Mucosal microbiota transplant, clearing the gut mucosa prior to FMT

Michael Harrop

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I posted about this a few years ago elsewhere and I'm copying all the info here for easy discussion.


"While fecal microbiota is partially normalized by extended co-housing, mucosal communities associated with the proximal colon and terminal ileum remain stable and distinct". Comparison of Co-housing and Littermate Methods for Microbiota Standardization in Mouse Models (May 2019). https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30488-7

For the people who don't know, mice eat each other's poop, thus naturally do FMT when co-housed.

This study seems to show that FMT is not enough to change the mucosal microbiome. Thus it seems like something like this would be necessary to enhance FMT:

By destroying the mucous membrane in the small intestine and causing a new one to develop, scientists stabilized the blood sugar levels of people with type 2 diabetes. https://www.theguardian.com/society/2018/oct/24/spectacular-diabetes-treatment-could-end-daily-insulin-injections

Duodenal Mucosal Resurfacing Elicits Improvement in Glycemic and Hepatic Parameters in Type 2 Diabetes—One-Year Multicenter Study Results (2018): https://diabetesjournals.org/diabetes/article/67/Supplement_1/1137-P/54118/Duodenal-Mucosal-Resurfacing-Elicits-Improvement

When destroying the membrane you're basically clearing the forest, which includes pathogens which may be responsible for diabetes. It's likely that if their method actually clears and replaces it without significant damage (unlike antibiotics) it could help many more conditions than diabetes.

Previously I emailed a bunch of IBS & CFS researchers asking them to test that mucosal clearing either by itself or in conjunction with FMT, but it didn't seem like any were willing/able.

I'm thinking there might be some type of layers. Like the microbes transferred by FMT are only able to occupy some top layer or small niches where they're able to feed on the food coming through, but unable to penetrate further down into the mucus.

This is very much inline with my own current FMT experience where the donor microbes seem to be very easily lost - such as by using iodized salt (iodine is an antimicrobial) - and I have to keep adding them.


Mucosal microbiota transplant?​

I was thinking more about "while fecal microbiota is partially normalized by extended co-housing, mucosal communities associated with the proximal colon and terminal ileum remain stable and distinct".

It should be possible to do a mucosal microbiota transplant by swabbing/collecting mucosa samples from the colon, immediately submerging them in saline to protect anaerobes, and then feeding that liquid to other mice and see how it compares to FMT/co-housing. I would also compare feeding the mucosa liquid while the recipient mouse was fasting vs not fasting.

I did a google scholar search for "mucus microbiota transplant" and didn't see anything on it.

We could even do it in humans, it would just be slightly more invasive for the donor than FMT. I've had a colonoscopy done while I was not sedated. It was painful as the object made its way through the turns especially, but perhaps we don't need to use such a large object, making it less painful.

For reference, the mucosal microbiota seems to be significantly different from the fecal microbiota:

Mucus: A Special Home of Our Microbes (2018): https://www.karger.com/Article/FullText/495115#scrollNav-4 "So far, we know that the mucus of surface epithelia seems to be one of the most important habitats for host-associated bacteria"

Differential clustering of faecal and mucosa-associated microbiota in healthy individuals (2018): https://doi.org/10.1111/1751-2980.12688 "Analysis of faecal samples that have been transported at ambient temperature does not adequately reflect the colonic mucosa-associated microbiota in healthy individuals"

Gut mucosal-associated microbiota better discloses Inflammatory Bowel Disease differential patterns than faecal microbiota (2018): https://www.dldjournalonline.com/article/S1590-8658(18)31260-X/abstract

Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria (Mar 2019): https://www.biorxiv.org/node/387169.full

Maybe the ultimate end game will be clearing the mucosa in the recipient and using mucosa microbiota from the donor, but for now, maybe whichever one is easier could be a significant improvement on its own compared to standard FMT.
 
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By destroying the mucous membrane in the small intestine and causing a new one to develop, scientists stabilized the blood sugar levels of people with type 2 diabetes. https://www.theguardian.com/society/2018/oct/24/spectacular-diabetes-treatment-could-end-daily-insulin-injections

Duodenal Mucosal Resurfacing Elicits Improvement in Glycemic and Hepatic Parameters in Type 2 Diabetes—One-Year Multicenter Study Results (2018): https://diabetesjournals.org/diabetes/article/67/Supplement_1/1137-P/54118/Duodenal-Mucosal-Resurfacing-Elicits-Improvement

When destroying the membrane you're basically clearing the forest, which includes pathogens which may be responsible for diabetes. It's likely that if their method actually clears and replaces it without significant damage (unlike antibiotics) it could help many more conditions than diabetes.

Unfortunate that they didn't seem to test the microbiota of the mucus before and after treatment. If it fully changes the mucus membrane then surely it must have a huge impact on the microbes living there. Maybe most of the microbes will be lost with it, which makes me wonder what microbes will end up in the new membrane and the risks of performing it on a larger part of the intestine than just the duodenum.

Maybe the ultimate end game will be clearing the mucosa in the recipient and using mucosa microbiota from the donor, but for now, maybe whichever one is easier could be a significant improvement on its own compared to standard FMT.

The problem with using Duodenal Mucosal Resurfacing though is that you won't be able to treat most of the small intestine since it relies on using an endoscope. In the article it also said that it took 1 hour to just treat the duodenum, so the feasibility of doing this to the entire small and/or large intestine seems rather low.

Ingesting something that can affect the mucosal layer is probably going to be the easiest method of altering the mucosa if this is important for the success of FMT.
 
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