At the current pace of research and studies, when do you think we could expect to see something come to 'market' that could be used - first as a diagnosis and then as a treatment/medication/technique.
As someone with IBS - right now I feel like there is no clear 'problem' defined for it. You are just categorized by the doctor (Rome 3 or whatever) and people go through various tests, medications, non-fda approved stuff to see what works.
I am eagerly looking forward to some progress in this area to hopefully fully understand whats going on and get a proper diagnosis
There are a variety of strategies being pursued to make pharmaceutical products out of microbiome research. Broadly those are:
1: "bugs as drugs" - genetically engineered microbes that perform some function. The idea here is that having the microbe in situ performing some function will be a much better way to administer a particular compound (or set of compounds), or remove a compound, than a traditional pharmaceutical. Large pharma companies have studied phenylketonuria as a metabolic disease for which the bugs as drugs approach would be great. Find a microbe that consumes phenlyalanine at a high rate and administer it at high levels (or get it to stably engraft in the host) and you have a treatment that would be vastly better than current dietary regimes.
2: "community engineering" - this takes many forms from fecal transplant, to trying to engraft a certain small cocktail of strains, to altering what the in situ community is doing by feeding a probiotic. The idea here is that there are tens of thousands of metabolites that microbes are producing in the gut, and by balancing or tailoring the set of metabolites that are made, you can improve health. Fecal transplants have good data for clearing recurrent C. diff in phase III clinical trials - this is the best developed of the microbial therapeutic strategies currently. Everything else is phase I or before.
3: "microbial natural products" - this is the world I work in (shameless self-promotion - if you want to come work at a very early stage microbiome startup email me at will@interface.bio). The idea here is to find the particular chemicals/metabolites that microbes make that have positive influences on our physiology. Most research here is focused on immune conditions, metabolic syndrome/dietary stuff, though there is increasing interest in depression and other conditions.
At a broad scale, I would say it will be 1-2 years before fecal transplants receive approval as a therapy for recurrent C. diff infection, at least 5 years before a bug-as-drug will be available, and at least 7 years before a microbe-derived natural product is on the market as a pharmaceutical. It takes an incredible amount of work to get from these associational studies to a pharma-grade product.
In the interim, I think there will continue to be a bunch of diagnostics and probiotics companies that (IMO) are bordering on absolute nonsense. There is very little predictive value to the tests supplied by most of these companies, and the data on probiotic efficacy is bad in humans. There is good evidence of probiotic and prebiotic effectiveness in animal husbandry (e.g. fish and livestock) but the data just aren't there in humans.
Thank you, appreciate the breakdown. With so much focus on the gut research recently I feel like we are on the cusp of bringing together lots of things and new understandings and that hopefully happens soon
Had a great doctor that helped me get started, after many that did a shoddy job, and this has been my experience as well.
Very much a 'seems like IBS, try low FODMAP, see what works and doesn't via experience,' which was pretty amazing/alarming how little is understood about our guts.
I'd love to know when the science is going to start catching up. Especially since I think it'll be interesting to find out if something has been added to our diets that's causing an increase in intolerance over the last decade+.
I recommend you check out the app from Monash [1]. It’s a paid app but really worth it and its been incredibly helpful for me (I say this as a user, not affiliated with them). AFAIK it contains the largest number of tested foods and they keep adding new foods and retesting and updating older food quantities and list out the specific fodmap associated with each food.
From what I have found online, every other source is either outdated or mostly copies the data from here.
ICYDK (From the studies I have read online) Researchers from Monash were the first ones to identify low fodmaps and they continually release research studies in this area.
To answer your question about chickpeas - right now I see 2 different tested versions in the app - one is Canned chickpeas - this says quarter cup (42g) should mostly be fine but half cup (84g) contains moderate amounts of Oligos-GOS (one of the fodmpas).
Green bell peppers - 52g should be ok but 75 to 80g contains high amount of sorbitol.
The app uses a traffic system (red, blue, green lights) to indicate the quantities
Another vote for the app. We've recommended it to others as well. (Only one of my doctors, the last, recommended it to me. I assume the others didn't know about it. All have been family medicine/general practitioners.)
What eventually got me is that certain foods which were listed as low FODMAP were also trigger foods for my symptoms.
So if it doesn't seem to be working, there may have a similar issue.
> Very much a 'seems like IBS, try low FODMAP, see what works and doesn't via experience,' which was pretty amazing/alarming how little is understood about our guts.
Yes exactly this.
> Especially since I think it'll be interesting to find out if something has been added to our diets that's causing an increase in intolerance over the last decade+.
One thing I read is that western diets severely lack in fiber which usually leads to loss of microbiome diversity [1]. But studies like this are still early stages, we need targeted results based on all this to really have any effect.
I don't have much knowledge on supplements or even diet - beyond it's intersection with the microbiome. From the microbial perspective I think traditional dietary stuff is enough - eat fibrous plants and legumes and that's all you need to do.
In your opinion, what is the best study that shows direct evidence that changes in gut flora can change health outcomes (preferably something that is a randomized control study). The only area I feel comfortable that good data exists is in the setting of fecal transplants for refractory clostridioides difficile infection. Thanks.
In general we only have mouse or other animal data for other indications.
There are retrospective analyses of patient cohorts receiving anti-PD1 or anti-CTLA4 therapies which have identified certain microbiome states as supportive of those therapies. I believe that these are probably real effects, though I don't think the particular microbes matter - instead I think it's the metabolites they produce and how those influence resting immune state (https://www.science.org/doi/10.1126/science.abf3363 - but you can find many more).
A paper I really like shows that a specific protein from a common gut microbe (Akkermansia muciniphila) confers resistance to diet induced weight gain, insulin insensitivity, etc. (https://www.nature.com/articles/nm.4236).
In general, I think the majority of microbiome work has been associational and demonstrative of the kind of hypothesis-free science that is prone to all sorts of statistical artifacts and misaligend incentives between truth-finding and paper publishing (garden of forking paths, file-drawer effect, etc. etc.)
How strong is the case that zero calorie sweeteners actually cause harmful changes to the microbiome that are linked to depression or other conditions?
Weird question perhaps, some research suggests that bacteria source nutrients from the cell lining in the gut if there is an absence of sufficient nutrients from the food coming into the digestive system. (example: https://www.cell.com/cell/fulltext/S0092-8674(16)31464-7)
That made me wonder what the triggers might be, since the studies see the corroding effect appear in diets deficient in polyphenols/insoluble fibres. At what interval do microbes need nutrients and is simply eating a highly-processed snack that has nothing much to offer bacteria in the gut a possible trigger in itself?
Fascinating question - and not one whose answer is known.
Fiber is good for microbes merely by the virtue that humans lack the glycan-degrading enzymes that are necessary to break it down, so it reaches the colon intact where the microbes can eat it. Humans can digest starch (though it can be physically and chemically modified to be harder to digest) but not the hundreds of other types of fibers that are found in a traditional diet.
I think there is good research that shows that higher fiber diets are associated with lower risk of developing a range of metabolic and immune pathologies, but the particular mechanistic linkages are so subtle that it will require absolutely massive studies to identify them. In general, we know that humans used to eat a much higher fiber diet (e.g. the Hadza people eat 70-150 grams of fiber a day), and we believe that produces a much healthier microbial composition.
The paper you cited is really interesting! I haven't read it - but the overall idea that the mucus lining of the gut can be degraded by microbes who are sourcing carbon, energy, and nitrogen from it is well established.
I think there is consensus that some amount of gut barrier integrity is due to microbial signals. This occurs in two ways - 1) our epithelial cells sense microbial products (proteins, carbohydrates, etc.) and respond by tightening the junctions between them. The overall idea being that you want to keep the bacteria in the colon, but you must balance some level of nutrient flow. 2) The goblet cells which produce mucus in the gut, respond to microbial signals to increase or decrease their mucus production.
There is a lot of research going on trying to understand how certain diets cause defective mucus production and in turn how that can allow microbes to get to close to the epithelial lining (usually the mucus is ~100 microns thick) which results in inflammation.
Recent evidence of another function of microbial activity in the gut of hibernating animals. In short, it appears that they help the host supply enough nitrogen for maintaining muscle mass during hibernation: https://www.science.org/doi/10.1126/science.abh2950
How much evidence is there of long-term effects of these types of treatments? Do you or other researchers in the space ever worry that you are in a sense curing the effect and not the cause (family and societal problems as I understand it), which would imply that efficacy would fall over time? Would sustained fecal transplants, etc. even work?
Is there a good way to test one's own gut microbiome? To determine how healthy it is or isn't, and to track how it changes over time. Basically I want to be able to tell how my diet and things like antibiotics affect it.
I think it's really hard - we don't know what a healthy state of the microbiome is. There is likely a lot of individuality, what is healthy for me is maybe not healthy for you. This probably has to do with early life immune system development and what we were exposed to as kids.
At a high level we know that diversity of microbial species in the gut (but for instance, not in the vagina) is linked to better overall health state. Is this because of the microbes? Probably not, it's probably that the microbes are a sensor/responding to an overall healthy diet/ecosystem.
In general, there are commercial services to track your microbiome and they are interesting from a data perspective, but I am not sure you will get much health information out of them.
We know the answer to a healthy diet - there are no microbial talismans - but it's just not sexy. Eat lots of plants, less sugar, and exercise. I wish it was as easy to follow this advice as it is to write haha.
How about the mainstream explanation? Energy used to be scarce, so high-energy foods tasted good. Now we have plenty of energy-dense and tasty food-like stuff without the actual nutritional content.
Thanks a ton - super curious research. What determines if individuals get Morganella and Kiebdiella bacteria? Is it genetic or can it be impacted by the food we eat?
What is the mechanism of how these bacterias interact with the brain through the enteric system?
We know that microbes colonize the gut in a somewhat predictable way as a function of age. As a newborn your gut is largely dominated by Bifidobacteria, and this slowly transitions to a more complex community over the next several years of life. Events like early childhood antibiotics, malnutrition, other disease, etc. can alter this trajectory. Interestingly this kind of ecological succession seems to be driven by an interplay of both immune maturation (as your immune system matures it starts being more selective about who it tries to let in) and by chemical processes. The gut becomes more anaerobic as the number of bacteria increase (and transition away from the Bifido dominated state) and that has a strong selective effect on the microbes that will grow well.
For specific commensal bacteria we know some of the mechanisms of colonization - there are particular genetic programs that bacteria turn on when they sense they are in the gut to enhance their ability to be retained and not washed out. These programs include physical attachment, motility, and chemical signalling to try to dampen the local immune response.
Pathogens are extremely good at getting in to the gut despite our best attempts at keeping them out. Salmonella typhimurium is notoriously adept at colonizing the host - the infectious dose you need is maybe 10 microbes taken orally in a susceptible host (compare that to 10 billion microbes/capsule in a probiotic).
For these specific bugs I don't know that much. I am excited to read more.
Can we actually do more than correlation yet on this very topic? I always see studies and articles that promise that gut health can solve depression. But I think this is bullshit. Depression is a protection mechanism from your brain and I would bet my ass that the causation is more depression => bad gut health. I would be very interested in your thoughts on that.
Regarding your advice on eating plants, do you know if it matters wheter they are cooked or eaten raw? I mean, is one preferable over the other, from a gut biome perspective. By the way, thanks a lot for your answers!
Far from being an expert on the subject, but I read a paper that said that eating raw vegetables would usually increase the degree on inflammation, but cooked vegetables had the opposite effect.
Potential correlations between gut serotonin and morganella levels? Leading to the question "Can SSRIs affect depression through mechanisms in the gut?".
Absolutely - the chemicals that microbes make in the gut pass into your blood stream and from there access the entire body. There are mechanisms the body uses to ensure these chemicals are detoxified (phase I and phase II metabolism in the liver) and that they are excreted if they reach too high a concentration.
More locally, the enteroendocrine cells (https://en.wikipedia.org/wiki/Enteroendocrine_cell) that line the gut translate much of the internal nutrient state of the gut up to the brain to tell you things about if you should eat, etc.
There is a lot of research on how we could alter satiety by finding the right language that these cells use. There are approved drugs on the market that mimic the activity of these cells (incretin mimetics) to reduce appetite/weight control.
