It looks like Seed’s CEO shared some preliminary findings on YouTube on the DS-01 probiotic’s benefits in recovery post antibiotic use. Specifically, in the recovery of rare species, butyrate producing organisms, and gut permeability. Has your opinion changed in light of these research findings? (See minute 53:00 in the following video https://youtu.be/gAx4XOhXkBQ?feature=shared)
This article is six months too late, sir. 😡 😭 I had pleurisy last October, took antibiotics and ibuprofen (first time in my life) and then some probiotics. I have had a fucked gut since. It got so bad by March that literally every single thing I ate made me ill: heartburn, indigestion, sinusitis, asthma, eczema, etc. I have gone carnivore in desperation. It’s been 6 or 7 weeks now and it fixed most, but not all, of my issues. I was going to do it for three months, but I caved and ate 1/2 raw green pepper today. Been a total nightmare to be honest. 😭
I had c-diff for many months, I lost weight and was down to 76 pounds. I could not eat or drink anything without it coming back out within seconds. I took probiotics daily hoping it would help and was put on antibiotics 4 times because I just couldn’t shake the C-diff. I was losing hope. I finally had a fecal transplant against doctors advice, they all said it wasn’t FDA approved. I was desperate after over 6 months of being very sick, malnourished and dehydrated. Within 2 days after my transplant I felt better and hope restored. It’s been 2 years and I’m still c-diff free and feeling healthy again. I also eat very healthy, no processed foods and eat as much organic as possible.
Unfortunately, it's not quite as simple as that. Ice crystals form during the freezing process and rupture the cell walls of most bacteria, killing them. To make matters worse, as soon as a turd is outside your body, the bacteria in it start dying from oxygen exposure because most of the "good guys" are strict anaerobes. This doesn't just reduce the numbers—it reduces the diversity in an uneven way, so the microbiome in a poop that comes out of your home freezer is going to be very different than the one it contained going in.
There are ways around this; in the lab, we mix a sample with anaerobic glycerin, and then flash-freeze in liquid nitrogen; this minimizes the size of the ice crystals that form (the faster the freeze, the better), and helps more of the bacteria survive. Unfortunately, that's not exactly something your average person can do at home—even if you rigged up a flash-freeze rig with dry ice and everclear, it's damn near impossible to make/maintain an anaerobic glycerin solution—as soon as you pop the stopper, oxygen from the air starts diffusing in. I've heard rumblings of someone starting a company that'll prep and store the material for you properly, the same way some people freeze their eggs, but I haven't looked into it and expect it would be expensive.
First, I don't know emphatic enough words to use for how much I appreciate what you're citing, contextualizing, and sharing. Seriously, thank you. What you've so far shared in your articles has already made a significant and meaningful difference in my life and health, as well as for many people I know.
In this article, you wrote "Eat apples like it’s your job" without further context. I'm guessing this is foreshadowing to a potential future post on apples, and pointing towards health benefits of (especially organic) apples' symbiotic microbiome: https://www.frontiersin.org/articles/10.3389/fmicb.2019.01629/full.
Are there other contexts around apples that make them so important in our diet, or is it better to wait until a future deep dive on the subject?
Seriously, thank you for the kind words. Means a lot to know this stuff resonates with people. I had seen that study, but was not planning a post on apples—that bit of advice was mostly just vibe based. (I mean, you know the saying, right?)
But now that you mentioned it, I think I'll have to write that post. It is a cool study, and nobody else seems to eat the core, which... that's the whole point of the apple, y'know?
Fecal microbiome analysis doesn't say anything about mucosal or luminal microbiome in any other section of the intestine. The fact that fecal analysis doesn't look the same after antibiotics plus probiotics may be true but so what?
https://journals.asm.org/doi/pdf/10.1128/msphere.00126-19 "Spatial and Temporal Analysis of the Stomach and Small-Intestinal Microbiota in Fasted Healthy Humans" See, for example, Figure 1 comparing the highly invasive sampling of different sections of the stomach, duodenum and jejunum vs fecal species of the same human individual.
https://www.nature.com/articles/s41598-022-05936-y "Analysis of colonic mucosa-associated microbiota using endoscopically collected lavage" Most of the figures in this original research paper include a fecal sample compared to different in situ sampling methods. Violin plots clearly show a lack of correlation between fecal vs in situ samples. Humans.
https://www.nature.com/articles/srep45840 "Microbial Biogeography and Core Microbiota of the Rat Digestive Tract" Again, figures showing diversity and species in different sections including comparison to stool. Rats.
It's a fair point that stool microbiome =/= mucosal microbiome, and maybe I shouldn't use fecal microbiome as shorthand for the broader GI tract.
That said, the Suez paper ALSO LOOKED AT THE MUCOSAL MICROBIOME in both humans and animals, and found significant, persistent changes at a variety of sites, so I'm not sure I understand your complaint.
Thanks for pointing more specifically at the paper from Elinav Lab ("Suez paper"). Yes, the analysis included mucosa/lumen sampled via endoscopy/colonoscopy twice with the second at 21 days post-antibiotics. Statements about months after refer only to stool samples.
Several additional points relative to "complaint":
Per Suez paper " While our study is not aimed or powered to assess the effectiveness, or lack thereof, of probiotics in ameliorating post-antibiotics clinical symptoms, we demonstrate that their putative ‘‘placeholder’’ effect may come at a price of significant prolongation of dysbiosis and delayed recolonization of the indigenous microbiome, resulting in altered reversion of the host gut transcriptome toward homeostatic configuration." The "dysbiosis" of this particular paper is (after =|= before) microbiome where "clinical symptoms" dysbiosis couldn't be assessed. Some people regularly suffer clinical symptoms with antibiotics for which probiotics offer some people relief. The "so what" part of qPCR level "dysbiosis" is the complaint with no perspective on clinical relief.
The Suez paper points to significant limitations. "Furthermore, our study was conducted in healthy adults voluntarily consuming antibiotics as part of this trial and was not aimed or powered to assess clinical responses to probiotics. Results may differ in the context of disease and in extreme age groups such as the pediatric population, in which the microbiome configuration has yet to stably mature and stabilize, or the geriatric population, which features other distinct microbiome changes." If you're not healthy, toddler or younger, geriatric, or lack an appendix, they make no claims.
Very importantly, the Suez paper references repeatedly a paired paper with relevance to complaints. The paired paper comes from the same lab and presumably same equipment/analysis software and same authors, but primary author shifted to Zamora. The Zamora paper was spawned from the Suez work when authors noticed bimodal distribution of response in healthy volunteers-- those with permissive guts and those with resistive guts. https://www.cell.com/cell/pdf/S0092-8674(18)31102-4.pdf "Probiotics transiently colonize the human gut mucosa in highly individualized patterns, thereby differentially impacting the indigenous microbiome and host gene-expression profile, a trait which is predictable by baseline host and microbiome features, but not by stool shedding." Basically, YMMV and stool =|= mucosa. Oh, and mice =|= humans.
The Zamora paper was, IMO, an outstanding piece of science. Just from the "simple" comparison between germ-free and normally colonized mice, it is unequivocal that the gut microbiome has an extremely significant effect on health of pretty much all species. It's also become clear that stool doesn't correlate well enough, consistently enough with clinical results (cf. all the failed trials for improving diseases with probiotics). The Zamora paper took the Suez result of bimodal distribution to discover permissive/resistive and a peak at the existence of a path to figure out what makes one permissive/resistive. A foot in the door basically for how one might start to figure out how to medicate/feed to make changes in the microbiome that consistently and predictably lead to clinical improvements. You can "walk" forward in time in the publications of the Elinav lab to see how they've been approaching the investigation here: https://www.weizmann.ac.il/immunology/elinav/publications
Yes, definitely don't use fecal microbiome as shorthand for the broader GI tract. The major science labs learned a huge lesson around 2015 when an analysis was performed that showed lab-to-lab analysis of the same samples produced significantly different results. It also showed that some species can't be distinguished repeatably. Phylum can be reliably determined and some species but not all species. The preliminary result was published in 2017 (note: the Suez,... 2018 and Zamora, ... 2018 papers were originally received in 2016 before being revised/published in 2018). You can see what the microbiome analysis community have been doing to rectify this problem by searching on "Microbiome Quality Control (MBQC) Project". Some original research is being published now including that they follow best practices as recommended by MBQC.
Bringing this back to the point of your post and my complaint, way too much setting of expectations that stool tell you anything about what's happening in the gut or that you can figure out what to do based on analyzing stool. No disagreement about the general recommendations IF one was NORMALLY HEALTHY (w/ appendix) before taking antibiotics. Probably, most of the recommendations are still helpful if one is not.
It takes courage and discipline to write and publish. You have it, I don't. Thanks for putting yourself out there and getting people thinking.
Aw shucks, thanks. It takes above all a willingness to be wrong. Maybe I am painting with too broad a brush, but it's the only one I've got.
I know the Suez paper isn't perfect, and I'm eagerly waiting for someone to replicate its experiments with better techniques or explore how this applies to less-than-healthy populations. If it turns out that, in e.g. people with IBS, the failure to return to baseline is actually a good thing, that'll be interesting to see.
I wish but no. Retired chemical engineer with long term gut problems. Once I grokked the similarity between the intestines and a chemical processing plant I started reading the literature deeply and carefully. Like many, I really wanted the stool to tell us something. The length and complexity of the intestinal processing plant plus the variation of inputs is just too great with the tools and methods available so far. Standard-of-care medicine is at least 20 years behind what ever consensus comes from the science.
I think publications submitted after about 2018 or 2019 who also say something about the MBQC are the start of being able to safely accumulate more accurate results between labs. You can also look for publications that use the reporting guidelines for human microbiome analysis tool https://www.nature.com/articles/s41591-021-01552-x
I would guess all of the authors' of this ^ paper would produce original work more likely to be reproducible. Extra points for those who provide the raw data to anyone interested because, again, more confidence in reproducibility of the work.
You have an engaging and fun writing style. I hope you figure out how to keep translating what the science of poop can tell us about how to live healthier lives.
Succinic acid is also part of the citric acid cycle from which it has epigenetic metabolic benefits. But AKG and malic acid are also part of the citric acid cycle and they are much more commonly supplemented (usually malic acid as magnesium malate and AKG as AAKG). Malic acid is also pretty abundant in fruits: http://www.spektrum.de/lexika/showpopup.php?lexikon_id=9&art_id=25817&nummer=9023 (this source is linked on the malic acid wikipedia). I couldn't find any information about succinic acid dietary sources except for grapes? I also saw someone on reddit mention apple cider vinegar might have some succinic acid, but I couldn't find an analysis of the composition of apple cider vinegar?
I was wondering, though, is there a huge difference in consuming the different citric acid cycle intermediates? If you get a lot of one of them, can you rely on the conversion between them to sort themselves out to escape the citric acid cycle and yield benefits elsewhere?
great question. I said lactic and succinic because those are the two mentioned as viable substrates for oxyrase, which is a commercial preparation of those reducing enzymes used for microbiology work. Totally possible that, with the living organisms, you'd be able to count on them doing the interconversion, but I just can't guarantee it. https://www.oxyrase.com/antioxidant-
Thank you again! Welcome back and congrats on the new position.
Great info...it seems like it boils down to the idea of letting the food do its thing. I think we get into trouble trying to distill it down to the ONE thing that does the trick versus the myriad phytochemicals/nutrients/matrices in the whole food. (Like chewing coca leaves as a stimulant versus processing it into cocaine). Our body seems to know what to do with the food.
I don’t have any symptoms but I did take probiotics post-antibiotics. With the study you mentioned was the only way to tell whether a microbiome didn’t return to baseline post-antibiotics via testing or did the participants experience symptoms?
They didn't report anything AFAIK; if you're feeling fine, for now I'd say leave well enough alone. Remember, there are a zillion kinds of probiotics out there and the findings from that one study don't necessarily apply to all strains/brands/formulations, y'know? it might be that the kind you took doesn't survive stomach acid, or the strains don't have the same recovery-inhibiting effects. Maybe worth going in for a physical to see if things like your cholesterol have changed dramatically since last time.
It looks like Seed’s CEO shared some preliminary findings on YouTube on the DS-01 probiotic’s benefits in recovery post antibiotic use. Specifically, in the recovery of rare species, butyrate producing organisms, and gut permeability. Has your opinion changed in light of these research findings? (See minute 53:00 in the following video https://youtu.be/gAx4XOhXkBQ?feature=shared)
No.
This article is six months too late, sir. 😡 😭 I had pleurisy last October, took antibiotics and ibuprofen (first time in my life) and then some probiotics. I have had a fucked gut since. It got so bad by March that literally every single thing I ate made me ill: heartburn, indigestion, sinusitis, asthma, eczema, etc. I have gone carnivore in desperation. It’s been 6 or 7 weeks now and it fixed most, but not all, of my issues. I was going to do it for three months, but I caved and ate 1/2 raw green pepper today. Been a total nightmare to be honest. 😭
Ah shit man, I'm sorry to hear it. I am also deeply suspicious of most NSAIDs besides aspirin.
If you have a very healthy and understanding friend and you want a protocol for a DIY FMT, just let me know.
I had c-diff for many months, I lost weight and was down to 76 pounds. I could not eat or drink anything without it coming back out within seconds. I took probiotics daily hoping it would help and was put on antibiotics 4 times because I just couldn’t shake the C-diff. I was losing hope. I finally had a fecal transplant against doctors advice, they all said it wasn’t FDA approved. I was desperate after over 6 months of being very sick, malnourished and dehydrated. Within 2 days after my transplant I felt better and hope restored. It’s been 2 years and I’m still c-diff free and feeling healthy again. I also eat very healthy, no processed foods and eat as much organic as possible.
So it seems like, we should keep a frozen sample of our stool before we take antibiotics?
Do you mind sharing your DIY fecal transplant? Thanks!
Unfortunately, it's not quite as simple as that. Ice crystals form during the freezing process and rupture the cell walls of most bacteria, killing them. To make matters worse, as soon as a turd is outside your body, the bacteria in it start dying from oxygen exposure because most of the "good guys" are strict anaerobes. This doesn't just reduce the numbers—it reduces the diversity in an uneven way, so the microbiome in a poop that comes out of your home freezer is going to be very different than the one it contained going in.
There are ways around this; in the lab, we mix a sample with anaerobic glycerin, and then flash-freeze in liquid nitrogen; this minimizes the size of the ice crystals that form (the faster the freeze, the better), and helps more of the bacteria survive. Unfortunately, that's not exactly something your average person can do at home—even if you rigged up a flash-freeze rig with dry ice and everclear, it's damn near impossible to make/maintain an anaerobic glycerin solution—as soon as you pop the stopper, oxygen from the air starts diffusing in. I've heard rumblings of someone starting a company that'll prep and store the material for you properly, the same way some people freeze their eggs, but I haven't looked into it and expect it would be expensive.
Here's the current version of the protocol. https://docs.google.com/document/d/1lma1BUONtoUHxZxy_oJ1sWZASExVDf8f/edit
First, I don't know emphatic enough words to use for how much I appreciate what you're citing, contextualizing, and sharing. Seriously, thank you. What you've so far shared in your articles has already made a significant and meaningful difference in my life and health, as well as for many people I know.
In this article, you wrote "Eat apples like it’s your job" without further context. I'm guessing this is foreshadowing to a potential future post on apples, and pointing towards health benefits of (especially organic) apples' symbiotic microbiome: https://www.frontiersin.org/articles/10.3389/fmicb.2019.01629/full.
Are there other contexts around apples that make them so important in our diet, or is it better to wait until a future deep dive on the subject?
First and foremost, aw shucks.
Seriously, thank you for the kind words. Means a lot to know this stuff resonates with people. I had seen that study, but was not planning a post on apples—that bit of advice was mostly just vibe based. (I mean, you know the saying, right?)
But now that you mentioned it, I think I'll have to write that post. It is a cool study, and nobody else seems to eat the core, which... that's the whole point of the apple, y'know?
Fecal microbiome analysis doesn't say anything about mucosal or luminal microbiome in any other section of the intestine. The fact that fecal analysis doesn't look the same after antibiotics plus probiotics may be true but so what?
https://journals.asm.org/doi/pdf/10.1128/msphere.00126-19 "Spatial and Temporal Analysis of the Stomach and Small-Intestinal Microbiota in Fasted Healthy Humans" See, for example, Figure 1 comparing the highly invasive sampling of different sections of the stomach, duodenum and jejunum vs fecal species of the same human individual.
https://www.nature.com/articles/s41598-022-05936-y "Analysis of colonic mucosa-associated microbiota using endoscopically collected lavage" Most of the figures in this original research paper include a fecal sample compared to different in situ sampling methods. Violin plots clearly show a lack of correlation between fecal vs in situ samples. Humans.
https://www.nature.com/articles/srep45840 "Microbial Biogeography and Core Microbiota of the Rat Digestive Tract" Again, figures showing diversity and species in different sections including comparison to stool. Rats.
https://sarkis.caltech.edu/documents/5030/nrmicro3552.pdf "Gut biogeography of the bacterial
microbiota" An old review but great diagrams and great writing.
It may still be true that using probiotics is or isn't useful/harmful, but fecal analysis neither supports nor negates any possibility.
It's a fair point that stool microbiome =/= mucosal microbiome, and maybe I shouldn't use fecal microbiome as shorthand for the broader GI tract.
That said, the Suez paper ALSO LOOKED AT THE MUCOSAL MICROBIOME in both humans and animals, and found significant, persistent changes at a variety of sites, so I'm not sure I understand your complaint.
Thanks for pointing more specifically at the paper from Elinav Lab ("Suez paper"). Yes, the analysis included mucosa/lumen sampled via endoscopy/colonoscopy twice with the second at 21 days post-antibiotics. Statements about months after refer only to stool samples.
Several additional points relative to "complaint":
Per Suez paper " While our study is not aimed or powered to assess the effectiveness, or lack thereof, of probiotics in ameliorating post-antibiotics clinical symptoms, we demonstrate that their putative ‘‘placeholder’’ effect may come at a price of significant prolongation of dysbiosis and delayed recolonization of the indigenous microbiome, resulting in altered reversion of the host gut transcriptome toward homeostatic configuration." The "dysbiosis" of this particular paper is (after =|= before) microbiome where "clinical symptoms" dysbiosis couldn't be assessed. Some people regularly suffer clinical symptoms with antibiotics for which probiotics offer some people relief. The "so what" part of qPCR level "dysbiosis" is the complaint with no perspective on clinical relief.
The Suez paper points to significant limitations. "Furthermore, our study was conducted in healthy adults voluntarily consuming antibiotics as part of this trial and was not aimed or powered to assess clinical responses to probiotics. Results may differ in the context of disease and in extreme age groups such as the pediatric population, in which the microbiome configuration has yet to stably mature and stabilize, or the geriatric population, which features other distinct microbiome changes." If you're not healthy, toddler or younger, geriatric, or lack an appendix, they make no claims.
Very importantly, the Suez paper references repeatedly a paired paper with relevance to complaints. The paired paper comes from the same lab and presumably same equipment/analysis software and same authors, but primary author shifted to Zamora. The Zamora paper was spawned from the Suez work when authors noticed bimodal distribution of response in healthy volunteers-- those with permissive guts and those with resistive guts. https://www.cell.com/cell/pdf/S0092-8674(18)31102-4.pdf "Probiotics transiently colonize the human gut mucosa in highly individualized patterns, thereby differentially impacting the indigenous microbiome and host gene-expression profile, a trait which is predictable by baseline host and microbiome features, but not by stool shedding." Basically, YMMV and stool =|= mucosa. Oh, and mice =|= humans.
The Zamora paper was, IMO, an outstanding piece of science. Just from the "simple" comparison between germ-free and normally colonized mice, it is unequivocal that the gut microbiome has an extremely significant effect on health of pretty much all species. It's also become clear that stool doesn't correlate well enough, consistently enough with clinical results (cf. all the failed trials for improving diseases with probiotics). The Zamora paper took the Suez result of bimodal distribution to discover permissive/resistive and a peak at the existence of a path to figure out what makes one permissive/resistive. A foot in the door basically for how one might start to figure out how to medicate/feed to make changes in the microbiome that consistently and predictably lead to clinical improvements. You can "walk" forward in time in the publications of the Elinav lab to see how they've been approaching the investigation here: https://www.weizmann.ac.il/immunology/elinav/publications
Yes, definitely don't use fecal microbiome as shorthand for the broader GI tract. The major science labs learned a huge lesson around 2015 when an analysis was performed that showed lab-to-lab analysis of the same samples produced significantly different results. It also showed that some species can't be distinguished repeatably. Phylum can be reliably determined and some species but not all species. The preliminary result was published in 2017 (note: the Suez,... 2018 and Zamora, ... 2018 papers were originally received in 2016 before being revised/published in 2018). You can see what the microbiome analysis community have been doing to rectify this problem by searching on "Microbiome Quality Control (MBQC) Project". Some original research is being published now including that they follow best practices as recommended by MBQC.
Bringing this back to the point of your post and my complaint, way too much setting of expectations that stool tell you anything about what's happening in the gut or that you can figure out what to do based on analyzing stool. No disagreement about the general recommendations IF one was NORMALLY HEALTHY (w/ appendix) before taking antibiotics. Probably, most of the recommendations are still helpful if one is not.
It takes courage and discipline to write and publish. You have it, I don't. Thanks for putting yourself out there and getting people thinking.
Aw shucks, thanks. It takes above all a willingness to be wrong. Maybe I am painting with too broad a brush, but it's the only one I've got.
I know the Suez paper isn't perfect, and I'm eagerly waiting for someone to replicate its experiments with better techniques or explore how this applies to less-than-healthy populations. If it turns out that, in e.g. people with IBS, the failure to return to baseline is actually a good thing, that'll be interesting to see.
I take it you're involved in the field somehow?
I wish but no. Retired chemical engineer with long term gut problems. Once I grokked the similarity between the intestines and a chemical processing plant I started reading the literature deeply and carefully. Like many, I really wanted the stool to tell us something. The length and complexity of the intestinal processing plant plus the variation of inputs is just too great with the tools and methods available so far. Standard-of-care medicine is at least 20 years behind what ever consensus comes from the science.
I think publications submitted after about 2018 or 2019 who also say something about the MBQC are the start of being able to safely accumulate more accurate results between labs. You can also look for publications that use the reporting guidelines for human microbiome analysis tool https://www.nature.com/articles/s41591-021-01552-x
I would guess all of the authors' of this ^ paper would produce original work more likely to be reproducible. Extra points for those who provide the raw data to anyone interested because, again, more confidence in reproducibility of the work.
You have an engaging and fun writing style. I hope you figure out how to keep translating what the science of poop can tell us about how to live healthier lives.
Succinic acid is also part of the citric acid cycle from which it has epigenetic metabolic benefits. But AKG and malic acid are also part of the citric acid cycle and they are much more commonly supplemented (usually malic acid as magnesium malate and AKG as AAKG). Malic acid is also pretty abundant in fruits: http://www.spektrum.de/lexika/showpopup.php?lexikon_id=9&art_id=25817&nummer=9023 (this source is linked on the malic acid wikipedia). I couldn't find any information about succinic acid dietary sources except for grapes? I also saw someone on reddit mention apple cider vinegar might have some succinic acid, but I couldn't find an analysis of the composition of apple cider vinegar?
I was wondering, though, is there a huge difference in consuming the different citric acid cycle intermediates? If you get a lot of one of them, can you rely on the conversion between them to sort themselves out to escape the citric acid cycle and yield benefits elsewhere?
great question. I said lactic and succinic because those are the two mentioned as viable substrates for oxyrase, which is a commercial preparation of those reducing enzymes used for microbiology work. Totally possible that, with the living organisms, you'd be able to count on them doing the interconversion, but I just can't guarantee it. https://www.oxyrase.com/antioxidant-
Thank you again! Welcome back and congrats on the new position.
Great info...it seems like it boils down to the idea of letting the food do its thing. I think we get into trouble trying to distill it down to the ONE thing that does the trick versus the myriad phytochemicals/nutrients/matrices in the whole food. (Like chewing coca leaves as a stimulant versus processing it into cocaine). Our body seems to know what to do with the food.
cheers
Excellent as always. Love a good how-to
Tough one. Is it bad enough that you'd consider pulling out the big guns and doing a home FMT?
I don’t have any symptoms but I did take probiotics post-antibiotics. With the study you mentioned was the only way to tell whether a microbiome didn’t return to baseline post-antibiotics via testing or did the participants experience symptoms?
They didn't report anything AFAIK; if you're feeling fine, for now I'd say leave well enough alone. Remember, there are a zillion kinds of probiotics out there and the findings from that one study don't necessarily apply to all strains/brands/formulations, y'know? it might be that the kind you took doesn't survive stomach acid, or the strains don't have the same recovery-inhibiting effects. Maybe worth going in for a physical to see if things like your cholesterol have changed dramatically since last time.