Fecal microbiota transplant: a miracle cure?

The frenzy surrounding fecal microbiota transplant (FMT) is real and it needs to be slowed down a bit: some patients have unrealistic expectations regarding the benefits of FMT in their particular case. Every week I receive dozens of letters about anything and everything. However, FMT is a not a magical cure! For now, it is indicated to treat a single disease: recurrent C. difficile infection. For all other indications, it is just a potential therapeutic avenue which cannot replace current treatments. Moreover, the future most likely lies in treatments combining stool transplant (or other therapies that target the microbiota) and more standard treatments that target the immune system, for instance.

Why does C. difficile respond that well to fecal microbiota transplant?

This infection is almost exclusively related to a disruption in the gut microbiota, while in other diseases, the role of the gut microbiota–although presumed– is only one of several contributing factors and its importance probably varies significantly from one disease to another. For instance, in the case of ulcerative colitis, for which we have the strongest data: clinical trials indicate a 20 to 30% rate of remission within a 8-12 week period; which is good, but very far from the results obtained in C. difficile infections (near 90%). This clearly shows that other factors (immune, genetic...) also play a role.

Are there obstacles to the development of clinical research focused on FMT?

Research on FMT is still at a very early stage since it started less than 10 years ago; which is why we must take the time needed to assess it properly. In France, the handling of feces is subjected to major regulations and the selection of donors is strictly regulated. As a result, clinical trials are expensive and require complex logistics. In addition, since hospitals do not automatically assign a budget to FMT, the mobilization of health professionals varies from one facility to another, thus depriving researchers from a specific structure to rely on. It is time for public authorities to better understand this issue and to invest in order to provide hospitals with the means to develop this line of research. In Assistance Publique-Hôpitaux de Paris (Paris public hospital system), we hope to quickly see the emergence of a structured approach to FMT in the healthcare system.

In animals, the physical trait “obese” or “thin” can be transferred through fecal microbiota transplant with a clearly established causal link. In humans, the situation is a little more complex but the presence of dysbiosis associated to metabolic disorders in obese or hypertensive subjects led scientists to conclude that FMT could be a promising avenue. Works are ongoing to assess the impact of the change in gut microbiota experienced by patients with metabolic syndrome^17,14.

Mixed benefits

Several clinical studies were conducted on obese patients with a metabolic syndrome. The first one was carried out on a small group of individuals and showed that stool transplant from thin donors improved the metabolic profile of recipients. The second included a larger number of patients and produced more mixed results. Only a few participants had an improved metabolic profile after the FMT, namely those who initially had a gut microbiota that was not very diversified. The response to transplant thus seems to be dependent on the patient’s initial gut microbiota. However, the benefits did not withstand the test of time...nor did the transformation of the gut microbiota, which quickly returned to its initial composition.

Complex relationships

Overall, these results highlight the complexity of the link between the gut microbiota and metabolic functions. According to some scientists¹³, metabolic and microbial responses to FMT could be based on interactions between the donor’s microbiota and the recipient’s. Several trials are ongoing to assess this technique’s ability to reduce metabolic disorders as well as several obesity-related parameters. These eagerly awaited results should open the way to new strategic approaches in the treatment of metabolic syndrome.

The presence of a gut dysbiosis–characterized by reduced levels of beneficial SCFAs-producing bacteria and increased levels of harmful bacteria associated to cognitive disorders–was observed in patients with hepatic encephalopathy. These observations led researchers to consider fecal microbiota transplant as a therapeutic alternative to antibiotics¹⁶.

A unique donor

An initial study focused on this indication was conducted on a small cohort of only twenty cirrhotic men, who were administered either the standard treatment, or FMT combined with an antibiotic pretreatment aiming at preparing the recipient’s digestive tube. The fecal microbiota came from one single donor, selected through an AI software based on the abundance in his/her microbial flora of bacteria that are precisely lacking in these patients.

A promising approach

None of the transplant recipients had an additional episode of encephalopathy, while 5 out of the 10 control patients relapsed. A slight increase in lactobacilli and bifidobacteria was also observed in the former, while no change was observed in the latter. Finally, only FMT produced an improvement in cognitive functions which led researchers to advocate for further investigation.

The microbiota of patients with irritable bowel syndrome is less diversified and shows greater abundance of enterobacteria, but with a lower content in bifidobacteria and lactobacilli. Functional gastrointestinal disorders are characterized by a decreased production of butyrate and an increased production of acetic and propionic acids, which are three substances associated with bloating. Abdominal pain, diarrhea and constipation are other symptoms of these disorders. In the US, an estimated 20% of the population is affected¹⁴.

Controversial effects

Aside from ulcerative colitis, irritable bowel syndrome is the only other gastrointestinal condition for which a treatment with fecal microbiota transplant has been studied in clinical trials¹⁴. One of them showed a decrease in intestinal discomfort, abdominal pain and flatulence in transplant recipients. However, the results varied depending on the initial nature of the gut microbiota: the best responders to fecal microbiota transplant had an initial high content of Streptococci and they had a greater increase in biodiversity. Other works confirm the increased diversity and abundance of the microbiota after the administration of fecal matter capsules; however, patients reported a better improvement in symptoms when they received... placebo! Although these results do not undermine the efficacy of FMT in people with functional gastrointestinal disorders, detailed microbiota analyses before and after the transplant are necessary, according to the researchers.

What about constipation?

Constipation is potentially associated to gut dysbiosis and has been the focus of several works aiming at assessing the usefulness of FMT in this transit disorder¹³. In a study conducted in about sixty adults suffering from slow transit that compared the standard treatment to 6 courses of FMT, the latter was shown to cause a significant improvement of symptoms and transit, and more generally, in the quality of life¹⁵. These encouraging results still need to be confirmed: studies are also ongoing with specific strains, lactobacilli and bifidobacteria¹³.

CIBDs progress as inflammatory flareups of variable duration and frequency depending on the patient, alternating with periods of remission. They cause acute abdominal pain, severe diarrhea (between 5 and 10 bowel movements per day), associated with blood and pus in ulcerative colitis (UC); and in severe forms, other symptoms and complications can occur such as fever, tachycardia, nausea and vomiting, weight loss and dehydration. CIBDs also trigger extra-intestinal symptoms, especially articular pain, skin and mucosa lesions (skin ulcerations, mouth ulcers, glossitis, i.e. tongue inflammation...) as well as hepatic and ocular disorders¹³.

Unbalanced microbiota

The gut microbiota analysis of patients with UC revealed they had a decreased diversity of microbial species¹⁴, especially a lower content of Firmicutes and Bacteroidetes. But it is mainly the low content of Faecalibacterium prausnitzii and the excessive content of Proteobacteria and Actinobacteria that are associated with these CIBDs. This imbalance causes a decrease in the production of short-chain fatty acids, beneficial substances which are food to colon cells and play an important role in the regulation of the immune system. That is why fecal microbiota transplant (FMT) has been considered to treat this disorder.

Moderate benefits in UC

Three of the four published clinical trials on UC concluded that this approach was beneficial. Overall, the beneficial effects were much more moderate than they were in the treatment of C. difficile colitis and depend on the donor–which is why donor selection is so important. And several results raise new questions: are only some microorganisms efficient? And if so, which ones? Should the patient receive an enema or an antibiotic therapy beforehand? Which administration route is preferable? Does the restoration of the gut microbiota work long-term or must transplants need to be repeated? These questions need to be answered before fecal microbiota transplant can be seriously considered as an alternative for the treatment of ulcerative colitis.

Until the 1990s, C. difficile colitis was a relatively rare infection which was not considered a health hazard: an antibiotic treatment was enough to get rid of it. But in a 20-year period, the frequency of this disease more than doubled, while the efficacy of the antibiotics therapy dropped to a 20-30% success rate^8,9. The bacterium is becoming increasingly resistant to antibiotics. It was not until the start of the 2000s and the sequencing of C. difficile genome when a particularly virulent strain was identified. It is resistant to antibiotics and able to produce 10 times the amount of toxins usually secreted by this bacterium.

Beware of relapse with repeated antibiotic courses!

Infection generally occurs after the destruction of the gut microbiota by repeated courses of antibiotics. C. difficile, which is present as resting spores in the colon, proliferates and changes to produce toxins that cause inflammation and diarrhea. Paradoxically, this infection is treated with antibiotics, which progressively exacerbate the gut microbiota disruption at each additional treatment course³ thus leading to a 35% rate of relapse².

FMT should be preferred to antibiotics for recurrent cases

In 1958, the surgeon Ben Eiseman published 4 cases of pseudomembranous colitis that were cured with FMT and sparked interest in this method. Several articles described its efficacy to treat the recurrent form of this disease. But the true turning point came in 2013 with the publication of the first clinical trial in humans. This trial was designed with a robust methodology and demonstrated the therapeutic superiority of FMT over antibiotic therapy to treat recurrent and drugresistant forms of C. difficile infections.

Is fecal microbiota a drug?

The answer depends on the country. In France and in the US, fecal microbiota is considered as a drug. It is not the case in the UK, Denmark or the Netherlands. In France, the National Agency for the Safety of Medicine and Health Products (ANSM) published in March 2014 and updated in 2016 a document regulating FMT which describes the procedure, especially the donor selection process.

Specific procedure

In France, FMT must be prepared under the responsibility of the in-house pharmacy of a health facility³. The collected stools are diluted, mixed, filtered and then filled into syringes before being administered. They can also be frozen, which provides the opportunity to create stool banks that are available at any moment⁵. The ANSM adds that “freezing could also limit the risk of transmission of infectious agents and bypass the pre-screening step (the screening could then be carried out on the transplant itself”.

The gut microbiota (or gut flora) is an organ in its own right, made of billions of microorganisms (bacteria, fungi, viruses...) constantly interacting with each other as well as with the organism they are colonizing (host). In the colon, microorganisms fiercely compete for available space and food, but they also work closely together to digest large molecules. As a treatment for Clostridium difficile infection, FMT is based on four mechanisms of action³:

We now know that a lesser microorganism diversity in the gut microbiota is associated to disorders such as diabetes mellitus, colorectal cancer, and complex gastrointestinal disorders such as chronic inflammatory bowel diseases (IBD). But in order to use this diversity as a biomarker, a proper picture of this diversity is required: fecal metabolites are an indicator of the microbiota composition, but what about blood metabolites?

40 predictive metabolites were identified

To find out, a team tried to predict the gut microbiota diversity based on 1,000 blood analytes in a cohort composed by 399 healthy American adults enrolled in a wellness program. The results show that 40 metabolites found in the host’s blood, of which 13 are of microbial origin, explain 45% of the gut microbiota diversity, and could thus predict it. The predictive capability of metabolites was confirmed in a different validation cohort including 540 people, who were more or less healthy.

Neither too much, nor too little diversity

Moreover, results suggest that instead of maximum diversity, optimal diversity should be prioritized to stay healthy. On the one hand, an association between polyphenol microbial metabolites and gut microbiota diversity has been observed, which could reflect a diet with a high content of fruits, vegetables and cereals (which in turn have a high content of polyphenols); and on the other hand, some microbial metabolites that predict diversity are related to cardiovascular or renal disorders. As a result, not only a lack of diversity but also an excess of it could turn out to be harmful, to the point where the authors mentioned the idea of an ideal range, characterized by “neither too much nor too little” diversity depending on the body mass index (BMI) value. Finally, the authors highlighted that associations between blood metabolites and gut microbiota diversity were not the same along the continuum of BMI, which suggests that limiting the analysis to “normal” and “obese” categories is too restrictive.

Towards clinical tests?

As a whole, these results attest to the close relationship between the host’s physiology and the gut microbiota, and suggest that the host’s blood metabolome is a major interface between the gut ecosystem and human health. Eventually, the ability of plasma markers to predict the gut microbiota diversity could open the way to the development of clinical tests to monitor the gut microbial health, through a simple blood sample, easy to handle.