What Are Poop Transplants and How Do They Work?

Microbes are tiny creatures that live in and on our bodies. Many of them, especially those in the gut, help to keep us healthy. Sometimes, when we eat spoiled food or take antibiotics, we wipe out many of these good microbes. Usually, our good microbes recover from these disturbances, but sometimes harmful microbes can take their place and cause disease. Clostridioides difficile is a harmful microbe that causes severe diarrhea. Usually, antibiotics can kill C. difficile and return the gut to a healthy state, but in some cases, this microbe can come back again and again. Some people end up dying from these recurrent, antibiotic-resistant C. difficile infections. Recently, scientists have found that recurrent C. difficile can be cured by transplanting poop from a healthy person into a sick person. This process is called fecal microbiota transplantation (FMT) and it saves thousands of lives in the U.S. each year.


Figure Figure
More than half of the cells in and on our bodies are microbial and they account for ½− pound of our body weight. These microbes can be found all over the exposed surfaces of our bodies, with most of them inside the gut.

MICROBES-FRIENDS NOT ENEMIES!
You may have heard of microbes, or maybe you have heard them MICROBE A microscopic organism. referred to as "germs" or "bugs." Despite these rather scary terms that remind us of disease, many of these organisms are actually good for you and play an important role in keeping you healthy. Although you cannot see these tiny creatures with your eyes, they are present all around you-in the air, on the wall, in the soil, and in and on your body (Figure ). The vast majority of microbes are harmless or even beneficial. They consist of bacteria, archaea, protists, fungi, and viruses, collectively known as your microbiota, which outnumber the MICROBIOTA All the microbes that live in and on your body.

Figure Figure
The gut is an ecosystem, like a forest or a coral reef. Often, a disturbed ecosystem, like a forest after a fire (A) or the gut microbiota after antibiotic treatment (B), recovers back to a healthy state. Occasionally, however, weedy species (such as C. di cile in the gut) can invade and take over after a disturbance, leading to a collapse of the normal ecology of the system. human cells in our bodies and make up between ½ and pound of your body weight.
We start out microbe-free in the womb [ ], and begin to collect our microbiota at birth [ ]. Humans are seeded with microbes from their moms and from their surrounding environments following birth. Over the course of a lifetime, we are colonized by di erent varieties of microbes depending on what foods we eat, where we live, how much we exercise, even whether or not we have a cat or a dog [ ]. Thus, our bodies are complex ecosystems. We give our microbiota a home and in return they help to keep us safe and healthy.
The gut is where most of our microbiota live. And the most abundant component of the gut microbiota are the bacteria. Gut bacteria help us digest our food, absorb vitamins and nutrients, protect our bodies from harmful microbes known as pathogens, and train our immune systems to prevent allergies, asthma, and other immune dysfunctions. Gut bacteria can even send signals to our brains, altering our moods and behaviors [ ]. We need a balance of the right kinds of bacteria in our guts to stay healthy.

HEALTHY VS. UNHEALTHY MICROBIOTA
What is a healthy gut microbiota? Each person has a unique microbiota and there is no one-size-fits-all definition for what comprises a healthy gut ecosystem [ ]. Even if we do not know exactly what a healthy microbiota looks like, we can often recognize an unhealthy microbiota when we see one. For example, eating spoiled food can introduce pathogens into the gut, leading to an upset stomach and diarrhea. Most of us have taken antibiotics at some point in our lives to get ANTIBIOTICS Medicines that kill or inhibit the growth of bacteria. rid of the bacteria that make us sick. However, antibiotics cannot tell the di erence between "good" and "bad" microbes. Each time we take antibiotics, it is like having a fire burn through our gut, damaging our internal ecology. Just like a forest after a fire, the gut ecosystem usually bounces back from antibiotic treatment. But sometimes, instead of bouncing back, weed-like microbes can take over, causing disease and preventing the good microbes from returning ( Figure ).

DEADLY CLOSTRIDIOIDES DIFFICILE INFECTIONS
Clostridioides di cile is a weed-like microbe known as an

CLOSTRIDIOIDES DIFFICILE
An opportunistic bacterial pathogen that causes severe diarrhea in nearly , people and is responsible for over , deaths each year in the U.S. opportunistic pathogen. Opportunistic gut pathogens are microbes

OPPORTUNISTIC PATHOGEN
A microbe that is usually harmless but can cause disease when the immune system is depleted or when the normal ecology of the microbiota is damaged. that do not normally cause harm, but when the gut ecosystem is damaged these bacteria can invade and cause a problem. For example, C. di cile can sometimes live in a healthy person's gut without causing trouble-the resident gut microbiota prevents it from producing toxins and causing an infection. However, when the gut ecology is damaged, like after taking a round of antibiotics, this weed-like pathogen can take over and cause severe diarrhea ( Figure A) Figure B). However, in -% of cases, the infection returns after vancomycin treatment [ ]. These recurrent C. di cile infections are highly resistant to further antibiotic treatment, leading to endless cycles of antibiotic treatment and infection recurrence, which can eventually result in patient death ( Figure C) [ ].

POOP TRANSPLANTS
Thinking back to our forest metaphor, imagine the ecosystem has burned down, been stripped of its native vegetation, and is now overgrown by weeds. One way to return the forest to its original state would be to cut down all the weeds and transplant flora and fauna from a nearby patch of unburned forest. Poop transplants, known as fecal microbiota transplants (FMTs), work in a similar way. First, a patient

FECAL MICROBIOTA TRANSPLANT (FMT)
A procedure in which poop from a healthy donor is transplanted into the colon of a sick patient.
is given a dose of antibiotics to reduce the abundance of C. di cile and then the patient is given a dose of healthy poop from a poop donor ( Figure D). Traditionally, poop transplants were administered by enema or through a tube going through the nose, down the throat, and into the gut, but now patients can swallow pills containing frozen or freeze-dried poop.
While the exact mechanisms are not completely understood, transplanted microbiota from a healthy person's gut regain control of the ecosystem and push C. di cile out. FMTs can be either autologous (healthy poop from yourself, collected before you were AUTOLOGOUS Obtained from the same individual. sick) or heterologous (healthy poop from another person). As gross as HETEROLOGOUS Obtained from a di erent individual. they sound, these poop transplants have been shown to be -% e ective in resolving recurrent C. di cile infections and have been https://www.openbi ome.org/about-fmt used to cure tens-of-thousands of patients in the U.S. Thus, FMT is a life-saving option for people with recurrent C. di cile.

SAFETY FIRST
FMTs are highly e ective and the Food and Drug Administration (FDA) has temporarily approved them as treatments for recurrent C. di cile infections. However, it is important to be extremely careful when choosing healthy poop donors. Currently, companies that make FMT material must test poop donors for most known human pathogens and for antibiotic-resistant bacteria. Poop donors are also subject to strict screening based on their lifestyle, travel, and medical history. Only the very best poop is acceptable, and approved donors can make up to $ per poop donation . Most healthy people carry one or more https://www.openbio me.org/stool-donation opportunistic pathogens in their gut, which are harmless when the gut ecosystem is healthy, but these organisms could cause trouble if they were transferred into a sick patient. bone marrow transplants, and their immune systems were extremely weak, making them especially susceptible to opportunistic pathogens. In one case, the poop donors were not screened using the most up-to-date regulations [ ]. In another case, proper screening was done but this screening was still not su cient to catch certain pathogens that caused problems in six patients, leading to updated screening criteria . Thus, it is crucial that FMT material be prepared in an https://www. openbiome.org /press-releases / / / / openbiomeannouncesenhanced-donor -screeningprotocolsfollowing-fda-alert FDA-regulated lab with strict procedures in place. Screening should be continuously updated in response to new pathogens like SARS-CoV-, and FMT procedures should always be performed by certified doctors. FMTs should never be performed at home! Furthermore, long-term risks from FMTs are not well-known yet, because these procedures have not been in use for very long. Despite the potential risks of FMT, properly-screened donor material is currently the most e ective treatment for recurrent C. di cile infections, with very few adverse e ects after tens-of-thousands of treatments across the U.S.

FMT: THE CURRENT BEST OPTION FOR RECURRENT C. DIFFICILE
Despite FMT's success, it remains a controversial treatment. Poop is highly variable between donors and cannot be controlled or regulated under the same rigorous standards that the FDA applies to other drugs. To solve this problem, many biotechnology companies are in a race to assemble artificial microbial communities that can be reproducibly manufactured under strict conditions, and which mimic the e ects of natural human poop in treating recurrent C. di cile infections. So far, none of these synthetic FMT alternatives have proven to be as e ective as FMTs. The major di culty with developing an alternative to FMTs is our lack of detailed understanding of exactly how FMTs work. While there is hope that someday soon a simpler treatment will be available, for now, FMTs are still the best option for fighting the deadly scourge of recurrent C. di cile infections.

CONFLICT OF INTEREST:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
COPYRIGHT © Patwardhan, Diener, Swegle, Howsmon and Gibbons. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

BECKY HOWSMON
Becky is a Project Manager with the Systems Education Experience (SEE) program at the Institute for Systems Biology (ISB) in Seattle, Washington. She is developing high school curriculum focused on systems medicine. She is passionate about creating opportunities that allow every student to explore their interests and realize their potential.

SEAN M. GIBBONS
Sean is an Assistant Professor at the Institute for Systems Biology (ISB) in Seattle, Washington. His lab studies the ecology and evolution of microbial communities. In particular, he is interested in how the gut microbiota influence human health and disease. *sgibbons@isbscience.org