Therapeutic Potential of Gut Microbiome Manipulation: Concepts in Fecal Microbiota Transplantation

 

Abstract

Microbial Alterations and Dysbiosis: The composition and diversity of gut microbiota is an indicator of health and various groups of commensal bacteria provide health advantages as they enhance metabolism, the immune system, cancer resistance, endocrine signaling and brain function. In general, the gut microbiome remains relatively resilient over time, however, antibiotic use, erratic diet, illness and other factors can lead to alterations and dysbiosis, which weaken various elements of the barrier, causing collapse of the mucus layer that separates epithelial cells and microbiota and reduced expression of antimicrobial peptides which control bacteria including C. difficile.

FMT- Invasive Gut Microbial Manipulation: FMT is administration of a form of fecal material from the donor into the intestinal tract of the recipient in order to directly modify the recipient’s gut microbial composition suitably to confer health benefits. FMT has been used to successfully treat recurrent Clostridium difficile infection (DCI). There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as inflammatory bowel disease, obesity, metabolic syndrome and functional gastrointestinal disorders.

Mechanisms and Effects of FMT: FMT involves administration of the whole microbiota from healthy donor stool into the recipient’s intestinal tract to normalize or modify intestinal microbiota composition and function. FMT has restorative potential for both composition and functionality of gut microbiota and results in normalization of microbial diversity and community profile in patients by multiple mechanisms including competition for nutrients among C. difficile and other microbiota, direct suppression by antimicrobial peptides, bile-acid-mediated inhibition of spore germination and vegetative growth; and activation of immune-mediated colonization resistance.

Mechanisms and Effects of FMT: M. FMT involves administration of the whole microbiota from healthy donor stool into the recipient’s intestinal tract to normalize or modify intestinal microbiota composition and function. FMT has restorative potential for both composition and functionality of gut microbiota and results in normalization of microbial diversity and community profile in patients by multiple mechanisms including competition for nutrients among C. difficile and other microbiota, direct suppression by antimicrobial peptides, bile-acid-mediated inhibition of spore germination and vegetative growth; and activation of immune-mediated colonization resistance.

Possible Scope of FMT Interventions: FMT is be considered for recurrent or relapsing CDI when there is failure to respond to conventional antibiotic therapy. For a moderate CDI, FMT is indicated when there is no response to standard therapy for at least 1 week. For severe CDI, it is indicated when there is no treatment response after appropriate maximal therapy for 48 h. FMT leads to a significant change in microbial diversity in patients with recurrent CDI and complete resolution of symptoms. However, the trials to treat ulcerative colitis (UC) with FMT have shown conflicting results. Further, the patients with Crohn’s disease (CD) and ulcerative colitis (UC) have increased incidence of CDI, and presence of CDI commonly complicates the course of these underlying diseases.

Limitations, Regulations and Complications: The occasional adverse effects of FMT are diarrhoea, abdominal cramping, belching and nausea, which are self-limiting and resolve in a variable period. An increased risk of IBD flare, fever and elevation in inflammatory markers following FMT may occur. Some serious adverse effects are upper GI bleeding, enteritis and peritonitis, which vary with the administration method and may be related to complications of the method itself rather than FMT. FMT is regulated in Canada as a ‘new biologic drug’, specifying the indications, patient’s consent, preparing the FMT from a known solitary donor and screening for potential pathogens prior to administration. The US Food and Drug Administration (FDA) considers stool as a biological product and drug, and mandates physicians to maintain similar precautions to administer FMT. FMT, so far is not regulated in West by the European Medicines Agency, or elsewhere in Asia, Africa or Australia.

Future Directions and Developments: There is increasing acceptance for the therapeutic use of FMT. However, the range of risks and benefits remains poorly defined because the published FMT experience remains limited. In future, FMT can be a pauci-strain type or multi-strain type depending on the fecal microbiota analysis of the recipient. The suitable strains can be picked-up from donor fecal sample, grown in cultures and transplanted through an appropriate route. Depending on the recipients’ microbiota diagnostic analysis, the FMT using suitable pauci-strains may be a promising development in near future

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