Faecal microbiota transplantation: From waste to therapeutics

“Organ donation: A gift of life” – a very familiar slogan in organ donation campaigns. But what if I told you that human faeces hold the potential to become an unexpected gift, offering hope to those in need?

Background 

The application of faeces as therapeutic agents can be traced back to 4th century China where human faecal suspension by mouth was used to treat food poisoning and severe diarrhoea (Kelly et al. 2015). However, faeces were rarely used in modern medicine until 1983 when a case of Clostridium difficile infection (CDI), an infection characterized by severe diarrhoea following antibiotic treatment successfully treated with faecal microbiota transplantation (FMT) was first documented (Kelly et al. 2015).

FMT is defined as the engraftment of healthy donor faecal microbiota into the gastrointestinal tract of a recipient to restore the normal gut microbial community structure (Borody and Khoruts 2012). Recently, it has emerged as a potential therapeutic option for microbiome-associated diseases ranging from CDI to metabolic diseases (Andary et al. 2024). 

Current treatment guidelines and methods

Currently, FMT is only indicated in CDI treatment despite its potential in many other medical conditions (Kelly et al. 2015). 

Considering the FDA guidelines for donors of human cells, tissues, cellular and tissue-based products, potential stool donors should be screened for risk of infectious agents, gastrointestinal comorbidities, factors that might affect the composition of intestinal microbiota such as antibiotics within 3 months, major immunosuppressive medication, systemic antineoplastic medication and additional recipient-specific consideration such as recent ingestion of potential allergen before the sample collection (Bakken et al. 2011). It is also appropriate to consider other issues including history of major gastrointestinal surgery, metabolic syndrome and systemic autoimmunity during donor selection (Bakken et al. 2011). 

Following stool collection from eligible donors, the samples are diluted, homogenized and filtered before administration via direct infusion (Biazzo and Deidda 2022). The samples can also be further processed into capsules and frozen for future use (Biazzo and Deidda 2022).

Mechanism of action

The established use of FMT for recurrent CDI is believed to be due to the restoration of the healthy indigenous gut microbiota (Khoruts and Sadowsky 2016). With the restoration of normal gut microbiota, the immune defence in the gastrointestinal tract is likely to be restored through various interactions between the microbiota and the host physiological functions. One of the basic interactions is the competitive exclusion of pathogens in the gut by the normal gut microbiota (Andary et al. 2024). Besides, according to Thursby and Juge (2017), some commensal bacteria are involved in the gut barrier integrity by induction of mucosal secretion IgA which provides immune protection against pathogen colonization. Production of antimicrobial peptides such as thuricin CD and nisin by Bacillus thuringiensis and many other Gram-positive bacteria is also effective to provide protection against Clostridium difficile (Khoruts and Sadowsky 2016). 

Figure 1: FMT for treatment of CDI. Source: Borody and Khoruts (2012)

Emerging applications 

Beyond CDI, there is growing interest in the potential of FMT to treat other diseases that are associated with dysbiosis, an imbalance in the microbiota composition. 

1. Inflammatory bowel disease (IBD)

Through FMT, short-chain fatty acid (SCFA)-producing species can be re-introduced into the gut environment (Andary et al. 2024). As a result of the increased production of SCFAs, the gut barrier integrity can be improved and the chronic inflammatory conditions can also be attenuated (Andary et al. 2024). In a systemic review and meta-analysis, FMT appeared to be effective in clinical remissions of IBD (Paramsothy et al. 2017). However, a Cochrane Review presented that the evidence of FMT for IBD treatment is very uncertain and no conclusive statements could be made (Imdad et al. 2023). Hence, further studies and more well-designed randomized controlled trials are still required. 

1. Metabolic disease

FMT can shift the host microbiota communities towards those healthy donors characterized by an increased abundance of SCFA-producers, butyrate producers as well as bacteriophages HV39 and 84 (Andary et al. 2024, Kelly et al. 2015). These microbial changes can modulate the host metabolic functions by improving the glucose disappearance rate and insulin sensitivity which can lead to better clinical outcomes in obesity and diabetes mellitus (Kelly et al. 2015, Andary et al. 2024). Although studies have shown that there is different Bacteroides and Firmicutes abundance in those who are lean and obese (Turnbaugh et al. 2006) and FMT from lean and obese mice can shift the phenotype of the antibiotic-treated mice towards the donor (Ellekilde et al. 2014), conflicting meta-analyses for the application of FMT in obesity exist (Hu et al. 2023, Proença et al. 2020). However, both suggest FMT as a promising adjunct therapy in glycaemic control. 

Figure 2: Description of the transfer of gut microbiota from lean and obese mice to antibiotic