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.

Non-alcoholic hepatic steatosis is characterized by excess fat in the liver, not related to excessive alcohol consumption. When left untreated, the liver becomes inflamed and progressively deteriorates: this disorder is then referred to as non-alcoholic hepatic steatosis (NASH) and may progress to fibrosis, cirrhosis, and finally liver cancer. It is frequently associated to metabolic diseases such as obesity, and to disruptions of the gut microbiota. However, we do not know the precise mechanisms responsible for the onset of this disease.

Alcohol-producing bacteria

While studying the case of a patient with NASH and auto-brewery syndrome (sidenote: Auto-brewery syndrome–or gut fermentation syndrome–is characterized by a state of intoxication following a high-sugar meal, while no alcohol was consumed. ) , Chinese researchers discovered that bacteria could be the cause of this syndrome, which had been attributed to yeast until then. Stool analysis revealed the presence of Klebsiella pneumoniae bacteria that are able to produce large quantities of alcohol, at levels up to 900 times higher than normal. Their study was broadened to include 43 patients with non-alcoholic hepatic steatosis and showed that 60% of them hosted these bacterial types in their gut microbiota, vs. only 6% of healthy individuals. To go further, researchers had healthy mice absorb these bacteria: after 4 weeks, mice also developed fatty liver disease. Liver damage was as important as that induced by excessive alcohol consumption in mice. Finally, they observed that the administration of glucose to sick mice hosting this bacterium could be a way of detecting alcohol in the blood. Indeed, bacteria need sugar to produce alcohol: it is the very principle of alcoholic fermentation!

Sugar-based test?

These findings could lead to the development of a simple and effective sugar-based diagnostic test. The researchers believe that detecting alcohol in the blood after glucose absorption could indicate the presence of excess amounts of this bacterium and could lead to the development of an antibiotic treatment targeting K. pneumoniae.

Immune checkpoint inhibitor (ICI) therapy is a form of immunotherapy that provides a new therapeutic option against some tumors, such as melanoma and non-small-cell lung cancer (NSCLC). Despite its efficacy, only a small number of patients can benefit from it. That is why it is important to better anticipate the response to treatment and improve routine prescription guidelines. To this end, a team of researchers investigated if the time of administration of broad-spectrum antibiotics (ATB) which are mainly used to treat respiratory infections–either prior or concomitantly to ICI– could have an impact on the treatment efficacy through gut microbiota modulation.

Patient survival decreased from 26 to 2 months

This prospective cohort study, conducted at 2 teaching hospitals, included 196 patients (137 male and 59 female, average age: 68 years) with cancer (119 NSCLC, 38 melanoma and 39 other types of cancer) who received ICI therapy for more than three years. The results indicate that antibiotic therapy given in the 30 days prior to ICI therapy (pATB, i.e prior antibiotics) clearly decreases overall patient survival, regardless of the type of cancer (2 months for patients who received pATB vs. 26 months for those who did not receive any prior antibiotic treatment). The percentage of tumors refractory to therapy is also considerably higher in patients who received pATB (81% vs. 44%). In conclusion, the time of administration of antibiotics seems crucial: while it does not have any negative impact if given concomitantly to ICI therapy, it worsens the prognosis when it is administered previously.

Understanding the role of the gut microbiota

The authors are aware that their results are limited by the small cohort size and by the lack of correlation analysis between antibiotic therapy and composition of the patients’ microbiota. But they are in line with results from previous studies indicating that gut dysbiosis is associated to a poor response to ICI therapy against cancer. One possible explanation is that the use of antibiotics could lead to long-lasting disruptions in the gut ecosystem which would then jeopardize the efficacy of T cells against cancer. However, this is still an imprecise hypothesis, and mechanistic studies should be carried out as soon as possible in order to understand how gut microbiota alterations induced by prior antibiotic use negatively impact the efficacy of ICI therapy.