My letters to the FDA and NIH. Sharing these both for the info, and as a template and encouragement for others to push for higher donor quality. (Nov 2018)

Michael Harrop

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I made some minor updates to the text/links.

FDA:​

Center for Drug Evaluation and Research (CDER)1-855-543-3784 or 1-301-796-3400 or [email protected] Center for Biologics Evaluation and Research (CBER)1-800-835-4709 or 1-240-402-8010 or [email protected]

I sent to [email protected], got a reply from [email protected], telling me "If you should have any other questions or concerns regarding this subject, please feel free to contact a representative from CBER's Consumer Affairs Branch at [email protected] or by phone at 1-800-835-4709."

6/4/2018 letter:​

"FMT donor quality, safety, availability, antibiotics, first-line treatment"

I have been following the microbiome literature very closely every day for a few years now. And I've put together this related wiki to summarize the literature for both laypeople and professionals: https://humanmicrobiome.info/

I think it should be very clear to anyone who's fully up to date with the literature that FMT is as safe as the donor is healthy, and that nearly all official sources of FMT are using ridiculously inadequate donor criteria, and thus low-quality donors. Not only does this increase the danger, but massively decreases efficacy, and thus the majority of clinical trials are nearly useless except for the purpose of demonstrating that low-quality donors are inadequate. And even then they are poor, due to lack of comparison in the same group with a high-quality donor. Trials using inadequate donors are also wasting tons of NIH money!!

In my opinion, the most dangerous current thing about FMT is the fact that high-quality donors are not freely available. People aren't going to just sit around and die when there's an obvious cure. So the fact that there hasn't been a major push to get extremely healthy people (IE: top young athletes) worldwide to donate to stool banks who then sell the stool freely to anyone is the major problem.

Another bewildering fact is that in the 3+ years I've been following the literature daily I haven't seen a single study comparing the efficacy of the "average" FMT donor currently being used to someone like an Olympic sprinter. A huge percentage of "professionals" working in this field (doctors, researchers, clinics, etc..) seem extremely ignorant about most of the research, general human health, and the gut microbiome's impacts on the entire body, to where many of them haven't got the slightest clue as to what makes a high-quality donor/healthy person. All the information listed in that wiki (at minimum!!) should be known by everyone working in or regulating this field, but it is absolutely not the case in my experience.

I think it's absolutely ridiculous that instead of demanding higher quality donor criteria, you instead keep antibiotics as the first line of treatment for C. diff. Antibiotic resistance is a major issue, and so is antibiotic damage to the human microbiome & immune system. Even though the first one gets a lot of coverage, the 2nd one is likely even more important and seems to be currently massively underestimated.

It is very clear from numerous patient feedback that a wide variety of antibiotics do permanent damage to the gut microbiome & immune function, including ones like Rifaximin, which are claimed to only cause beneficial shifts in the gut microbiome. There are numerous people on https://old.reddit.com/r/ibs and elsewhere who have reported the same/similar permanent detriments from Rifaximin. Yet most donor criteria only require no antibiotic use in the past 3 months!! And some, like Openbiome, the primary US stool bank, only ask about the past 8 weeks to 12 months for disease symptoms and the past 8 weeks for antimicrobials... This is extremely shocking and appalling. They said their Clinical Advisory Board approved it: https://www.openbiome.org/team/#cab - What the f**k?! TWELVE "professionals" on that list!! All of whom are that ignorant on the gut microbiome? This is yet another example of the MAJOR problems in our current health, education, & research systems: https://forum.humanmicrobiome.info/threads/doctors-are-not-systematically-updated-on-the-latest-literature-what-t.27/

Even in cases where an antimicrobial does minimal/temporary damage, having zero-lifetime antibiotic use is a very good sign that the person's gut microbiome is strong/healthy enough that they never need one. IE: disease resistant and curative.

Wide range of drugs affect the growth of gut microbes and promote antibiotic resistance. These accidental bactericides included proton-pump inhibitors such as omeprazole, calcium-channel blockers, antihistamines, painkillers and antipsychotics. (2018): https://www.theguardian.com/science/2018/mar/19/wide-range-of-drugs-affect-gut-microbes-not-just-antibiotics - https://www.economist.com/news/science-and-technology/21738985-they-may-also-though-be-source-new-antibiotics-non-antibiotic-drugs-promote
And these other drugs are rarely considered with regard to donors.

Current testing/sequencing technology is extremely limited, and culture even more so. Current testing cannot be relied on for donor screening (safety or efficacy), or for a complete analysis of the damage to the gut microbiome from antibiotics. Even so, there have been many studies showing permanent damage from antibiotics to the gut microbiome & immune function. Those kinds of studies often focus on genus-level (or higher), which is woefully inadequate [citations 1-6], and often also ignores damage/changes to the immune system (not to mention phages, archaea, fungi) such as: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395657/

The current literature strongly points to fecal transplants being a panacea, with the major caveat being that the donor is high-quality enough. What makes a high-quality donor is covered in the wiki.

I believe the literature, along with extensive personal experience & feedback from other patients, strongly concludes that virtually anything wrong with the donor can be passed to the recipient. And if the donor isn't in absolute perfect physical and mental health with 0 lifetime antimicrobial use then they do not contain a sufficient gut microbiome to cure other people's diseases/dysbiosis. There are also children who have zero-lifetime use along with virtually perfect health, but their stool is not type 3 on the bristol scale, and thus they have poor curative properties. The bristol scale is based on intuition and generalities, but from the experiences of myself and others, it seems type 3 is one of the major signs of a high-quality donor. Yet many questionnaires/screenings don't even ask about that! This 2017 study saying otherwise is only for c.diff (which requires much less strict donor criteria): https://www.gastrojournal.org/article/S0016-5085(17)32233-3/pdf. And it's likely that they were only comparing low-quality donors with each other due to deficiencies in donor selection: https://forum.humanmicrobiome.info/threads/analysis-of-openbiomes-safety-and-efficacy.55/

But also I believe it is a matter of "the highest quality donors all have type 3 stools, but not every type 3 stool donor is high quality". This Anna Karenina hypothesis provides support: https://web.archive.org/web/20230607102627/https://old.reddit.com/r/HumanMicrobiome/comments/6w43a7/a_grand_unified_theory_of_unhealthy_microbiomes/


Citations 1-6:

Studies which use phylum-level percentage comparisons are completely useless from a microbiological point of view. Species-level should be the bare minimum: https://archive.is/O39RL

Gut microbiota assembly is based on functions encoded in bacterial genomes provided by a consortium of bacteria with different growth characteristics that adapt to environmental factors rather than on specific species: https://archive.is/Np2Im

Moving forward we need to appreciate compositional profile vs functionality of the gut microbiota. It is now appreciated that it is not just which bacteria inhabit the gut but also their genetic make up and the capability of these different species to produce different neuroactive and influential metabolites: https://archive.is/j3g8d

The importance of species identity and interactions on multifunctionality depends on how ecosystem functions are valued http://onlinelibrary.wiley.com/doi/10.1002/ecy.1954/abstract

Interactions between species introduce spurious associations in microbiome studies: http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005939

Even with species like H. Pylori, it can have positive or negative relations depending on the disease state: http://onlinelibrary.wiley.com.sci-hub.cc/doi/10.1111/cen3.12401/full


NIH:​

Contacted NIH on 6/4/2018 at https://www.nih.gov/about-nih/contact-us - "Fecal Microbiota Transplant trials using low-quality donors are wasting tons of NIH money"

Was pretty much the same text, minus 1 or two paragraphs.



Original 05 Nov 2018 (2 comments).
 
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