FMT Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases (2022)

[Fmt2024]

https://www.nature.com/articles/s41591-022-01964-3

Some excerpts from the article that are interesting. I am against using antibiotics but this article did show some promising evidence that they could help with engraftment. Also interesting, is using multiple routes of delivery helps engraftment as well. I encourage you to read the article and check out the graphs. Very interesting information here.

Together, these data confirm that the extent of donor microbiome engraftment is variable and influenced by pre-FMT donor–recipient relatedness.

Indeed, route of delivery emerged as the variable most significantly associated with strain engraftment also in univariate testing (P = 0.0093; Fig. 2b). So far, no consensus exists as to a recommended route of administration in FMT protocols40 and, whereas our results suggest that combined routes increase the engraftment likelihood, the observation is based on only four studies adopting this approach.

Importantly, intake of antibiotics (14 studies with antibiotic intake before FMT, 10 without) and disease category (12 studies on infectious diseases, 12 on noninfectious) were significantly associated with strain engraftment in cohorts that employed a single administration route (n = 19 datasets, permutation test antibiotics treatment and infectious disease versus no antibiotics and noninfectious disease, P = 0.027), and both were associated with the first two PLS components while being highly correlated with each other (Supplementary Fig. 6; Methods).

the presence of a species after the transplant is dictated primarily by the amount (or absence) in the donor and in the recipient as well as taxonomy and general prevalence.

Our results provide further support for administering FMT by combined routes and including antibiotic preconditioning in FMT working protocols to increase donor microbiome engraftment, even though the potential side effects of antibiotic treatments for noninfectious diseases59 should be considered.

 

[Michael Harrop]

I have this in the wiki under "Outcomes" https://humanmicrobiome.info/fmt/#outcomes -- "Another 2 slightly conflicting meta-analyses in Sep 2022 looking at engraftment outcomes and more". It links to a disreputable website so I'll copy the contents here and link to this thread instead.

Two slightly conflicting FMT meta analyses published at the same time in the same journal looking at engraftment outcomes and more (Sep 2022)​

First study:​

Drivers and determinants of strain dynamics following fecal microbiota transplantation (Sep 2022, meta-analysis) https://www.nature.com/articles/s41591-022-01913-0

Donor strain colonization is independent of clinical outcome

Recipient, not donor, factors drive post-FMT strain dynamics

high levels of donor strain colonization observed in patients with rCDI may be due in part to a more precarious microbial community (possibly instigated or exacerbated by antibiotic use), rather than being a disease-specific effect

Post-FMT strain outcomes are species specific and predictable

donor strain takeover was more likely in species with complementary strain populations between donor and recipient, while diverse recipient populations (not dominated by individual strains) were more resilient than uneven ones. Moreover, incoming species that were phylogenetically complementary to the recipient community (that is, adding novelty—for example, by filling an unoccupied niche) were more likely to colonize or turn over the resident population

Resident ‘gatekeeper’ species inhibit donor strain engraftment

Given that FMT targets the gut microbiome, engraftment and clinical success are expected to correlate, implying that successful microbiome modulation mediates clinical effects. However, this hypothesis had not previously been systematically tested and is indeed not supported by our data.

Recipient factors consistently outweighed donor factors in driving FMT strain-level outcomes. Thus, our data did not support the super-donor hypothesis which states that certain donor microbiome properties are crucial to colonization and, by proxy, clinical success.

This is incorrect. The super-donor hypothesis is about FMT efficacy, not strain-level outcomes. This meta analysis showed that engraftment is not associated with clinical success, so there are no implications regarding super-donors.

Second study:​

Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases (Sep 2022, meta-analysis) https://www.nature.com/articles/s41591-022-01964-3

Donor strain engraftment varied substantially across cohorts, and such variability was explained best by mixed FMT administration routes (combining upper and lower gastrointestinal (GI) tract), by the administration in the recipient of antibiotics before FMT (therapeutically or as preconditioning), and by the recipient being affected by infectious diseases.

patients who received antibiotics before FMT—as part of their therapy for underlying diseases or as pretreatment before FMT—had a significantly higher fraction of donor strains compared with the fraction of retained strains

Previous studies suggest that strain engraftment might be associated with clinical success of FMT, but consolidated evidence is still lacking. When considering single studies, we found that recipients experiencing clinical success showed significantly higher engraftment only in the VaughnB_2016 cohort. When analyzing all cohorts together, we found an overall positive association between strain engraftment rate and clinical response to FMT.

The limited total sample size, the binary categorization of success of clinical treatments, and the heterogeneity of conditions tested represent limitations in our analyses, but the results overall suggest that both higher microbial engraftment and, partially, the overall convergence of microbial species abundances between recipient and donor might improve clinical success of FMT.

Post-FMT strain engraftment rates are phylum- and species-dependent

suggests that ability to engraft is linked to the microbes’ capability of surviving in diverse environments

we found no association between the engraftment of individual species and clinical success

Machine learning can predict post-FMT microbial composition

ML models can pinpoint suitable FMT donors

The choice of donor has a higher influence on the post-FMT microbiome in patients with infectious disease and/or those that were treated with antibiotics

We also found that the donors with higher richness were predicted to induce higher richness in the recipient post-FMT

Our results provide further support for administering FMT by combined routes and including antibiotic preconditioning in FMT working protocols to increase donor microbiome engraftment, even though the potential side effects of antibiotic treatments for noninfectious diseases should be considered.

the link we observed between engraftment and clinical success of the FMT treatment needs to be substantiated in appropriately sized studies with higher number of patients in both outcome arms (for example, clinical failures for rCDI are relatively rare) and with more fine-grained evaluation of clinical success. Dedicated studies and randomized controlled trials are also needed to clarify the influence of protocol-related variables, such as antibiotic preconditioning or combined routes of delivery, on strain engraftment.

 

[Fmt2024]

Very interesting articles!

 

[Michael Harrop]

Another interesting result from Fecal Microbiota Transplantation engraftment after budesonide or placebo in patients with active ulcerative colitis using pre-selected donors: a randomized pilot study (Apr 2024, n=24) "clinical response appeared donor-dependent"

In total, 24 patients were enrolled. Pretreatment with budesonide did not increase donor microbiota engraftment (p=0.56) nor clinical response, and engraftment was not associated with clinical response. At week 14, 10/24 (42%) of patients achieved (partial) remission. Remarkably, patients treated with FMT suspensions from one donor were associated with clinical response (80% of responders, p<0.05) but had lower overall engraftment of donor microbiota.

Response to FMT may be related to transfer of specific strains instead of overall engraftment, demonstrating the need to characterize mechanisms of actions of strains that maximize therapeutic benefit in ulcerative colitis.

 

[Fmt2024]

Another interesting result from Fecal Microbiota Transplantation engraftment after budesonide or placebo in patients with active ulcerative colitis using pre-selected donors: a randomized pilot study (Apr 2024, n=24) "clinical response appeared donor-dependent"

Interesting, my hypothesis is that total strain engraftment at least somewhat correlates with clinical improvement but its regaining those missing microbes that cause it. Its also possible that engraftment of microbes unrelated to the disease could unrelated beneficial effects.

Im extremely fascinated by this article, which I know you’re well aware of, finding a super donor who had 100% efficacy in treating UC.
https://gut.bmj.com/content/72/1/90

They also mention her here along with some other interesting stuff regarding factors in engraftment: https://www.sciencedirect.com/science/article/pii/S2949928324000087#bib25

There is some good evidence on the effectiveness of bowel cleansing/lavage in increasing engraftment as well. Likely a reason why patients with C. Diff have higher engraftment rates, both involve nasty diarrhea that removes bacteria of ecological niches. Will give that a try with my upcoming FMT.