Fecal Microbiota Transplantation: Indications, Methods, Evidence, and Future Directions

Fecal microbiota transplantation (FMT) has attracted great interest in recent years, largely due to the global Clostridium difficile infection (CDI) epidemic and major advances in metagenomic sequencing of the gastrointestinal (GI) microbiota, with growing understanding of its structure and function. FMT is now recommended as the most effective therapy for relapsing CDI and, with further refinement, may even be used in “first-time” CDI. There is interest also in other conditions related to GI dysbiosis—for example, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes mellitus—although quality evidence is at present lacking. A few trials are now underway in FMT for ulcerative colitis. Many unanswered questions remain, including FMT methodology—for example, optimal route of administration, what makes a “good donor,” safety issues, and long-term effects of FMT

The role of faecal microbiota transplantation in the treatment of inflammatory bowel disease

Purpose of the review Faecal microbiota transplantation (FMT) has emerged as a potent form of therapeutic microbial manipulation. There is much interest in exploring its potential in conditions such as inflammatory bowel disease (IBD) where disturbances in the gastrointestinal microbiota play a crucial role in disease pathogenesis. Recent findings There are 4 randomized controlled trials of FMT as induction therapy in ulcerative colitis, with meta-analyses suggesting significant benefit over placebo. Allied microbial studies have identified potential microbial and metabolic predictors of therapeutic efficacy and highlighted the importance of optimizing future donor and patient selection. Recent literature has evaluated the use of complementary microbial manipulation through pre-antibiotics to improve treatment efficacy. Studies have also assessed the durability of FMT response and its use in maintenance therapy of UC. While data on FMT are more limited in Crohn’s disease and pouchitis, cohort and pilot randomized controlled data a now also emerging in these areas

Clinical and microbiological studies of faecal microbiota transplantation in ulcerative colitis

Introduction: While the gastrointestinal (GI) microbiota plays a critical role in ulcerative colitis (UC) pathogenesis, UC treatments are predominantly immunologically based. Traditional methods of therapeutic microbial manipulation such as antibiotics and probiotics demonstrate at most modest benefit. Faecal microbiota transplantation (FMT), the introduction of faecal suspension derived from a healthy donor(s) into the GI tract of a diseased individual, has the advantage that it provides the full microbiota spectrum from a healthy individual. Given the remarkable efficacy of FMT in Clostridium difficile colitis, FMT may be of value in UC.AIM: To determine the efficacy and safety of multi-donor FMT in UC and the effect of FMT on the resident microbiota of recipient patients.METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial of multi-donor FMT in UC was conducted, coupled with microbial analyses including 16S rDNA high throughput pyrosequencing to investigate the underlying microbiological basis. To establish the benefit of FMT in IBD and identify predictors of improved outcomes, a systematic review and meta-analysis was performed.RESULTS: Faecal donor recruitment was challenging (10% success rate), with a significant proportion failing stool testing due to GI parasites. Multi-donor FMT definitively demonstrated efficacy in UC, meeting the primary endpoint of steroid free clinical remission and endoscopic remission or response (11/41 [27%] of FMT-treated patients vs 3/40 [8%] placebo-treated patients; RR 3.6; p=0.021) along with most secondary endpoints. No significant difference in number or type of adverse events was noted between FMT and placebo, these being primarily self-limiting GI complaints. Recipient microbial diversity increased with, and persisted after FMT, with those achieving primary outcome displaying greater diversity at baseline, during and 8-weeks post FMT. Several bacterial taxa were associated with clinical outcome. Meta-analysis confirmed FMT was effective in UC, particularly with multiple infusions and lower GI tract administration, but long-term durability and safety remain unclear.CONCLUSION: These studies demonstrate FMT is an effective treatment for UC, with satisfactory short-term safety. FMT induces durable changes in the intestinal microbiota profile of UC patients, with increased microbial diversity, differential abundance of bacterial taxa, and changes correlating with therapeutic outcomes

Safety of drugs used for the treatment of Crohn’s disease

Introduction: Medications in treating Crohn’s disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn’s disease in adult patients. Areas covered: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on ‘trial’ and ‘real-world’ data for the biologic agents. Safety in pregnancy and the elderly are also presented. Expert opinion: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy

Tryptophan Metabolism ‘Hub’ Gene Expression Associates with Increased Inflammation and Severe Disease Outcomes in COVID-19 Infection and Inflammatory Bowel Disease

The epithelial barrier’s primary role is to protect against entry of foreign and pathogenic elements. Both COVID-19 and Inflammatory Bowel Disease (IBD) show commonalities in symptoms and treatment with sensitization of the epithelial barrier inviting an immune response. In this study we use a multi-omics strategy to identify a common signature of immune disease that may be able to predict for more severe patient outcomes. Global proteomic approaches were applied to transcriptome and proteome. Further semi- and relative- quantitative targeted mass spectrometry methods were developed to substantiate the proteomic and metabolomics changes in nasal swabs from healthy, COVID-19 (24 h and 3 weeks post infection); serums from Crohn’s disease patients (scored for epithelial leak), terminal ileum tissue biopsies (patient matched inflamed and non-inflamed regions, and controls). We found that the tryptophan/kynurenine metabolism pathway is a ‘hub’ regulator of canonical and non-canonical transcription, macrophage release of cytokines and significant changes in the immune and metabolic status with increasing severity and disease course. Significantly modified pathways include stress response regulator EIF2 signaling (p = 1 × 10−3); energy metabolism, KYNU (p = 4 × 10−4), WARS (p = 1 × 10−7); inflammation, and IDO activity (p = 1 × 10−6). Heightened levels of PARP1, WARS and KYNU are predictive at the acute stage of infection for resilience, while in contrast, levels remained high and are predictive of persistent and more severe outcomes in COVID disease. Generation of a targeted marker profile showed these changes in immune disease underlay resolution of epithelial barrier function and have the potential to define disease trajectory and more severe patient outcomes

Profiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice

Host molecular responses to fecal microbiota transplantation (FMT) in ulcerative colitis are not well understood. Here, we profile the human colonic mucosal transcriptome prior to and following FMT or placebo to identify molecules regulated during disease remission. FMT alters the transcriptome above the effect of placebo (n = 75 vs 3 genes, q < 0.05), including modulation of structural, metabolic and inflammatory pathways. This response is attributed to responders with no consistency observed in non-responders. Regulated pathways in responders include tight junctions, calcium signalling and xenobiotic metabolism. Genes significantly regulated longitudinally in responders post-FMT could discriminate them from responders and non-responders at baseline and non-responders post-FMT, with GBP5 and IRF4 downregulation being associated with remission. Female mice with a deletion of GBP5 are more resistant to developing colitis than their wild-type littermates, showing higher colonic IRF4 phosphorylation. The colonic mucosal response discriminates UC remission following FMT, with GBP5 playing a detrimental role in colitis

Australia IBD microbiome (AIM) study : protocol for a multicentre longitudinal prospective cohort study

Introduction: Crohn’s disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia’s first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. Methods: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated selfreport questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. Ethics and dissemination: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals