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Another reason not to 'poo poo' faecal microbiome transplantation

The side effects of cancer therapy have long been considered a necessary yet unavoidable aspect of undergoing otherwise lifesaving treatment. However, research published in EBioMedicine (by regular #pooisNOTtaboo bloggers Hannah and Kate) now suggests that a centuries old technique may have a variety of new uses in supporting people with cancer.

We have previously explained in this blog that cancer therapy drastically altered the diversity and types of bacteria that inhabit our gut. This process, called dysbiosis, is thought to be involved in some of the acute gastrointestinal complications of cancer therapy, such as diarrhea. More recently, dysbiosis has also been linked with secondary complications such as blood stream infection and graft versus host disease (GvHD); some of the deadliest and most burdensome side effects experienced by people with cancer. GvHD remains the largest driver of treatment-related mortality in stem cell transplant recipients, and is without effective intervention. It requires extensive hospitalisation, with figures estimating an additional 20,000USD to manage people with GvHD and 66% of patients reporting personal financial burden causing depression/anxiety.

In this review, we outline a number of reasons why maintaining or restoring microbial health, using faecal microbiome transplantation (FMT), in people with cancer would be of great clinical benefit. We also address the issue of delivering FMT to people that may be immunocompromised. This is particularly important when thinking about the use of FMT in people undergoing cancer therapy, especially those with blood cancers who are often given very high doses of chemotherapy that affect their immune system’s ability to fight infection. For this reason, people have been very hesitant to give FMT to people undergoing cancer therapy. We show that based on current safety data, collected from over 303 patients across 44 individual studies, there appears to be no additional risk of giving FMT to immunocompromised people compared to immunocompetent people. In fact, we suggest that there may be benefits to immunocompromised people, with a diverse microbiome having the ability to boost natural defenses such as intestinal barrier integrity, antimicrobial peptide production and promote colonisation resistance.

But how exactly does FMT work?

For many people, it can be difficult to understand exactly how FMT works... I mean, how on earth could someone else’s poo be beneficial? The most honest answer is that we really dont understand fully the mechanisms by which FMT works, but its use in treating Clostridium difficile infection (CDI) has shed some light on the magic of FMT. CDI is a bacterial infection that occurs in people who have had antibiotics, or who are exposed to the bacteria in hospital. CDI is currently the only indication for which FMT is actually approved for, with most recent data showing a success rate of >90%!

This incredible success rate is thought to reflect a number of underlying mechanisms achieved by FMT. Firstly, in people with CDI, antibiotics usually disrupt the diversity of bacteria in peoples’ guts. This allows CD to expand and dominate the microbial environment. Delivering a diverse microbiome using FMT helps control CD expansion, preventing it from dominating the intestinal landscape. This process is called colonisation resistance.

Another way FMT is thought to be effective is by restoring bile acid production and metabolism. Bile acids are produced by the liver, and in addition to their role in fat digestion and absorption, they have critical antimicrobial properties. However, they only express this ability when “good” bacteria convert them into their activated state. So without the good bacteria, bile acids are unable to control the expansion of CDI.

Finally, it is well known that the microbiome and immune system are intimately involved. By restoring the diversity of the microbiome using FMT, it has also been suggested to reactivate appropriate immune defenses that can mount responses against CDI as well as strengthen our intestinal defenses. However, this mechanism is likely to be extremely complex, and is still not very well understood.

Applications of FMT in people undergoing cancer therapy

The use of FMT in oncology is vast, and continuing to grow. As we describe in EBioMedicine, autologous stool banking holds great promise in oncology. This process is when we collect stool from patients before they start their cancer therapy, which we process and store until we can re-deliver it back to them. Autologous FMT is considered to be safer than donor FMT, as it eliminates the risk of disease transmission (from donor to recipient). There have also been reports of certain traits being transmitted from donor to recipient, including obesity.

We outline how autologous stool banking could be used to restore microbial diversity after chemotherapy to prevent blood stream infection, graft versus host disease and even neurocognitive dysfunction (“chemobrain”). FMT also has particularly exciting potential in the management of survivors of childhood cancer, where the chronic impact of their treatment on their gut bacteria has been suggested to underpin the high risk of disease seen later in life. We also describe how donor FMT could be used to change a person’s microbiome to a composition that is known to have a positive impact on the outcomes of their treatment. This has enormous potential in changing the outcomes of immunotherapies (a new form of cancer therapy), which has been extensively linked with the microbiome.

Regulatory considerations for FMT

Another aspect we looked at in this paper is how FMT is regulated around the world. As a new, and slightly unusual method of treatment, many regulatory bodies are still working out the best way of ensuring FMT is safe and effective. Regulations include things like what conditions people can receive FMT for, where the funding comes from and how it is decided who can receive the treatment. The table below explains the policies of some countries- you can see how different they are around the world!

Key issues that are being considered worldwide include whether stool banks for FMT should be used, what any donation process should be like and what tests should be done on samples, and finally, ensuring that access to FMT is fair and equitable. You can get an idea of what’s going on in Australia from the TGA website, or in the USA from the FDA website.

Finally, in future, it may be possible that FMT is not delivered in the way it is now (enema or colonoscopy from a donor sample), but may be given as an oral capsule, and might not even come from a donor sample! There is some current research working on developing a synthetic faecal transplant, made up of bacteria and metabolites cultured in the lab instead of coming from a donor. National and international regulations need to ensure that any future developments in FMT technologies can be sufficiently regulated. It will be interesting to see how these regulations develop!

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