The gut metabolite indole-3 propionate promotes nerve regeneration and repair | Hacker News Reader

The gut metabolite indole-3 propionate promotes nerve regeneration and repair

nature.com

233 pointsbookofjoe69 comments

I searched for some foods to increase Indole-3 Proprionate and this page is pretty good. [1] It tells what to eat (fermented foods, fiber, sprouted seeds) and what to avoid (sugar, simple starches, omega-6-heavy oils). It also introduced me to fermented bean curd. Can't want to try it.

[1] https://go.ixcela.com/metabolite-library/ipa

Indoles in general are common gut metabolites and an indole proprionate sounds like a further metabolic product.

This leads me to believe that trying to increase indole-3-proprionate specifically may be a fruitless journey (pun not intended), and one would be better off by optimizing for a hospitable environment for beneficial microbes in general, for example by cutting out carbs but increasing intake of flavonoids.

I suspect you may be right. Many supplements that have been tried just get broken down in digestion and don't actually increase target levels in the target tissues, rather we need to find ways of increasing the intake of precursor or figuring out which microbiota are involved in the metabolism and giving them a helping hand or just adding them altogether

I don't have a citation handy but I know eating fermented foods and increased fiber have both been linked to increased gut bacteria diversity. Thus seems in line with what the GP poster found for practical advice.

Its all about PREbiotics which are the food source for probiotics or your gut bacteria. Which encompasses some fiber and also sort of is its own thing. Long chain inulin and resistant starch are both some good ones

If anyone goes through the citations here to find the explanation of how refined carbs (fruit, white rice/flour) and omega-6 oils detriment IPA production, would love to read about it.

I think it's coming from this source (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872783/) which more or less just generally claims that "Western Diets" are disruptive to gut microbomes.

Annoyingly, it doesn't really pin down what exactly it characterizes as "the western diet". It does include extracted oils and refined simple sugars (glucose and friends). But where exactly stuff like pasta/rice/flour sit is less clear in their description.

You can look up SAD, the standard American diet for a reference.

They displace food containing more fiber and by doing that change gut flora to that which does not produce IPA.

Fruit is not a refined carb...

I assumed that simple sugars count as "refined carbs" and simple sugars are found in lots of stuff including fruits. Btw, my hope is that this very restrictive diet actually isn't necessary for this metabolite.

By definition they aren't refined. You would have to remove the fiber to make those sugars refined as a first step. Fruit isn't pure simple sugars and it certainly doesn't act that way in the gut when buffered with fiber.

prepare for a whole new world. I started with a red fermented bean curd that had so many flavors that I stood dumbfounded while my brain tried to sort it all out.

I didn't know about most of these fermented soy products - https://en.wikipedia.org/wiki/List_of_fermented_soy_products

But Tempeh is a pretty common one for vegans. I've used it in curries and stir fries.

I think the problem is that Tempeh is always cooked, so I would expect any critters in there to be dead (not that they haven't done good work making it more digestible).

My Indonesian friend introduced me to tempeh, which has to be one of the most versatile (and healthy) foods. You can toast it for a quick snack, but it disappears into nearly every type of sweet or savory dish, or it can be the main attraction. I've put it into a meat red-sauce for added texture and protein. +1 would eat again.

Tempeh in Indonesia is great; it takes nothing like the tempeh I’ve had in the states. Admittedly I stopped trying over a decade ago because the disparity was so great. Can you finally get good tempeh in the US?

Anything I buy packaged is sad compared to fresh, home-made tempeh. I'd start looking at "alternative" grocers that also have fresh seitan.

seven different types, twelve methods of cooking...

https://en.wikipedia.org/wiki/Tempeh

I've never had Tempeh, but I love tofu, edamame, natto and other soy products. This is definitely on my list to try and explore the many varieties.

Was it LightLife tempeh? That's the kind I get. I've never had anything else, so I don't have anything better to ruin it for me.

The recommendations on that page don't make much sense? The foods recommended are not major dietary sources of tryptophan (cf. [1]) and while a variety of fermented foods are mentioned, I am not aware of the use of the crucial bacterium Clostridium sporogenes in any deliberate fermentative cultures, such as are used for yogurt or kombucha, which rather contain [checks fridge] Lactobacillus, Bifidis, and Streptococcus species. But Clostridia are typically found in the gut of breast-fed newborns within a week of birth [2], suggesting they don't need much help.

I will also note that there has been some work done on the incorporation of Clostridium sporogenes into probiotics, but it doesn't come from kefir or miso, and... well... just read it! [3]

1: https://en.wikipedia.org/wiki/Tryptophan#Dietary_sources

2: https://jasbsci.biomedcentral.com/articles/10.1186/s40104-01...

3: https://scholarworks.calstate.edu/downloads/x920g252b

The "omega-6-heavy oils" makes me think of the work of Dr. Nemechek (https://www.nemechekconsultativemedicine.com/nemechek-protoc...), who works primarily with Autism. He found that a variety of brain injuries that of various types (including things like concussion), which historically have resolved themselves, have, in recent years, stopped healing. So a concussion that would have naturally healed a few decades ago, keeps giving the patient problems. One of his primary recommendations is to decrease the "omega-6 to omega-3" oils, because it seemed that omega-6 cause brain injuries not to heal. And it's worth noting that almost all vegetable oils (canola, soybean, etc), which are in almost all "processed foods" are high in omega-6.

This indole-3 link could be the reason why omega-6 oils are so bad.

TL;DR: Don't eat processed vegetable oils (other than coconut and olive oil).

Just be aware that that's a whole lot of conjecture with little solid evidence behind it. Saying "these brain injuries historically resolved but don't any more" sounds much more like a change in diagnostics to me.

The evidence against seed oils / processed vegetable oils is not very compelling yet (here's a pretty balanced summary: https://www.healthline.com/nutrition/are-vegetable-and-seed-... )

Am I misunderstanding your comment? Olive oil and coconut oil have terrible omega-6/omega-3 ratio, where as canola is pretty good.

https://www.cancerschmancer.org/articles/healthiest-cooking-...

The study is behind paywall, does it say to eat it? The abstract just says delivery of Indole-3

Natto is amazing for SCFA (not specifically propionate though - more Glutamate)

I believe traditional salami also has a little propionate

I tried Natto and really really wanted to get to eat it every day. However, one portion gave me huge long lasting headaches. The flavour was good, and I am used to eat ferments (I make my own vegan yoghurt). I was really sad because Natto is supposed to have so many great properties.

Weird. Maybe try another brand? Some of them have weird sauces included too you can skip

Natto is also a great source of vitamin K2 (and I think the only vegan one).

By far the highest source of K2 out of EVERYTHING (like nothing else even comes close). Its truely great stuff for your stomach

Thanks for this. It's interesting how many of these studies reaffirm what we already knew. Eat yogurt, fruits, vegetables, nuts, etc. Avoid sugar. We might not have known why these were good for us but I've been seeing these "guidelines" for about 30 years now.

The really interesting thing about fermented foods is that EVERY single culture (often completely independent of each other) developed their own unique ferments. Many were also shared but have varietal differences. There are TONS most people have never heard about. It is really sad that with the advent of refridgeration we lost so many in common culture (many or most are still niche). And I am not saying fridges are inherently bad - we just should have also PRESERVED (get it? BADOOSH) these practices

Why is that interesting? It used to be very hard to keep foods. Fermentation is an easy way to do it. It would be much more interesting if it only sprouted a few times.

Genuine question that's likely to sound flippant: Does beer count as a "fermented food" in this context? What about wine?

I don't know the pedantic answer to "is that fermented food"

However, alcohol is quite an irritant and (along with caffeine) is the first thing a doc will tell you to cut out if you have intestinal problems

Speaking (only) from personal experience, it can be such an irritant that it more than outweigs the benefits of other probiotics and "good foods" -- even in small amounts (e.g. 1 drink)

There are also non alcoholic beers, which I have been exploring a bit. My favorite so far is athletic brewing's Run Wild IPA.

"Here we show that IF [intermittent fasting] promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum."

I don’t have a subscription, but I’d be interested to know how long the IF protocol was (both duration of fasting and number of weeks of IF) and what the human equivalent is. I understand that there are reasons why a short IF regimen in mice equates to a very long IF regimen in humans.

The pre peer-reviewed version is available here:

https://www.researchgate.net/publication/347663867_The_inter...

> The IF group did not have access to food (fasting) during the first 24 h and then every second day after that (e.g. fasting during 0–24 h, 48–72 h, 96–120 h) with ad libitum access to food on the alternating days (24–48 h, 72–96 h, 120–144 h). Pre-weighed food was provided in the food hopper of their home cage at 9:30 am (unless a fasting day for the IF groups), and leftover food was weighed 24 h later.

I don't know much about this, but I've noticed an increase in interest around adaptogens like ashwagandha, reishi, cordyceps, and lion's mane:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991026/

Going by my intuition, I suspect that the anti-microbial properties of roots and fungi affect which gut bacteria are active. Since bacteria can make anything, it seems plausible that certain diets support healing and even some degree of regeneration.

Indole occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many perfumes.

https://en.wikipedia.org/wiki/Indole

“Geez Honey, your perfume smells like shit”

“No, really, that’s a compliment”

Sounds like ambergris.

Ambergris synthesis uses two opposite substances: ambroxide and ambrinol. The former is clean, fresh. The later, similar to indole, smells pretty awful in isolation, but gives depth to the composition when both are mixed.

Indole is the characteristic smell of withered flowers.

It is a semiochemical for many flowering plants.

Lilies always seem like they are on the precipice of smelling like death. I wonder if it’s the same thing.

Now I have the urge to find lilies and thoroughly confirm this.

To me it's sweet from a distance and gets almost chemical smelling when you get close. When you really get up in there it feels like there's about to be a phase change in the smell to something very unpleasant.

Interesting, however the indole ring is very common in biomolecules, and is also present in tryptophan, serotonin, melatonin and others. Most of these will not have fecal odors, I3PA probably won't either. For another stinky indole derivative, check out 3-methylindole.

A derivate of that family is Skatole [1], with its name appropriate to the fact that 1 gram can stink out a whole factory hall (at 0.001446 mg/m³ stink tolerance [2], 1 gram stinks up to 714.000 m³ of volume).

Fascinatingly, the same is valid here as for indole: at extremely low doses the stuff can end up being used in perfume [3].

[1] https://en.wikipedia.org/wiki/Skatole

[2] http://web.archive.org/web/20170507164421/https://www.bmlfuw...

[3] https://www.parfumo.de/Duftnote/Skatol

I know you'd like to think your shit don't stank, but
Lean a little bit closer, see
Roses really smell like poo-poo-ooh

Yeah, roses really smell like poo-poo-ooh

I’ve smelled pure indole before and it doesn’t stink. It smells like mothballs.

However some indole derivatives smell bad so my guess is that description came from impure indole.

Having worked on microbiome / metabolome interactions I've seen indole-3 propionate pop up for different phenotypes / pathologies. Wondering if that was actually the correct metabolite or just something related.

I have zero knowledge on biology and medicine, could someone explain this to humble people like me?

This... someone should make an ELI5. It is always useful for people like us :)

Yes :)

This is certainly interesting, but without a wider understanding of how the whole body works, it's not particularly useful on its own.

Indole-3-Propionic Acid (IPA) is one of the strongest antioxidants in the body and is a critical marker of a healthy gut microbiome. IPA plays a crucial role in maintaining a healthy gut.

It [1] strengthens the tight cellular junctions of the intestinal wall and [2] acts as a potent neuroprotective agent that inhibits beta-amyloid fibril formation, important for brain health. The bacteria Clostridium Sporogenes produce IPA from the amino acid tryptophan.

[1] can help with sensitivities to dairy, gluten, eggs, and soy, and feeling unwell after most meals, related to food particles “leaking” through the intestinal cell wall and triggering an immune response. IPA helps prevent that leakage.

IPA production depends on the health of the gut microbiome. Including fermented foods like kimchi, sauerkraut, kefir, yogurt, miso, fermented pickles, and fermented bean curd several times per week may benefit the gut microbiome and increase IPA production.

Adequate fiber in the diet is also important for maintaining a healthy gut. Examples of fiber-rich foods include vegetables, fruits, whole grains, and sprouted beans and legumes. Refer to the fiber recommendation in the client’s report for a full list of fiber-rich foods. The fiber in these items is a food source for specific bacteria in your gut, and it assists in the production of short-chain fatty acids (SCFA).

As bacteria in the gut ferment dietary fiber, short-chain fatty acids are produced. Short-chain fatty acids, like butyrate, are important for a variety of health processes including immune function, digestive health, and weight maintenance.

To support IPA levels, Ixcela recommends consuming sprouted seeds (e.g., chickpeas, mung beans, and black beans) at least 3 times per week. Sprouts can often be found in the produce section of the grocery store.

Avoiding foods that are detrimental to the gut is important for maintaining optimal IPA levels. Foods to avoid include refined carbohydrates, simple sugars, and omega-6 oils (vegetable or nut oils).

Pre-peer reviewed report free here: researchgate.net/publication/347663867_The_intermittent_fasting-dependent_gut_microbial_metabolite_indole-3_propionate_promotes_nerve_regeneration_and_recovery_after_injury

"The stress—protective activity of adaptogens was associated with regulation of homeostasis via several mechanisms of action, which was linked with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of stress response" Source: ncbi.nlm.nih.gov/pmc/articles/PMC3991026/

… in mice.

Hard to find human volunteers for sciatic nerve crushing.

It also propagates roots in plants in the form of indole-3 butyric acid

That's a substance distinct from indole-3-propionic acid, so it is not a form of indole-3-propionic acid.

TLDR on increase i-3p:

- eat fermented food with non processed carbs (ex. rice & kimchi)

- practice intermittent fasting

Both of which I am doing and I can attest to the increased productivity, mental acuity. In fact when I was eating well by Western standards, I didn't quite feel like this, probably because it takes forever to digest stuff like steak, fries etc.

Why do I need nerve regeneration and repair? I get it if someone is sick or whatever but healthy people probably shouldn't get caught up in these snake oil treatments that they never needed in the first place. It's great to raise awareness but unnecessary for majority of healthy people.

Who said you do? A lot of people have nerve damage from injury or surgery.

I don't see where anyone promoted this as a normal regimen for the general public.

depends on how you define healthy. for instance, someone might have minor nerve damage from a severe injury but can otherwise function like normal for the rest of their life.

do they NEED nerve regeneration? no. would it improve their quality of life? yes.

It seems gut microbes are in full rage lately.

Like the inner workings of the brain, the way the microbiome of our body impacts our life is poorly understood. There will definitely be a lot of FUD that will come from this, but the TLDR for many of these studies seems to be: eat better quality foodstuffs and you'll be better off.

It seems like we fucked up with antibiotics a lot...

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