Scientific frontiers in faecal microbiota transplantation: joint document of Asia-Pacific Association of Gastroenterology (APAGE) and Asia-Pacific Society for Digestive Endoscopy (APSDE)

Abstract

Objective: The underlying microbial basis, predictors of therapeutic outcome and active constituent(s) of faecal microbiota transplantation (FMT) mediating benefit remain unknown. An international panel of experts presented key elements that will shape forthcoming FMT research and practice.

Design: Systematic search was performed, FMT literature was critically appraised and a 1-day round-table discussion was conducted to derive expert consensus on key issues in FMT research.

Results: 16 experts convened and discussed five questions regarding (1) the role of donor and recipient microbial (bacteria, viruses, fungi) parameters in FMT; (2) methods to assess microbiota alterations; (3) concept of keystone species and microbial predictors of FMT, (4) influence of recipient profile and antibiotics pretreatment on FMT engraftment and maintenance and (5) new developments in FMT formulations and delivery. The panel considered that variable outcomes of FMT relate to compositional and functional differences in recipient's microbiota, and likely donor-associated and recipient-associated physiological and genetic factors. Taxonomic composition of donor intestinal microbiota may influence the efficacy of FMT in recurrent Clostridioides difficile infections and UC. FMT not only alters bacteria composition but also establishes trans-kingdom equilibrium between gut fungi, viruses and bacteria to promote the recovery of microbial homeostasis. FMT is not a one size fits all and studies are required to identify microbial components that have specific effects in patients with different diseases.

Conclusion: FMT requires optimisation before their therapeutic promise can be evaluated for different diseases. This summary will guide future directions and priorities in advancement of the science and practice of FMT.

Keywords: bacteria; donor; faecal microbiota transplantation; fungi; recipient; virus.

Conflict of interest statement

Competing interests: FZ invented the concept of GenFMTer and TET and devices related to it.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Flow diagram of studies included after systematic search.

Figure 2

Potential mechanisms of faecal microbiota transplantation (FMT). Potential mechanisms of FMT include direct interaction or competition between donor and recipient gut microbiota to achieve homeostasis, effect of donor microbiota on the host immunity and effect of microbiota on modulating host metabolism and physiology. Competitive niche exclusion is a plausible mechanism behind the therapeutic effects of FMT in the treatment of Clostridioides difficile infections (CDI) by introducing competitors and/or modifying the diseased gut environment to the detriment of Clostridioidesdifficile. For example, introduction of non-toxigenic C. difficile strains can reduce the recurrence of CDI in subjects. Another competition-based strategy harnessed by gut micro-organisms is the production of bacteriocins. Quorum sensing systems have also been detected in C. difficile and are known to affect toxin expression profiles in other coexisting micro-organisms. FMT can alter host bile acid metabolism concomitant with alterations to gut microbiota composition. In CDI, a consistent metabolic signature with reduced primary bile acids and increased secondary bile acid production capacity has been reported after FMT. FMT restores Firmicutes phylum bacteria and secondary bile acid metabolism, providing a prime example of FMT re-establishing normal gut microbiota and host metabolism. FMT also has the ability to restore gut microbiota and mucosal immunity and systemic immunity of the host. In mice models of colitis, FMT reduced colonic inflammation and initiated a simultaneous activation of different immune pathways, leading to interleukin (IL-10) production by innate and adaptive immune cells including CD4+ T cells, invariant natural killer T (iNKT) cells and antigen-presenting cells (APC), and reduced the ability of macrophages, monocytes and dendritic cells to present MHCII-dependent bacterial antigens to colonic T cells. These results demonstrate the immunomodulating capability of FMT to therapeutically control intestinal homeostasis and highlight FMT as a valuable therapeutic option in immune-related pathologies. For instance, a reconstitution of the gut microbiome and a relative increase in the proportion of Foxp3+ regulatory T cells within the colonic mucosa were potential mechanisms through which FMT could abrogate immune check point inhibitors associated toxicity. online supplementary file 1 Please refer to Appendix 3 for references. iNKT, invariant natural killer T; MHCII, major histocompatibility complex class II.

Figure 3

For faecal microbiota transplantation (FMT) administration, lower GI delivery can be achieved through enema or colonoscopy, whereas upper GI delivery is through infusion via gastroscopy or via nasoenteric tubes. Oral capsules are non-invasive and is an ideal delivery method for FMT. Formulation to improve delivery, ensuring organism survival and ensure colonisation along the GI tract are needed.6 An encapsulation technique based on a water-in-oil emulsion can provide better insulation of FMT material from GI environment.7 One potential solution is the use of bile absorbent resins. The use of bile acid binding agents such as cholestyramine, when combined with Vcaps HPMC capsules, provided a 1700-fold increase in freeze-dried and rehydrated Lactobacillus casei in a simulated intestinal fluid containing 1% bile.8 Alternatively, a layer-by-layer encapsulation approach using mucoadhesive polysaccharides, chitosan and alginate has been shown to improve cytoprotection, bioavailability and engraftment of Bacillus coagulans in porcine and human intestines.9 Capsule design content release is dependent on intestinal stimuli.10 Other approaches include genetic engineering, for example, Escherichia coli engineered to bind to colorectal cancer cell receptors and catalyse production of molecules with anticancer activity.11 This novel approach can be considered for FMT if constituent strains that contribute to clinical efficacy are identified. They can then be engineered to improve binding and colonisation in the gut of FMT recipients. Please refer to Appendix 3 for references.(online supplementary file 1)