Black-Box Nature of Faecal Microbiota Transplantation

Introduction:

"Faecal Microbiota Transplantation" (FMT) or "Stool Transplant" or "Poop Transplant", a fascinating medical treatment that captivates people's attention, particularly in understanding the importance of gut microbiome. While FMT has emerged as a prominent and effective therapy for treating refractory Clostridioides difficile infections (C. difficile infections), it is equally crucial for both health professionals and the public to be aware of its evolving long-term risks. This article endeavours to provide a detailed understanding of FMT and perplexing nature of the microbiome.  

Understanding C. difficile infections:

Our gut is an ecosystem for trillions of diverse microbial communities. This rich diversity of microorganisms contributes to essential physiological processes within our body. Among these microbes, Clostridioides difficile (C. difficile) is a particular type of germ that can live in our gut without causing problems for many people. However, this spore-forming bacterium has the potential to disrupt our normal healthy microbial community. When we consume antibiotics to fight other infections (like cough), these medications unfortunately wipe out not only harmful microbes but also many beneficial bacteria in our gut city, leaving it vulnerable to opportunistic infections. The increase in growth of unhealthy microbes leads to dysbiosis which in turn results in weakened immune system, neurological disorders, gut disorders, and various microbial infections (most notably recurrent C. difficile infections). For many people mild C. difficile infections can be remedied with certain antibiotics. However, recurrent forms of the disease can be treated with FMT, that focuses on repairing and renovating the natural balance of our gut to fight off tenacious C. difficile infections.  

What is "Faecal Microbiota Transplantation"?

It is a medical administration of medically treated faecal solution (contains healthy microbiota) from donor into the intestinal tract of an infected person. It is essentially used to heal the recurrent infections caused by anaerobic bacteria Clostridium difficile. The injected healthy microbes from donor straightway alters the recipient's gut microbial community that accords health related advantages.  

How is Faecal Microbiota Transplantation done and Gut microbiome is altered?

Transfer of healthy microbes (processed stool sample) from the healthy donor to the dysbiotic colon can re-establish the balanced microbiome community. To achieve this re-establishment, FMT is administered through different approaches. The sample from the donor is thoroughly screened and medically prepared for transplantation is then delivered to recipient's digestive tract by one of the following ways:

• Upper Endoscopy (Gastroscopy) - The sample is injected through a thin, flexible tube with endoscope(camera) is advanced through mouth, oesophagus, and into the upper gastrointestinal tract.
• Colonoscopy - The sample is placed in patient's colon directly through a thin tube with endoscope, allowing for targeted delivery.
• Oral Capsules - Taking capsules orally, filled with donor's sample that reaches the intestinal tract.
• Enema procedure - It is relatively less-invasive than scope procedures, where the sample is introduced into the recipient's rectum via a catheter like normal enema procedure.   

Efficacy and Benefits of FMT:

FMT renders several advantages, specifically for people suffering from recurrent C. difficile infections. Here we summarize some of the key benefits of FMT:

• Higher Success Rate: FMT has higher success rate (often exceeding 80%) in treating recurrent C. difficile infections, particularly when compared to continued antibiotic use for its recurrence.
• Breaks the Repetition cycle: FMT effectively breaks the cycle of recurrence of unhealthy microbes in our gut. In this way, the natural balance of our gut is re-established.
• Reduced Antibiotic Dependence: As FMT introduces and expands the population of beneficial microbes, the need for continuous antibiotic use is reduced.
• Favourable Safety Profile: Meticulous screening of the donor sample offers relatively safe transplant therapy.     

Navigating the Potential Risks of FMT:

While no medical therapy is entirely risk-free, FMT also carries inherent side effects and long-term risks that people should be aware of before undergoing the procedure. Common and typical side effects like constipation, abdominal cramps, bloated stomach, loose stools, and flatulence are temporary. However, it is important that people are conscious of potential long-term risks associated with FMT:        

• Exacerbation of Inflammatory Bowel Disease (IBD): Disease caused by the inflammation in intestinal tract is called as IBD. This could be due to dysbiosis. At present, FMT has some promise for treating IBD (study is under investigation). However, there have been rare theoretical concerns about its potential to induce IBD in some susceptible patients after the procedure. The arrival of new microbial communities can sometimes alter the gut microbiome, which in turn stimulate the immune response that results in inflammation in the gut and auto-immune conditions in rare cases.
• Worsening Obesity Problems: Studies (including animal studies using mice models) suggest that, sample from the obese donor to non-obese recipient, can lead to metabolic changes and obesity in the recipient's body. These observed effects in the recipient's body depend on donor's microbiome that may potentially result in chronic conditions like diabetes.
• Procedure-related Infections:

1) Transmission of Pathogens: Despite careful medical screening of donor's sample in FMT, some pathogens are undetectable at the time of screening, and they may be transmitted to the recipient's gut, where they become active. Especially when accompanied by a weakened immune system, the transmitted pathogens can cause various infections like norovirus, drug resistant E. coli, etc.

2) Due to therapeutic procedures: Invasive procedures like colonoscopy, and endoscopy used during FMT, carry their own intrinsic risks such as perforation and bleeding.

• Aspiration Pneumonitis: FMT carries an indirect risk of causing aspiration pneumonitis. Inhalation of chemicals or sample itself directly into lungs can accidentally occur during the transfer of sample via nasogastric/nasoduodenal tube delivery, potentially leading to serious respiratory complications.         

FMT as Public Health Concern:

Beyond the patient-level risks, the following key aspects of FMT have become Public Health Concern.

• Limited Standardization and Regulatory Control: At present, FMT has become primarily accepted medical therapy for C. difficile infections. Still, the broader practice of Faecal Microbiota Transplantation (FMT) largely operates without comprehensive standardization and regulation. Here, the standardization involves collection, composition, storage, and processing the stool sample. This poses significant public health challenges for ensuring quality, and safety across different providers. 
• Long-term Unintended Consequences: FMT involves processing and transplantation of human biological product, which may potentially contain undetected pathogens. These pathogens in a sample from single donor to multiple recipients intensify the risks of transmission diseases. While the presence of unidentified pathogens may cause acute infections, the composition of newly modified microbiome (in recipient's gut) may have an influence on chronic conditions like metabolic changes and even certain cancers is also a concern. This multifarious aspect of FMT has become an important public health concern, as recipients may become more susceptible to the transmission of infectious diseases and face other long-term health issues.  
• Ethical Principles and Donor Considerations: FMT relies on human faecal material for therapeutic purposes. This raises important questions concerning donor rights, and the informed consent regarding the use of their biological sample. Hence, ensuring the transparent recruitment of donors, free from coercion, and maintaining safety measures through rigorous screening of the sample have become critical public health concerns.   
• Accessibility and Equity: Even though FMT becomes a standard treatment for recurrent C. difficile infections, many people lack equal access to the treatment due to financial constraints in approaching the treatment. Only a particular segment of population can afford safer therapies, while others turn to uncertain alternatives, which carry increased risks due to a lack of proper screening and medical supervision. This concern can be overcome by improving the infrastructure of medical standards such as setting up more FMT-dedicated facilities, and broadening insurance coverage.         

On-going research parameters of FMT:

There are many FMT studies and researches are going on to expand the therapy's potency and implementations. Scientists and Doctors are actively investigating the following core aspects of FMT:

• Improved Donor Screening Criteria
• Identifying Optimal Recipient-related Factors for treatment success
• Refining Sample Administration Procedures
• Establishing Long-term Monitoring and Pathways for Personalized care
• Developing broad Standardization Protocols      

Mastering the understanding of unpredictable behaviour of microbes and pathogens in the gut is the ultimate challenge for the researchers. Future research studies on microbiome can help overcome these difficulties, and aid in inventing new delivery methods of FMT.

Conclusion:

On the global level, FMT is accepted as a successful therapy for the people with recurrent C. difficile infections. However, the therapy may not be suitable for patients who are on medications for other health conditions. Advanced scientific methods and computational tools, particularly in multi-omics studies can significantly increase the potency of microbial research, especially in human microbiome project. As mentioned in this article, FMT can carry long-term risks for some patients. Addressing these factors require a multifaceted approach, basically by increasing people's awareness on FMT's benefits and potential risks.