. Before such transplants,the donors intestine has normally been flushedwith antibiotics. But rates of infection andrejection from such transplants are very highbecause, it is thought, some for-eign bacteria and immune cellssurvive the cleaning processand 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 studymicrobes as they colonize the walls of the gutafter transplanting an intestine: which onesarrive first, and how they restore the ravagedmicrobial communities. An all new ecosystemof organisms had to populate that bowel fromscratch, says Fishbein. Their new appreciation

of that ecosystem, along with their grow-ing surgical experience, suggests

that 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 bya heavy course of antibiotics and, perhaps, howto minimize that damage. Most people studythis in animal models, but this is a real-personmodel, says Brett Finlay, a microbiologist atthe University of British Columbia in Vancou-ver, Canada. Its an artificial system in somesense, but its a neat model.

How the moist, pink intesti-nal tubing lives in such harmo-nious contact with bacteria haspuzzled scientists for decades.

But its hard to get in there,especially in a healthy person,says David Relman, who studiesmicrobiology and immunology

at Stanford University, California. And to doit in a way that doesnt perturb the system, andto do it every week or every day, well, forgetit. For this reason, most researchers interestedin the contents of human innards have had tocollect and filter faeces.

Beautiful opportunityThe transplant scenario is a unique and attrac-tive alternative. For the first few months after

an operation, the end of the gut that wouldnormally go into the rectum is left pokingout of the abdomenso that doctors can checkthe transplant is stable. As often as necessary,doctors can probe this stoma, or opening,

STRAIGHT FROM THE GUT

Oesophagus to anus,

her entire gastro-

intestinal tract was in

the garbage can.

Tom Fishbein

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with an endoscope to pinch off biopsies of theintestinal wall with its microbial communityintact. Yellow faeces and glistening, pink skinare signs that the new intestine has success-fully taken. That is beautiful stuff, says StuartKaufman, medical director of the intestinal-transplantation programme at Georgetown.We live for poop like this.

The adult samples are also beautiful stuff forresearchers who want to chart the arrivals of thedifferent bacterial species. The material is puton ice and shipped to the lab of Jonathan Eisen,

a microbial geneticist at the University of Cali-fornia, Davis. There, graduate student AmberHartman identifies the inhabitants by analysingdistinguishing gene sequences that vary slightlybetween different species of bacteria.

Its far too early to draw firm conclusions fromtheir 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 largefamily of facultative anaerobes, which can growwith 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 that

each 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 preliminaryobservations suggest that the more chaotic the

variations over time, the worse the outcome ofthe transplant. One thing that becomes veryobvious 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 themicrobiota becomes more stable and reaches

equilibrium as a patient recovers, but that

requires following more patientsover longer times, and intestinaltransplants are rare.

A different bloody, messy

procedure arr ives a l l toooften though: a birth. Here,too, researchers see a fascinat-ing opportunity to explore how

microbes colonize a gut, onethought to be sterile inside the

womb. During birth and in the hoursafter, babies can swallow bacteria from

the mothers birth canal, faeces and fromwhatever environment they arrive in.No one knows yet whether bacteria move

into a babys spanking new innards in the sameway they grab a foothold in a used, adult trans-plant. Much of what scientists know about the

former process has been learned from a studyof Relmans, in which he and his colleagues col-lected used nappies from 14 babies beginningwith the first stool after birth and at regularintervals throughout the first year of life1. Whatthey found mirrored some of the discoveriesin the transplanted intestines: every babysmicrobiota is unique but dynamic, with differ-ent populations of bacterial species shifting inabundance. And as in the transplant study, thebabies showed a succession of colonization, withfacultative bacteria settling in first, followed bya more complex and diverse population.

Nice and dirtyWhatever parallels may emerge from thesestudies, there is one obvious difference: thetransplanted gut has already been soiled by thefaeces, microbes and immune cells it hostedbefore. And, until recently, doctors did all theycould to scour away the muck.

Paradoxically, the surgeons at Georgetownbegan to notice that the more antibiotics theyused 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 ina body crippled by immunosup-pressant drugs. But about a yearago, Georgetown and other centres beganshifting their practice to do exactly that. Earlyevidence indicates that those who receive a gutreplete with its native microbiota have fewerchaotic fluctuations.

That makes sense in retrospect, notes Eisen,because people who need transplants may doso precisely because they had trouble coloniz-ing their bowels properly to begin with. Insome patients those with Crohns diseaseor ulcerative colitis, for example the native

bacteria may turn on the body, inflaming the

gut and scarring the intestinal walls. So thenew intestine might be more likely to help if itcomes with its own set of inhabitants. To takeout all the microbes seems completely inane,

Eisen says.The Georgetown researchers have now

started to investigate how those bacterialfluctuations during colonization are control-led. They suspect that a gene called NOD2,which is expressed in some immune cells, isessential for keeping the chaos to a minimum.The NOD2 protein recognizes components ofbacterial cell walls and controls the productionof defensins, small proteins that kill particularbacterial species.

The team has found that about 35% of theirtransplant patients carry mutations inNOD2,regardless of the intestinal disorder, and that

those with mutations are 100-fold more likelyto have a failed transplant compared with con-trols2. The hypothesis is that this mutationsomehow lowers production of defensins, so theimmune system is unable to maintain the appro-priate proportions of bacterial species. Perhapspatients with a mutantNOD2gene might benefitfrom doses of the bacteria that they are missing.In one patient with aNOD2mutation who laterdied, 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. Its likewatching colonization of a disturbed ecosys-tem without knowing what was originally inthe forest, says Eisen. That may be helpedby the National Institutes of Healths HumanMicrobiome Project and other new researchefforts that aim to catalogue the microbes inthe human body (see page 578). We need thatfield guide to microbes to understand whensomething is not normal, Eisen says.

In the meantime, clinical signs are still thebest predictors of a transplantssuccess. Two years after a newgut was slotted into Stephanies

body, she still has scars criss-crossing her abdomen but she is ahealthy weight and eats whatever

she wants. It is still not clear which microbesto thank: the donors bugs that survived frombefore the transplantation, or new microbesthat settled there afterwards. Whoeversmicrobes have prevailed, theyre probablygood ones, says Fishbein, because shes doneexceptionally well. IApoorva Mandavilli is a freelance writer

based in New York.

1. Palmer, C. et al. PLoS Biol.5, e177 (2007).2. Fishbein, T. et al. Gut57, 323330 (2008).

See Editorial, page 563, and News Feature, page 578.

CA

MERON/CORBIS

An opportunity to track gut colonization.

We live for poop

like this.

Stuart Kaufman

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