9 ms·

Scientists discover links between Alzheimer's disease and gut microbiota

300 points by CharlesW 3y ago

wdwvt1 3y ago
Microbiome researcher here. As usual, when a microbiome paper reaches HN, I emerge to urge caution. You should be extremely skeptical of the larger conclusions drawn from this paper. The biology of Alzheimer's disease (AD) is poorly understood, and the contribution of dietary and microbiome factors are extremely unclear. I think you should treat the evidence from this paper (and shared in this thread) as more like "fails to converge" than "I will use this data to update my priors". I want to note, first, that the researchers should be commended on clearly communicating their procedures, crafting a well written paper, and doing some nice experiments (in figure 4 particularly). The main criticisms I have relate to the conclusions drawn, and then echoed in this HN thread. 1. The behavioral analysis was not conducted in a blinded way - the researchers doing the behavioral analyses knew if the rats were AD or non-AD groups. From supplement "The experimenter was blinded to the FMT human donor but not to the rat group." The degree to which rodent behavior reflects human behavior is unclear (I would argue very little) but you should definitely be skeptical of measures with significant subjectivity done without blinding. 2. The paper has many materially important assertions not backed by the data. > However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species A phylum is an extremely diverse group of microbes - the phylum Bacteroidetes contains microbes that likely diverged hundreds of millions of years ago (from their LCA). Claiming that an entire phylum is "pro-inflammatory" is not even wrong. The different Bacteroidetes found in humans can be "pro-inflammatory" or "anti-inflammatory" depending on a truly staggering number of factors (diet, what other microbes are there, host immune status, host epithelial integrity). To claim that it's clear that AD patients have more of a "bad phylum" exemplifies the strong claim X weak evidence of this paper. > ...and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites. Ahh yes, the beneficial metabolites of my favorite Firmicutes - Clostridium botulinum (most toxic metabolite known to man), Clostridium difficile (kills >20,000/year in the US), etc... Again, you can't paint with this broad a brush and have the conclusion mean anything. > Importantly, a positive correlation was observed between the abundance of the health-associated SCFA producer Coprococcus and the MMSE score, and inverse correlations were detected between the abundance of the disease-associated pathobionts Desulfovibrio, Dialister and the MMSE score, supporting a microbiome signature for cognitive performance in Alzheimer’s disease. Desulfovirbio has evidence of potential linkage to AD (a quick google found correlational, but no causal evidence). On the other hand, a quick google showed that other groups disagree about Dialister - Vogt et al 2017 (PMID: 29051531) find that Dialister is reduced in AD patients and the less Dialister you have, the worse your symptoms! Again, claims stronger (and in this willfully ignoring) than evidence. 3. The main data from this paper is generated in a standard fecal transplant experiment. In short, feces from AD patients is given to some rats, and feces from healthy donors (HD) is given to other rats. Figure 2-4 rely on this setup. These are not independent verifications or tests of the hypothesis "Do AD bacteria --> AD?". Any systematic difference between the feces with the AD label and the HD label could be causal for the results the authors see. This is a major confounder in all microbiome work. Behavioral changes associated with AD are going to change food intake and bowel habit, which in turn will substantially change microbial characteristics of the gut. Other than the microbes, there are a huge number of human derived proteins, metabolites, signaling molecules, viruses, etc in the stool. The researchers don't eliminate these, and their data would be consistent with this as an explanation just as much as the microbes. Even the best studies cannot create a design that blocks every confounder, but FMT paradigm suffers from a really large number of them and the authors don't address this. There are some experiments you can do - for example, you could culture the individual microbes you believe to be responsible for the AD pathology, introduce them into rats, and show the _microbe alone_ is enough to cause the disease (this resolves the last confounder cited). The authors don't do this. There are many other considerations in designing FMT experiments that I could quibble with (like why not germ-free animals - that is the standard rather than the microbiota depletion they do), but the main point is: any systematic difference in AD vs HD feces could cause the differences in rat physiology they observe. 4. Figure 2 is an excellent example of a broader phenomenon in microbiome papers: statistically significant results with extremely small effect sizes. Consider 2D-I. The authors show (for instance) that the mean water content of stool differs significantly in their AD- vs. HD-colonized rats. The effect size is maybe ~12%. Everything in 2G-I is smaller than this. Do we think that losing 12% of the water from feces is a part of the physiological cascade that leads to AD? While this could be true (or this could be evidence of some other underlying change being caused by the AD microbes) the effects are extremely small. I think it's much more likely that some other systematic difference in the feces (as outlined in 3) is causal for these small-scale changes seen. This is similar to the data in Figure 3. Consider 3B - the AD microbiota induces a (significant) ~0.23% change in the "discrimination index". What size is that effect? It might be large, but considering there is no comparison to differences in whatever the human equivalent of this index is (if it even exists) I am going to guess it's more on the 'too small to be meaningful' side. > These observations were further corroborated by correlating the clinical human donor profile to the Alzheimer’s behavioral readouts of the recipient rats. They test 50 different metadata correlations, don't correct for multiple hypotheses, and find one correlation at p<0.05 and one at p<0.08. This does not match the tone of that sentence. 5. Quoting from the paper: "Rats colonized with faecal material from Alzheimer’s donors exhibited no change in locomotor parameters in the Open Field Test (Supplementary Fig. 6A), no change in anxiety-related behaviours in the Elevated Plus Maze (EPM) (Supplementary Fig. 6B), or in antidepressant-like behaviour in the Forced Swim test (FST) (Supplementary Fig. 6C), indicating no specific effects of the Alzheimer’s human gut microbiota on comorbid features of Alzheimer’s disease in rats." So clearly whatever the effect of the microbiota is, it's not enough to trigger these measures of pathology. Does that suggest that the microbiota causes only some AD features? If you read their abstract "Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease" they certainly don't qualify the result this way. 6. Figure 4 - there are some nice experiments here. They show differences in neuronal survival conditioned on AD or HD feces. There are microbial metabolites that affect neuronal survival that are certainly not linked to AD causally (e.g. the short chain fatty acids). Evaluate this in the context of point 3 above: the authors show differences in neuronal survival, but whether that is due to changes in AD patients microbiome that are _caused_ by the disease (e.g. they eat weird and get weird microbes that don't make short chain fatty acids) rather than _casual for_ the disease cannot be evaluated from this data. 7. Figure 5 has no evidence of microbial cause. The authors show that serum from AD patients injected into rats caused reduced neurogenesis. As outlined in point 3 above - this could be (and seems much more liekly to be) from any of the human-derived factors floating in the blood. They try to address this by saying "gut microbiota composition explains up to 58% of the variance of individual plasma metabolites" and citing a paper (PMID: 36151114) but this is a very misleading citation. First, the authors of the cited paper corrected that figure to 46%. Second, that figure is for a SINGLE metabolite, not the whole plasma metabolome. Quoting from the cited paper "We detected the largest variance explained (46%) for an uncharacterized common metabolite with the provisional identifier X-11850.". The gut microbiome makes a lot of chemicals, but your body makes many many more. The idea that gut-derived metabolites are the predominant thing in the bloodstream is...not correct. The authors similarly try to suggest with figure 6 that because the AD-transplanted rats show a different plasma metabolome, that means the serum injection experiment points to the microbes. This is not causal evidence, and it isn't a test of what they say it is.
- JPLeRouzic 3y ago
  Many thanks, It's a bit sad that this comment is in the lower half of the thread, while the comments in the higher half are at the same time: clearly uninformed on the topic and still making strong statements.
- simonswords82 3y ago
  Hey thanks for this info, all of which I'm sure is super insightful for people who understand this level of detail. What would you say the average person in the street should eat in terms of supplements, vitamins and food in general to maintain excellent microbiome based on your learnings?
  - ruiisnwn 3y ago
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- wodenokoto 3y ago
  As a micro biome researcher do you think I should be eating more kimchi?
  - ruiisnwn 3y ago
    [flagged]
- azan_ 3y ago
  Thanks for that great write-up. I wonder if there are microbiome studies with actually large effect sizes in diseases which we do not typically associate with infectious factors (e.g. diabetes).
- dekhn 3y ago
  This ex-scientist thanks you for your service
- gsn1234 3y ago
  Thanks for taking the effort to write that up. Comments like yours are what makes reading the HN forum worthwhile for me.
jononomo 3y ago
I would bet that the root of both is diet. A diet that leads to Alzheimers will result in a certain kind of gut microbiota. I would guess that sugar and carbs generally, along with fiber, are the problem.
- Ylpertnodi 3y ago
  There's a lot of athletes and sportspeople that wouldn't mind an extra test to see if the carbs works out: especially as many of them really keep the fat levels down when athleting.
CaffeinatedDev 3y ago
I have a cousin studying the gut microbiome's role in mood, and it seems to play a role. I wonder if there are companies that specialize in creating tailored probiotics to help individuals struggling with mental diseases.
m463 3y ago
It seems like they killed the gut bacteria with antibiotics, then transferred the bacteria from alzheimer's patients, causing symptoms. I wonder if a second gut transplant from non-alzheimer's patients would reverse it?
- aaronheid 3y ago
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- hanniabu 3y ago
  I think that once you start having symptoms that it's too late because the bacteria has already spread outside your gut and at that point it'll be too difficult to put it back in check, it's passed the threshold
Jerry2 3y ago
Do we know which bacteria/microbiota is causing this? Any benefits from taking probiotics?
- suoduandao2 3y ago
  I believe there’s some benefit from boulardi yeast but I don’t know the reference except that it’s part of the bredeson protocol. Smells nice in a cleaning vinegar solution though.
- deleted 3y ago
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- mattdeboard 3y ago
  Do you but I dunno if asking HN for advice on Alzheimer's prevention is the move
- SomewhatLikely 3y ago
  The article mentions: In addition, similar to a previous report using a transgenic mouse model of Alzheimer’s disease,56 the relative abundance of the pathobiont genera Desulfovibrio was significantly increased in Alzheimer’s patients compared to cognitively healthy control subjects
underdeserver 3y ago
Holy crap. We really don't know anything, do we.
cpncrunch 3y ago
If you look at the scatter graphs, it's not terribly impressive. Lots of overlap, and most of the results show no difference. The one that does show a large difference still has a lot of overlap in the scatter graph, and it seems to be some outliers that bring down the mean value. It's kind of an extraordinary claim, which requires extraordinary evidence. This isn't that. What interests me more is why HN users keep posting this study, and voting it to the top of the home page.
- deleted 3y ago
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- dappermanneke 3y ago
  almost everyone on HN is interested in biology and especially biohacking but does not actually realise they have none of the necessary expertise to judge claims coming from that field; the level of discourse on these topics is sometimes worse than what I spot on reddit
  - kridsdale3 3y ago
    Pish Posh! My understanding of C pointers makes me one of the smartest people in the world! Why else would I have cleared the hurdle at $COMPANY during a tremendous bull market! Clearly I can learn any discipline by mucking about for a few afternoons. What is a billion years of natural selection to my towering intellect?
    - renewiltord 3y ago
      Lots of people said this about SpaceX and Tesla. Besides, our towering intellect did destroy millions of years of Small Pox evolution. Turns out some people are smart. Other people who do the same thing are stupid but it isn't a marker.
  - hanniabu 3y ago
    Yes, when a topic you're intimately familiar with comes up, it's unbearable reading the comments. Worst part is when you try to set the record straight and wind up with -5 votes and a dead comment within minutes.
rkhassen9 3y ago
I wonder if simply taking antibiotics at some point, clearing everything out and repopulating the flora could help? My guess is no - that something in the system is triggered by the fecal transplant but that gut flora isn't the main source, but it would be an interesting thing to look at. I'm not in this field and do not know how to mine this data or properly posit the question, but maybe something along the lines of: "How many people who have taken a strong antibiotic in the last 10 years get alzheimer's vs people who have not taken any antibiotics?" Seems like this data should be out there, right? Maybe someone who works with this kind of data or research can weigh in. Can you imagine if the cure is that simple? Just take strong antibiotics at an early stage....!?!
- tomjakubowski 3y ago
  N=1. I had various digestion problems, probably due to gut flora imbalances. After several years of trying to fix the problem with diet changes suggested by my doctor (more fiber), I traveled abroad and came home with a very nasty food borne illness. After one Z-pack and several days of being "backed up", my gut was suddenly back to normal and has been fine since.
  - criddell 3y ago
    Rebooting fixes so many problems.
    - DANmode 3y ago
      Just don't reboot every year, or multiple times per year. You can cause worse issues than you started with!
  - keyle 3y ago
    Can you explain Z pack and backed up?
    - vvilliamperez 3y ago
      "Z-pak" is a dosage of the antibiotic Zithromax, or Azithromycin, taken as a "pack" of pills over the course of 5 or more days. I'm guessing backed up means constipated
cmpalmer52 3y ago
Are shady fecal transplant clinics a thing yet? Take these antibiotics for a week, then we’ll hose fecal matter from healthy, young, thin people into your intestines like a reverse enema. Move over sperm banks and blood banks, the poop bank is much easier. Only sorta joking.
- deleted 3y ago
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- kridsdale3 3y ago
  This was an entire episode of South Park last year.
- hanniabu 3y ago
  The process hasn't been perfected and is still pretty risky even at official places
- theGnuMe 3y ago
  You should apply to YC.
rkhassen9 3y ago
Does anyone know if there is correlative data showing lower incidents of Alzheimer's among people who've had a GI reboot with antibiotics? or how to find it?
mwigdahl 3y ago
... in rats.
jmcgough 3y ago
As someone who used to research neurogenesis in rats - there isn't great evidence that adult mammalian neurogenesis occurs in humans, so don't assume that this will translate to humans.
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- dereify 3y ago
  i was under the impression that DG adult neurogenesis was pretty much settled? is there any controversy abt this?
beef234 3y ago
Analysis of gut microbiota composition by bacterial 16S rRNA gene sequencing in a subset of Alzheimer’s patients (Supplementary Fig. 1A–E) revealed no significant change in alpha and beta diversities between control subjects and Alzheimer’s patients (Supplementary Fig. 1B–D). However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species,53 and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites.54 At the genus level, Alzheimer’s patients had on average a significant reduction in the relative abundance of Clostridium sensu stricto 1 and the short chain fatty acid (SCFA) butyrate-producing genera Coprococcus, which is associated with healthy ageing in general55 (Fig. 1C). In addition, similar to a previous report using a transgenic mouse model of Alzheimer’s disease,56 the relative abundance of the pathobiont genera Desulfovibrio was significantly increased in Alzheimer’s patients compared to cognitively healthy control subjects
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armatav 3y ago
It would be cool if you could create technology to diff a donor microbiota to a recipient microbiota in humans and check the causality.
mbrochh 3y ago
The keto community already knows that Alzheimers is a metabolic disease. Don't eat carbs, have an active livestyle = don't become insulin resistant and you won't get Alzheimers. In the meantime I'll just keep watching how long researchers are going to dance around the bush until they finally get it...
mobilejdral 3y ago
I had to triple check the date because I was pretty sure that this was known before. Maybe it is simply the confirmation aspect of it? Edit: > Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, *confirming a causal role* of gut microbiota in Alzheimer’s disease ... From: https://faculty.sites.uci.edu/kimgreen/bio/glucocorticoids-and-alzheimers-disease/ https://faculty.sites.uci.edu/kimgreen/bio/glucocorticoids-a... Citing many papers > One early event in AD is an increase in circulating glucocorticoids You could sum up Alzheimer's as: Diet/Lifestyle + a congenital form of Cushing's syndrome and you have increasing glucocorticoids which imply downregulation of the PVN, less progesterone and low levels of Prolactin reducing oligodendrocyte reducing myelin sheaths. Add in APOE e4 without choline in the diet and you have accumulation of lipids to round it all out. There is a reason why Omega 3 + B+D vitamins are talked about as preventative as they all reduce inflamation. See this for example: https://www.grassrootshealth.net/two-nutrients-proven-stop-brain-shrinking/ https://www.grassrootshealth.net/two-nutrients-proven-stop-b... Edit2: For the curious here is a larger brain dump on the topic with many more links when I had to untangle the pathway earlier this year while working on something else. https://www.reddit.com/r/DrWillPowers/comments/16ae4zy/alzheimers_and_meyerpowers_syndrome/ https://www.reddit.com/r/DrWillPowers/comments/16ae4zy/alzhe...
- Beestie 3y ago
  Japan researchers have know about this for years. I don't know if Japan makes a big deal about publishing their findings but I watched a documentary several years ago which that went into very specific detail about the relationship between specific gut bacteria and Alzheimers. No disrespect to King's College - perhaps there is no overlap but this is more of an advancement than it is a breakthrough.
- pajep 3y ago
  For those that are curious and not well verse in research level biology, what kind of food, drink and lifestyle will help maintain a gut biome that prevent Alzheimer
  - chiefalchemist 3y ago
thenerdhead 3y ago
> For the first time, researchers have found that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming its role in the disease. I just read “I Contain Multitudes” by Ed Yong where this topic was unsure as there’s only a handful confirmed links to things like depression, obesity, etc. Now it is confirmed for Alzheimer’s. This is extraordinary.
- stevenwoo 3y ago
  It's an interesting avenue, though a problem is that updates and interviews with Ed Yong post book appear to show they could only treat one thing - c diff effectively with fecal transplants and that is apparently temporary, with recent studies show it lasting possibly a year before another transplant is necessary, and that probiotics via food like yogurt/kefir cultures only last as long as you eat the food regularly, there is no way (yet) to permanently fix a broken (as in the same as someone who had regular, non highly processed diet for baseline versus people who had switched from their pre highly processed diet to the highly processed modern diet) microbiome. Here's his Fresh Air interview, https://www.npr.org/2016/08/18/490432969/eating-yogurt-is-not-enough-rebalancing-the-ecosystem-of-the-microbes-within-us https://www.npr.org/2016/08/18/490432969/eating-yogurt-is-no... but he's written a lot of stuff since then, too, for the Atlantic.
  - thenerdhead 3y ago
    Great interview! This summarizes the book well: > The microbiome is not a panacea for our health problems. It doesn't explain them all in their entirety. I think it just shows how important microbes are in our lives and what a strong influence they have. I'm optimistic. With the current AI wave and being able to process datasets once impossible to do, we can at least come up with findings (that we may not understand) but may help us to understand these diseases and life conditions through the lens of trillions of microbes.
  - WanderPanda 3y ago
    I know nothing about this but to me „highly processed“ seems like such a broad term that it seems unlikely that every form of processing is bad. Would be great if we could instead enumerated the handful worst offenders which would make it easier for people to see the causal relationship and adapt their behavior in a more fine-grained way
ChuckMcM 3y ago
I certainly hope they are going to replicate while knocking out one species of gut biota each time. Would be super helpful right? Edit: Experiemental design we establish indvidual colonies of each of the biota detected in our earlier work, we then recombine them in the ratios found in the original work and replicate the previous results. We then creation combinations lacking a single organism from our mix and look for replication. Finally we vary the percentages of the biota in our origianal mix and look to see if that affects our ability to replicate.
- garba_dlm 3y ago
  except our bodies already kinda do that on their own how would killing species of gut biota would helpful? helpful for whom to accomplish what?? we're headed to a future in which you have to take special pills so that the food doesn't kill you. like the glysophate and GMOs but applied against ALL life, including humans. if this is too far fetched for you then I also hope we don't get there.
  - lelanthran 3y ago
    > except our bodies already kinda do that on their own > how would killing species of gut biota would helpful? helpful for whom to accomplish what?? OP wasn't talking about practical uses, he was talking about further experimentation in which the researchers narrow down exactly which gut bacteria has the effect. Something like a binary search, or a git bisect.
    - acka 3y ago
      > git bisect please forgive me for reading this as 'gut bisect' the first time around :)
    - ChuckMcM 3y ago
      insert this.gif :-). One of the things that would be interesting would be to understand if a specific kind of bacteria in the gut was the cause or if it was a ratio of some sort. One could imagine an easy to use diagnostic test[1] that could help inform you if you needed to do something or not. If this causality pans out (and it would if it was replicated several times) then this would go a long way to helping people figure out if they needed to do something to avoid "early onset Alzheimers" or even Alzheimers in general. An acquaintance had a fecal transplant (yeah it sounds yucky but it isn't really) which consisted of a course of broad spectrum anti-biotics followed by the introduction of a "non-Cdiff gut biome". It "cured" their issue completely and it hasn't returned. [1] When the Microbiome project was a thing I submitted mine. The fecal test was pretty easy (if 'yucky' from a poopy sort of way).
dang 3y ago
Related, although it looks like different work: Link between Alzheimer's disease and gut microbiota is confirmed (2020) - https://news.ycombinator.com/item?id=35202457 https://news.ycombinator.com/item?id=35202457 - March 2023 (19 comments)
Eumenes 3y ago
does this mean anal sex could theoretically transmit Alzheimer's?
- Llamamoe 3y ago
  Extremely unlikely and you'd have to be doing a threesome+. Gut bacteria are present throughout the entire digestive tract, and you can't really reach very far into the anus no matter what you've got.
- NeuroCoder 3y ago
  It really depends on what you mean by that. In terms of this article, the gut biome would have to be changed by that. There are definitely different things people do in preparation for anal sex that could change that environment but I'm not sure how much anal sex itself actually changes that. This doesn't account for STDs that have been known to involve the nervous system for a long time already.
- nonameiguess 3y ago
  [flagged]
adamredwoods 3y ago
Original published: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad303/7308687 https://academic.oup.com/brain/advance-article/doi/10.1093/b...
- cpncrunch 3y ago
  Doesn't look very impressive. Lots of overlap in the scatter graphs, and no mention of whether they corrected for multiple comparisons. Overall it looks like the typical breathless press release clickbait that HN users seem to constantly post here.
  - azan_ 3y ago
    They did correct for multiple testing - "P-values were multiple-test corrected using the Benjamini-Hochberg False Discovery Rate (FDR) procedure and a cutoff of 0.1 was applied to select the differentially abundant genera". However, they used Wilcoxon test which has unacceptably high FDR [1]. [1] https://www.nature.com/articles/s41467-022-28034-z https://www.nature.com/articles/s41467-022-28034-z
kraig911 3y ago
The vagus never is the super highway of the brain it appears. I also feel our parasympathetic nervous system is vastly understudied.
tiahura 3y ago
I thought it was gum disease? Or was it herpes?
- Llamamoe 3y ago
  It's all of those things. Infectious disease increasingly seem to be behind or involved in most neurodegenerative, neurodevelopmental, chronic fatigue, severe psychiatric disorders. Herpesviral reactivation specifically seems to be involved in everything a little, but my hunch is that this is often secondary to other immune system burden.
m15i 3y ago
how does antibiotic medication affect our gut microbiota generally, and our alzheimer’s disease risk specifically?
- XorNot 3y ago
  This is asking the wrong question: for example, there are antibiotics you are prescribed for IBS because generally they tend to have a balancing effect on the gut microbiome. I've done a course every year or two when things get unmanageable, since it's a good reset. In this context, a treatment which reduced risk would likely be a combination of antibiotics and probiotics to try and shift the biome to a different one.
  - Llamamoe 3y ago
    This is antibiotic marketing bs. There are antibiotic that harm pathogenic or prone-to-overgrowth bacteria harder than others, but they ALL lead to a state of dysbiosis and susceptibility to subsequent colonization/overgrowth/dysregulation And this is the exact reason whymost of the time, GI problems come back or are replaced with different symptoms after antibiotics, and why we need more Fecal Microbiota Transplant research.
    - XorNot 3y ago
      No, it isn't. The whole point of antibiotics for IBS treatment is that you already have an overgrowth, and you want to disrupt that and level the playing field. This is literally the reason I've been on short course antibiotics (<1 week or a single 4 tab dose) at different points, because it eliminates the constant bloating and gives probiotics a chance to work.
      - Llamamoe 3y ago
        The exact reason why overgrowth happens is because an opportunistic strain takes advantage of a dysbiotic state - even if you suppress it with antibiotics, your gut still lacks the robustness of composition necessary to be resilient. In fact, no antibiotic is selective enough to not impoverish your microbiome. Probiotics might help, but a few or a few dozen non-gut-sourced strains simply cannot compare to the hundreds present in healthy stool. The effects on microbiota-dependent conditions are often weak to none.

300 points by CharlesW 3y ago

Microbiome researcher here. As usual, when a microbiome paper reaches HN, I emerge to urge caution. You should be extremely skeptical of the larger conclusions drawn from this paper. The biology of Alzheimer's disease (AD) is poorly understood, and the contribution of dietary and microbiome factors are extremely unclear. I think you should treat the evidence from this paper (and shared in this thread) as more like "fails to converge" than "I will use this data to update my priors". I want to note, first, that the researchers should be commended on clearly communicating their procedures, crafting a well written paper, and doing some nice experiments (in figure 4 particularly). The main criticisms I have relate to the conclusions drawn, and then echoed in this HN thread. 1. The behavioral analysis was not conducted in a blinded way - the researchers doing the behavioral analyses knew if the rats were AD or non-AD groups. From supplement "The experimenter was blinded to the FMT human donor but not to the rat group." The degree to which rodent behavior reflects human behavior is unclear (I would argue very little) but you should definitely be skeptical of measures with significant subjectivity done without blinding. 2. The paper has many materially important assertions not backed by the data. > However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species A phylum is an extremely diverse group of microbes - the phylum Bacteroidetes contains microbes that likely diverged hundreds of millions of years ago (from their LCA). Claiming that an entire phylum is "pro-inflammatory" is not even wrong. The different Bacteroidetes found in humans can be "pro-inflammatory" or "anti-inflammatory" depending on a truly staggering number of factors (diet, what other microbes are there, host immune status, host epithelial integrity). To claim that it's clear that AD patients have more of a "bad phylum" exemplifies the strong claim X weak evidence of this paper. > ...and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites. Ahh yes, the beneficial metabolites of my favorite Firmicutes - Clostridium botulinum (most toxic metabolite known to man), Clostridium difficile (kills >20,000/year in the US), etc... Again, you can't paint with this broad a brush and have the conclusion mean anything. > Importantly, a positive correlation was observed between the abundance of the health-associated SCFA producer Coprococcus and the MMSE score, and inverse correlations were detected between the abundance of the disease-associated pathobionts Desulfovibrio, Dialister and the MMSE score, supporting a microbiome signature for cognitive performance in Alzheimer’s disease. Desulfovirbio has evidence of potential linkage to AD (a quick google found correlational, but no causal evidence). On the other hand, a quick google showed that other groups disagree about Dialister - Vogt et al 2017 (PMID: 29051531) find that Dialister is reduced in AD patients and the less Dialister you have, the worse your symptoms! Again, claims stronger (and in this willfully ignoring) than evidence. 3. The main data from this paper is generated in a standard fecal transplant experiment. In short, feces from AD patients is given to some rats, and feces from healthy donors (HD) is given to other rats. Figure 2-4 rely on this setup. These are not independent verifications or tests of the hypothesis "Do AD bacteria --> AD?". Any systematic difference between the feces with the AD label and the HD label could be causal for the results the authors see. This is a major confounder in all microbiome work. Behavioral changes associated with AD are going to change food intake and bowel habit, which in turn will substantially change microbial characteristics of the gut. Other than the microbes, there are a huge number of human derived proteins, metabolites, signaling molecules, viruses, etc in the stool. The researchers don't eliminate these, and their data would be consistent with this as an explanation just as much as the microbes. Even the best studies cannot create a design that blocks every confounder, but FMT paradigm suffers from a really large number of them and the authors don't address this. There are some experiments you can do - for example, you could culture the individual microbes you believe to be responsible for the AD pathology, introduce them into rats, and show the _microbe alone_ is enough to cause the disease (this resolves the last confounder cited). The authors don't do this. There are many other considerations in designing FMT experiments that I could quibble with (like why not germ-free animals - that is the standard rather than the microbiota depletion they do), but the main point is: any systematic difference in AD vs HD feces could cause the differences in rat physiology they observe. 4. Figure 2 is an excellent example of a broader phenomenon in microbiome papers: statistically significant results with extremely small effect sizes. Consider 2D-I. The authors show (for instance) that the mean water content of stool differs significantly in their AD- vs. HD-colonized rats. The effect size is maybe ~12%. Everything in 2G-I is smaller than this. Do we think that losing 12% of the water from feces is a part of the physiological cascade that leads to AD? While this could be true (or this could be evidence of some other underlying change being caused by the AD microbes) the effects are extremely small. I think it's much more likely that some other systematic difference in the feces (as outlined in 3) is causal for these small-scale changes seen. This is similar to the data in Figure 3. Consider 3B - the AD microbiota induces a (significant) ~0.23% change in the "discrimination index". What size is that effect? It might be large, but considering there is no comparison to differences in whatever the human equivalent of this index is (if it even exists) I am going to guess it's more on the 'too small to be meaningful' side. > These observations were further corroborated by correlating the clinical human donor profile to the Alzheimer’s behavioral readouts of the recipient rats. They test 50 different metadata correlations, don't correct for multiple hypotheses, and find one correlation at p<0.05 and one at p<0.08. This does not match the tone of that sentence. 5. Quoting from the paper: "Rats colonized with faecal material from Alzheimer’s donors exhibited no change in locomotor parameters in the Open Field Test (Supplementary Fig. 6A), no change in anxiety-related behaviours in the Elevated Plus Maze (EPM) (Supplementary Fig. 6B), or in antidepressant-like behaviour in the Forced Swim test (FST) (Supplementary Fig. 6C), indicating no specific effects of the Alzheimer’s human gut microbiota on comorbid features of Alzheimer’s disease in rats." So clearly whatever the effect of the microbiota is, it's not enough to trigger these measures of pathology. Does that suggest that the microbiota causes only some AD features? If you read their abstract "Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease" they certainly don't qualify the result this way. 6. Figure 4 - there are some nice experiments here. They show differences in neuronal survival conditioned on AD or HD feces. There are microbial metabolites that affect neuronal survival that are certainly not linked to AD causally (e.g. the short chain fatty acids). Evaluate this in the context of point 3 above: the authors show differences in neuronal survival, but whether that is due to changes in AD patients microbiome that are _caused_ by the disease (e.g. they eat weird and get weird microbes that don't make short chain fatty acids) rather than _casual for_ the disease cannot be evaluated from this data. 7. Figure 5 has no evidence of microbial cause. The authors show that serum from AD patients injected into rats caused reduced neurogenesis. As outlined in point 3 above - this could be (and seems much more liekly to be) from any of the human-derived factors floating in the blood. They try to address this by saying "gut microbiota composition explains up to 58% of the variance of individual plasma metabolites" and citing a paper (PMID: 36151114) but this is a very misleading citation. First, the authors of the cited paper corrected that figure to 46%. Second, that figure is for a SINGLE metabolite, not the whole plasma metabolome. Quoting from the cited paper "We detected the largest variance explained (46%) for an uncharacterized common metabolite with the provisional identifier X-11850.". The gut microbiome makes a lot of chemicals, but your body makes many many more. The idea that gut-derived metabolites are the predominant thing in the bloodstream is...not correct. The authors similarly try to suggest with figure 6 that because the AD-transplanted rats show a different plasma metabolome, that means the serum injection experiment points to the microbes. This is not causal evidence, and it isn't a test of what they say it is.

JPLeRouzic 3y ago
Many thanks, It's a bit sad that this comment is in the lower half of the thread, while the comments in the higher half are at the same time: clearly uninformed on the topic and still making strong statements.
simonswords82 3y ago
Hey thanks for this info, all of which I'm sure is super insightful for people who understand this level of detail. What would you say the average person in the street should eat in terms of supplements, vitamins and food in general to maintain excellent microbiome based on your learnings?
- ruiisnwn 3y ago
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wodenokoto 3y ago
As a micro biome researcher do you think I should be eating more kimchi?
- ruiisnwn 3y ago
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azan_ 3y ago
Thanks for that great write-up. I wonder if there are microbiome studies with actually large effect sizes in diseases which we do not typically associate with infectious factors (e.g. diabetes).
dekhn 3y ago
This ex-scientist thanks you for your service
gsn1234 3y ago
Thanks for taking the effort to write that up. Comments like yours are what makes reading the HN forum worthwhile for me.

jononomo 3y ago

I would bet that the root of both is diet. A diet that leads to Alzheimers will result in a certain kind of gut microbiota. I would guess that sugar and carbs generally, along with fiber, are the problem.

Ylpertnodi 3y ago
There's a lot of athletes and sportspeople that wouldn't mind an extra test to see if the carbs works out: especially as many of them really keep the fat levels down when athleting.

CaffeinatedDev 3y ago

I have a cousin studying the gut microbiome's role in mood, and it seems to play a role. I wonder if there are companies that specialize in creating tailored probiotics to help individuals struggling with mental diseases.

m463 3y ago

It seems like they killed the gut bacteria with antibiotics, then transferred the bacteria from alzheimer's patients, causing symptoms. I wonder if a second gut transplant from non-alzheimer's patients would reverse it?

aaronheid 3y ago
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hanniabu 3y ago
I think that once you start having symptoms that it's too late because the bacteria has already spread outside your gut and at that point it'll be too difficult to put it back in check, it's passed the threshold

Jerry2 3y ago

Do we know which bacteria/microbiota is causing this? Any benefits from taking probiotics?

suoduandao2 3y ago
I believe there’s some benefit from boulardi yeast but I don’t know the reference except that it’s part of the bredeson protocol. Smells nice in a cleaning vinegar solution though.
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mattdeboard 3y ago
Do you but I dunno if asking HN for advice on Alzheimer's prevention is the move
SomewhatLikely 3y ago
The article mentions: In addition, similar to a previous report using a transgenic mouse model of Alzheimer’s disease,56 the relative abundance of the pathobiont genera Desulfovibrio was significantly increased in Alzheimer’s patients compared to cognitively healthy control subjects

underdeserver 3y ago

Holy crap. We really don't know anything, do we.

cpncrunch 3y ago

If you look at the scatter graphs, it's not terribly impressive. Lots of overlap, and most of the results show no difference. The one that does show a large difference still has a lot of overlap in the scatter graph, and it seems to be some outliers that bring down the mean value. It's kind of an extraordinary claim, which requires extraordinary evidence. This isn't that. What interests me more is why HN users keep posting this study, and voting it to the top of the home page.

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dappermanneke 3y ago
almost everyone on HN is interested in biology and especially biohacking but does not actually realise they have none of the necessary expertise to judge claims coming from that field; the level of discourse on these topics is sometimes worse than what I spot on reddit
- kridsdale3 3y ago
  Pish Posh! My understanding of C pointers makes me one of the smartest people in the world! Why else would I have cleared the hurdle at $COMPANY during a tremendous bull market! Clearly I can learn any discipline by mucking about for a few afternoons. What is a billion years of natural selection to my towering intellect?
  - renewiltord 3y ago
    Lots of people said this about SpaceX and Tesla. Besides, our towering intellect did destroy millions of years of Small Pox evolution. Turns out some people are smart. Other people who do the same thing are stupid but it isn't a marker.
- hanniabu 3y ago
  Yes, when a topic you're intimately familiar with comes up, it's unbearable reading the comments. Worst part is when you try to set the record straight and wind up with -5 votes and a dead comment within minutes.

rkhassen9 3y ago

I wonder if simply taking antibiotics at some point, clearing everything out and repopulating the flora could help? My guess is no - that something in the system is triggered by the fecal transplant but that gut flora isn't the main source, but it would be an interesting thing to look at. I'm not in this field and do not know how to mine this data or properly posit the question, but maybe something along the lines of: "How many people who have taken a strong antibiotic in the last 10 years get alzheimer's vs people who have not taken any antibiotics?" Seems like this data should be out there, right? Maybe someone who works with this kind of data or research can weigh in. Can you imagine if the cure is that simple? Just take strong antibiotics at an early stage....!?!

tomjakubowski 3y ago
N=1. I had various digestion problems, probably due to gut flora imbalances. After several years of trying to fix the problem with diet changes suggested by my doctor (more fiber), I traveled abroad and came home with a very nasty food borne illness. After one Z-pack and several days of being "backed up", my gut was suddenly back to normal and has been fine since.
- criddell 3y ago
  Rebooting fixes so many problems.
  - DANmode 3y ago
    Just don't reboot every year, or multiple times per year. You can cause worse issues than you started with!
- keyle 3y ago
  Can you explain Z pack and backed up?
  - vvilliamperez 3y ago
    "Z-pak" is a dosage of the antibiotic Zithromax, or Azithromycin, taken as a "pack" of pills over the course of 5 or more days. I'm guessing backed up means constipated

cmpalmer52 3y ago

Are shady fecal transplant clinics a thing yet? Take these antibiotics for a week, then we’ll hose fecal matter from healthy, young, thin people into your intestines like a reverse enema. Move over sperm banks and blood banks, the poop bank is much easier. Only sorta joking.

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kridsdale3 3y ago
This was an entire episode of South Park last year.
hanniabu 3y ago
The process hasn't been perfected and is still pretty risky even at official places
theGnuMe 3y ago
You should apply to YC.

rkhassen9 3y ago

Does anyone know if there is correlative data showing lower incidents of Alzheimer's among people who've had a GI reboot with antibiotics? or how to find it?

mwigdahl 3y ago

... in rats.

jmcgough 3y ago

As someone who used to research neurogenesis in rats - there isn't great evidence that adult mammalian neurogenesis occurs in humans, so don't assume that this will translate to humans.

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dereify 3y ago
i was under the impression that DG adult neurogenesis was pretty much settled? is there any controversy abt this?

beef234 3y ago

Analysis of gut microbiota composition by bacterial 16S rRNA gene sequencing in a subset of Alzheimer’s patients (Supplementary Fig. 1A–E) revealed no significant change in alpha and beta diversities between control subjects and Alzheimer’s patients (Supplementary Fig. 1B–D). However, at phylum level, Alzheimer’s patients had a higher abundance of Bacteroidetes (Fig. 1C) reported to comprise many pro-inflammatory species,53 and a lower abundance of the phyla Firmicutes and Verruocomicrobiota, reported to produce beneficial metabolites.54 At the genus level, Alzheimer’s patients had on average a significant reduction in the relative abundance of Clostridium sensu stricto 1 and the short chain fatty acid (SCFA) butyrate-producing genera Coprococcus, which is associated with healthy ageing in general55 (Fig. 1C). In addition, similar to a previous report using a transgenic mouse model of Alzheimer’s disease,56 the relative abundance of the pathobiont genera Desulfovibrio was significantly increased in Alzheimer’s patients compared to cognitively healthy control subjects

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armatav 3y ago

It would be cool if you could create technology to diff a donor microbiota to a recipient microbiota in humans and check the causality.

mbrochh 3y ago

The keto community already knows that Alzheimers is a metabolic disease. Don't eat carbs, have an active livestyle = don't become insulin resistant and you won't get Alzheimers. In the meantime I'll just keep watching how long researchers are going to dance around the bush until they finally get it...

mobilejdral 3y ago

I had to triple check the date because I was pretty sure that this was known before. Maybe it is simply the confirmation aspect of it? Edit: > Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, *confirming a causal role* of gut microbiota in Alzheimer’s disease ... From: https://faculty.sites.uci.edu/kimgreen/bio/glucocorticoids-and-alzheimers-disease/ https://faculty.sites.uci.edu/kimgreen/bio/glucocorticoids-a... Citing many papers > One early event in AD is an increase in circulating glucocorticoids You could sum up Alzheimer's as: Diet/Lifestyle + a congenital form of Cushing's syndrome and you have increasing glucocorticoids which imply downregulation of the PVN, less progesterone and low levels of Prolactin reducing oligodendrocyte reducing myelin sheaths. Add in APOE e4 without choline in the diet and you have accumulation of lipids to round it all out. There is a reason why Omega 3 + B+D vitamins are talked about as preventative as they all reduce inflamation. See this for example: https://www.grassrootshealth.net/two-nutrients-proven-stop-brain-shrinking/ https://www.grassrootshealth.net/two-nutrients-proven-stop-b... Edit2: For the curious here is a larger brain dump on the topic with many more links when I had to untangle the pathway earlier this year while working on something else. https://www.reddit.com/r/DrWillPowers/comments/16ae4zy/alzheimers_and_meyerpowers_syndrome/ https://www.reddit.com/r/DrWillPowers/comments/16ae4zy/alzhe...

Beestie 3y ago
Japan researchers have know about this for years. I don't know if Japan makes a big deal about publishing their findings but I watched a documentary several years ago which that went into very specific detail about the relationship between specific gut bacteria and Alzheimers. No disrespect to King's College - perhaps there is no overlap but this is more of an advancement than it is a breakthrough.
pajep 3y ago
For those that are curious and not well verse in research level biology, what kind of food, drink and lifestyle will help maintain a gut biome that prevent Alzheimer
- chiefalchemist 3y ago

thenerdhead 3y ago

> For the first time, researchers have found that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming its role in the disease. I just read “I Contain Multitudes” by Ed Yong where this topic was unsure as there’s only a handful confirmed links to things like depression, obesity, etc. Now it is confirmed for Alzheimer’s. This is extraordinary.

stevenwoo 3y ago
It's an interesting avenue, though a problem is that updates and interviews with Ed Yong post book appear to show they could only treat one thing - c diff effectively with fecal transplants and that is apparently temporary, with recent studies show it lasting possibly a year before another transplant is necessary, and that probiotics via food like yogurt/kefir cultures only last as long as you eat the food regularly, there is no way (yet) to permanently fix a broken (as in the same as someone who had regular, non highly processed diet for baseline versus people who had switched from their pre highly processed diet to the highly processed modern diet) microbiome. Here's his Fresh Air interview, https://www.npr.org/2016/08/18/490432969/eating-yogurt-is-not-enough-rebalancing-the-ecosystem-of-the-microbes-within-us https://www.npr.org/2016/08/18/490432969/eating-yogurt-is-no... but he's written a lot of stuff since then, too, for the Atlantic.
- thenerdhead 3y ago
  Great interview! This summarizes the book well: > The microbiome is not a panacea for our health problems. It doesn't explain them all in their entirety. I think it just shows how important microbes are in our lives and what a strong influence they have. I'm optimistic. With the current AI wave and being able to process datasets once impossible to do, we can at least come up with findings (that we may not understand) but may help us to understand these diseases and life conditions through the lens of trillions of microbes.
- WanderPanda 3y ago
  I know nothing about this but to me „highly processed“ seems like such a broad term that it seems unlikely that every form of processing is bad. Would be great if we could instead enumerated the handful worst offenders which would make it easier for people to see the causal relationship and adapt their behavior in a more fine-grained way

ChuckMcM 3y ago

I certainly hope they are going to replicate while knocking out one species of gut biota each time. Would be super helpful right? Edit: Experiemental design we establish indvidual colonies of each of the biota detected in our earlier work, we then recombine them in the ratios found in the original work and replicate the previous results. We then creation combinations lacking a single organism from our mix and look for replication. Finally we vary the percentages of the biota in our origianal mix and look to see if that affects our ability to replicate.

garba_dlm 3y ago
except our bodies already kinda do that on their own how would killing species of gut biota would helpful? helpful for whom to accomplish what?? we're headed to a future in which you have to take special pills so that the food doesn't kill you. like the glysophate and GMOs but applied against ALL life, including humans. if this is too far fetched for you then I also hope we don't get there.
- lelanthran 3y ago
  > except our bodies already kinda do that on their own > how would killing species of gut biota would helpful? helpful for whom to accomplish what?? OP wasn't talking about practical uses, he was talking about further experimentation in which the researchers narrow down exactly which gut bacteria has the effect. Something like a binary search, or a git bisect.
  - acka 3y ago
    > git bisect please forgive me for reading this as 'gut bisect' the first time around :)
  - ChuckMcM 3y ago
    insert this.gif :-). One of the things that would be interesting would be to understand if a specific kind of bacteria in the gut was the cause or if it was a ratio of some sort. One could imagine an easy to use diagnostic test[1] that could help inform you if you needed to do something or not. If this causality pans out (and it would if it was replicated several times) then this would go a long way to helping people figure out if they needed to do something to avoid "early onset Alzheimers" or even Alzheimers in general. An acquaintance had a fecal transplant (yeah it sounds yucky but it isn't really) which consisted of a course of broad spectrum anti-biotics followed by the introduction of a "non-Cdiff gut biome". It "cured" their issue completely and it hasn't returned. [1] When the Microbiome project was a thing I submitted mine. The fecal test was pretty easy (if 'yucky' from a poopy sort of way).

dang 3y ago

Related, although it looks like different work: Link between Alzheimer's disease and gut microbiota is confirmed (2020) - https://news.ycombinator.com/item?id=35202457 https://news.ycombinator.com/item?id=35202457 - March 2023 (19 comments)

Eumenes 3y ago

does this mean anal sex could theoretically transmit Alzheimer's?

Llamamoe 3y ago
Extremely unlikely and you'd have to be doing a threesome+. Gut bacteria are present throughout the entire digestive tract, and you can't really reach very far into the anus no matter what you've got.
NeuroCoder 3y ago
It really depends on what you mean by that. In terms of this article, the gut biome would have to be changed by that. There are definitely different things people do in preparation for anal sex that could change that environment but I'm not sure how much anal sex itself actually changes that. This doesn't account for STDs that have been known to involve the nervous system for a long time already.
nonameiguess 3y ago
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adamredwoods 3y ago

Original published: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad303/7308687 https://academic.oup.com/brain/advance-article/doi/10.1093/b...

cpncrunch 3y ago
Doesn't look very impressive. Lots of overlap in the scatter graphs, and no mention of whether they corrected for multiple comparisons. Overall it looks like the typical breathless press release clickbait that HN users seem to constantly post here.
- azan_ 3y ago
  They did correct for multiple testing - "P-values were multiple-test corrected using the Benjamini-Hochberg False Discovery Rate (FDR) procedure and a cutoff of 0.1 was applied to select the differentially abundant genera". However, they used Wilcoxon test which has unacceptably high FDR [1]. [1] https://www.nature.com/articles/s41467-022-28034-z https://www.nature.com/articles/s41467-022-28034-z

kraig911 3y ago

The vagus never is the super highway of the brain it appears. I also feel our parasympathetic nervous system is vastly understudied.

tiahura 3y ago

I thought it was gum disease? Or was it herpes?

Llamamoe 3y ago
It's all of those things. Infectious disease increasingly seem to be behind or involved in most neurodegenerative, neurodevelopmental, chronic fatigue, severe psychiatric disorders. Herpesviral reactivation specifically seems to be involved in everything a little, but my hunch is that this is often secondary to other immune system burden.

m15i 3y ago

how does antibiotic medication affect our gut microbiota generally, and our alzheimer’s disease risk specifically?

XorNot 3y ago
This is asking the wrong question: for example, there are antibiotics you are prescribed for IBS because generally they tend to have a balancing effect on the gut microbiome. I've done a course every year or two when things get unmanageable, since it's a good reset. In this context, a treatment which reduced risk would likely be a combination of antibiotics and probiotics to try and shift the biome to a different one.
- Llamamoe 3y ago
  This is antibiotic marketing bs. There are antibiotic that harm pathogenic or prone-to-overgrowth bacteria harder than others, but they ALL lead to a state of dysbiosis and susceptibility to subsequent colonization/overgrowth/dysregulation And this is the exact reason whymost of the time, GI problems come back or are replaced with different symptoms after antibiotics, and why we need more Fecal Microbiota Transplant research.
  - XorNot 3y ago
    No, it isn't. The whole point of antibiotics for IBS treatment is that you already have an overgrowth, and you want to disrupt that and level the playing field. This is literally the reason I've been on short course antibiotics (<1 week or a single 4 tab dose) at different points, because it eliminates the constant bloating and gives probiotics a chance to work.
    - Llamamoe 3y ago
      The exact reason why overgrowth happens is because an opportunistic strain takes advantage of a dysbiotic state - even if you suppress it with antibiotics, your gut still lacks the robustness of composition necessary to be resilient. In fact, no antibiotic is selective enough to not impoverish your microbiome. Probiotics might help, but a few or a few dozen non-gut-sourced strains simply cannot compare to the hundreds present in healthy stool. The effects on microbiota-dependent conditions are often weak to none.