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Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80 Page 11 of 20

caveats, the usefulness of such organizations for the field of microbiome-based therapy is ever growing.

New disease targets
The great efficacy of FMT in treating CDI has spurred the investigation into its use to treat other health
[14]
conditions (See Sorbara et al. for a detailed review) . Because FMT success in CDI is driven, at least in
part, by competition for nutritional resources, there are several CTs testing FMT potential to reduce or
ablate colonization of the intestinal tract with multiresistant bacteria. So far, a reduction in recurrent
infections of > 50% has been demonstrated [131,142] . In a similar way, modulating the native healthy vaginal
microbiome is being used to improve women’s health.

Inflammatory bowel disease, which involves CD and ulcerative colitis (UC), is a GI disease characterized by
chronic inflammation of the GI tract and changes in a shift in the microbiome composition [143-145] . UC is the
[14]
second condition for which more CTs have been registered . The efficacy compared to CDI is lower (35%-
40% vs. > 70%), but positive results and the need for steroid-free therapies continue to move this research
forward.

The treatment of Metabolic Syndrome with FMT has shown equivalent results, in which approximately only
50% of the recipients show clinical improvement. In-depth metagenomic analysis of several clinical trials
has expanded our understanding of the ecological drivers of FMT at the strain level and has unraveled key
determinants of success, such as engraftment or displacement of specific species and additional players such
as viruses [120,127,146,147] .

Because the microbiome plays a key role in modulating the immune system, FMT treatment is being tested
in an array of immune-related diseases, ranging from acute graft-versus-host disease (GVHD) to Type I
diabetes or Multiple sclerosis, with variable but again promising results, especially in the treatment of
GVHD [14,139] . Increasing data demonstrate that the ability of the gut microbiome to metabolize xenobiotic
compounds and to regulate immune responses has profound consequences for anticancer therapies [15,31,53] .
For instance, FMT can increase the effectiveness of immunotherapy and reduce the toxicity of
chemotherapy, suggesting that microbiome-based treatments might become the new leading personalized
anticancer therapies [15,53,148] .

Risks
The large amount of CTs performed to date have established that microbiota-based therapies are safe, but
[149]
they are not void of some side effects and clinical risks that can be mitigated . The most common side
effects reported are mild diarrhea, abdominal cramping, and belching. These symptoms are generally
resolved within 3 h and are also seen in control groups that receive their own fecal material. Administration
through oral capsules has not shown a reduction of these side effects .
[150]

A recent systematic review on the safety of FMT suggests that there can be additional risks including
infectious (fever, bacteremia), autoimmune disease (peripheral neuropathy, Sjogren’s syndrome, idiopathic
thrombocytopenic purpura, and rheumatoid arthritis, IBD flare among patients with UC), or metabolic
syndrome [12,149,151] . However, these risks are seen in a minor percentage of cases and can be mitigated through
strict screening of donors, which is becoming a mandatory procedure in clinical trials.

Regulatory framework
Until 2022, FMT and other microbiota-based therapies remained in a regulatory grey area in European
countries. These therapies were not classified as drugs due to the wide diversity of gut microbiota