Nanoparticle-remodeled gut microbiota slows neurodegeneration via gut–brain axis

The good ol shitswap.

Maybe I'm too chicken to receive someone elses poo but I took what I consider to be the more scientifically controlled middle ground, mixing large amounts of probiotics with MCT oil and using it rectally. 36 strains, about 2 trillion CFU. To my surprise I have found several doctors that love this idea and one that also does it. It's not as diverse and that is exactly why I do it. I know what cultures I am getting and what benefits each one has.

Or maybe I have discovered a fetish.

There are online communities of people attempting FMT on themselves. I remember seeing them even cite an online source of FMT supplies from some sketchy company operating internationally to avoid regulations. Others used very understanding family members or friends as sources.

I haven’t followed the topic for a long time, but I distinctly remember how many people were disappointed with the results of their self administered FMT. This is probably because they had unreasonable expectations about their health conditions being caused by the microbiome. The only real success stories were from people who had C. Diff and treated it with a combination of antibiotics and FMT.

However, there were a lot of negative stories. Some people had major bowel problems for a while. One person even died, though it was speculated that it was due to some of the microbiome altering antibiotics he was experimenting with.

Interesting research topic, but please don’t DIY it.

Don't worry, it's not just this field, roughly 70% of medical studies are fake or severely flawed [0].

[0] https://news.ycombinator.com/item?id=37572394

It's hard to discern discourse in a field one is unfamiliar in, I'd tried with the Alzheimer's fiasco. Here's my tuppence:

The plaques are known to be linked to Alzheimer's, the debunking of one paper that messed with its figures does not detract from the whole body of research. The inefficacy of plaque-targeting treatments may not be proof that the plaques are not causal in nature, only that their damage is not reversible/fully understood.

In a massive field, one researcher does not constitute "full of faked data," despite how concerning it is.

The problem is viewing individual papers as the unit of truth in science. The "self-correcting" nature of science will actually reject entire papers, and entire directions of inquiry. Including, maybe, a casual relationship between beta amyloid and AD, but maybe not.

The other key part of science is holding everything in a state of uncertainty. There's some "facts" but mostly just hints and clues. And with Alzheimer's disease in particular we are trying to make progress with completely inadequate vision; we really can't even measure so much of what we want to measure. Feynman said it back in the 1960s, too, physicists have failed to deliver the tools to biologists to really measure what needs to be measured. There have been advancements, and DNA sequencing technology in the past decade has been turned into the most clever sorts of information theoretic microscopy by combining DNA sequences with many other biochemical processes. But we as a species still can not measure a lot of the things we'd like to measure.

> In particular, even treatments that directly reduce amyloid-β in the brain did not restore cognitive abilities.

Correct, but this doesn’t constitute “fake data”. It could be that amyloid-β is a marker rather than a causative factor. Or it could be that amyloid-β related damage is downstream, and remove amyloid-β after the damage has been done won’t remove the other damage.

It’s too quick to wave away an entire field because a single theory didn’t pan out. Most medical research proceeds with a lot of dead ends before it is figured out.

Sometimes the only difference between random button pushing and science is if you write it down.

Faff around and find out is the essence of the scientific method.

That said, I never trust a paper that gets posted directly to HN much. But then, single papers are never to be trusted!

I can't speak to chiral gold, but as for exploring the connection between microbiota and neurodegenerative diseases, this is a hot area of study. Take a sentence from the abstract:

>The gut–brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling.

You can pretty much formulate a few dozen google searches from various keywords in that sentence + "microbiome," "microbiota," and/or "GI immune signaling," etc and come up with hundreds of papers. The GI tract is host to the majority of our immune system. Many of the molecules used for signaling (and all kinds of other tasks) come directly from the bacteria there, or else are dependent on bacterial metabolites as inputs.

On a related note, I expect we will hear more about the metabolome in health and medicine research. As microbiome is the set of all microbes in the body, metabolome is the set of all metabolites (bacterial and endogenous) in the body. In this study, serum levels of an indole were found to be altered in Alzheimer's patients:

>indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls.

In another study of MS patients, two other indoles, as well as butyrate, were found to be lower in serum concentration compared to healthy controls [1]:

>Highlights - Gut microbiota and metabolites profiles of individuals with MS differ from healthy controls. Individuals with MS have reduced serum levels of indolepropionate. Individuals with MS have reduced serum levels of indolelactate and its producing bacteria. Individuals with MS have lower levels of species and genes involved in butyrate production.

Indoles in particular may be an interesting avenue of research [2]:

>What is the function of the indole in bacteria? Indole has recently been implicated as an important small molecule signal utilized by many bacteria to coordinate various forms of behavior. Indole plays a role in numerous bacterial processes, including: biofilm formation and maintenance, virulence factor production, antibiotic resistance and persister cell formation.

[1] - https://www.cell.com/cell-reports-medicine/pdf/S2666-3791(21...

[2] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175420/

Something of an educated guess, but microbiota because there are current hypotheses that rely on the gut-brain interaction, gold probably because its inert, and chirality is most likely because their target requires specific kinetics.

Alzheimer's is the most common form of dementia, affecting tens of millions of mostly elderly people, characterized by the brain getting “gummed up” by various mechanisms like reduced interconnectivity of your neurons, the formation of these plaques of a protein called amyloid beta on the brain tissue, tangles of a different protein called tau, and little “pearls” of a sort called vacuoles wrapping not sand grains but little lumps of hardened proteins. So there's a theme of proteins being where they're not supposed to be and misfolding and so on.

There are several partial causes of these protein problems, including genetic factors, chronic high blood pressure, smoking history, depression history. One can alternatively characterize this as a sort of inflammatory response, which puts it in a bucket with Parkinson's and ALS and other things tied to oxidative stresses and long-term inflammation.

I am not a physician but was trained as a physicist, part of where I know about this stuff comes from trying to research a speculative YouTube video that I never got around to making called “the biophysics of weight loss” where I would tell people that from a physics perspective, the scale in your bathroom lies, calories are necessary but not sufficient to understand the problem, feedback networks are complicated, and just in general tried to educate the public about basic physics from a direction that is not Newtonian mechanics. (So if you want to start with energy, what is the most frequent interaction with measured amounts of energy everyone has? It's either diet or the wattage ratings on electric bulbs, diet seemed more fun.)

So where this gets interesting for me is, in trying to talk about the complex feedback loops and signaling and satiety around diet, diet and lifestyle factors do seem to affect these chronic levels of inflammation. Just a simple example, your blood has to maintain a strong homeostasis with respect to how much sugar is in there, too little and your cells don't have what they need, too much and bacteria could thrive inside of you. One mechanism the body uses is, if we detected the blood as too sugary, we dump this signaling molecule called insulin in there too. Muscle tissue will take up blood sugar without insulin, but fat cells need the insulin as a “key” to open a lock that lets sugar in for long-term storage as fat. But the fat cells have what we in computing would call backpressure—they don't just respond directly to insulin, they calibrate their response to what they can handle. If too much sugar is coming in and I can't store it, I reduce my sensitivity to the insulin, so that I take in less sugar for a given amount. If this happens chronically enough, you get a general insulin resistance, and that leads to high blood sugar, type-2 diabetes.

Well, elevated blood sugar does something else that is linked to Alzheimer's: the Maillard reaction. This is the crusty delicious browning that happens when we sear a steak, or bake bread. The natural sugars in the muscle and natural proteins in the flour are enough in either case, the formula is sugar plus protein plus heat equals denatured brown crusty proteins. You are warm enough on the inside that this does “sous vide” your proteins very slowly, it is part of aging. So if your blood sugar is high, you age faster. The term in the literature is “advanced glycation” if you want to read more about this.

I don't have diet recommendations, I am just interested because I can ask prospective students “if we turned you into a hot dog, how far would it stretch” and other silly things like that. I will say, keto was originally invented to help with epileptics, and it does that by moving the brain off of sugars and to a fuel that the brain “prefers” (in the sense of having fewer barriers to letting it in) called ketone bodies. Intermittent fasting also does this on shorter timescales.

Anyway, the story about the gut microbiome maybe playing into this is even more complicated, some people talk about “leaky gut,” others say that that is crackpot, but the basic gist is that there is a theory that if you do not eat enough soluble and insoluble fiber, your gut microbiome (which needs to eat both to survive) essentially maybe eats you a little bit instead as it starves. And this causes you to be at war with your gut microbiome, and it means that the good bacteria that are not eating you are less able to crowd out the bad ones that want to eat you... And the claim is that this creates a constant chronic low-level inflammation, so there's that oxidative stress and early aging problem again, and so forth. I don't know that I believe this? But it does have me staying away from fruit juices, which are like fruit but you removed both the soluble and insoluble fiber.

Read Ed Yong's book "I Contain Multitudes". This area has been more/less blocked for many decades and with recent innovations and pipelines we may be able to start finding causal patterns.

Interesting. So 'chiral' is another word for 'handedness' - your hands are chiral, in that you can't rotate your left hand in such a way that it looks like your right hand (yes I know what the Greek word for 'hand' is).

So I assumed that these would be gold atoms with a chiral molecule around them - the ligand, that is. However, from a quick search it appears that there are these gold nanoparticles that are chiral shapes. In other words, the structure of the particle is chiral, not the molecule itself.

In any case, I doubt you can get them over the counter any time soon, but who knows.

edit: Here is a nice looking review that is free to read : https://www.nature.com/articles/s44222-022-00014-4

Seems like there are a variety of different techniques but Figure 2d in that review shows an image referencing - 'Lee, H.-E. et al. Amino-acid- and peptide-directed synthesis of chiral plasmonic gold nanoparticles. Nature 556, 360–365 (2018)'

Yes but we have to start somewhere.

Which is stronger evidence for humans than "in nowhere".

This is the stupidest glib reply format on par with “citation needed” and “tell me you’re [thing] without telling me you’re [thing]”

Animal models are used in research. Is this news to you? Do you think people don’t know that?

And not just any mice; specially bred mice.

So it's not even generalizable to all mice, much less humans.

More studies are needed.

Ib my younger days I used to get all excitef about new scientific breakthroughs. After decades I know better and apply the heuristic of disregard whenever I come across the hidden punch-line "In mice".

It really is a very good metric for preventing you to get sucked into hype that will 99.99 percent of the time result in exactly zero real world impact 10 years later.