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The Probiotic Paradox: When Probiotics Fail or Even Do Harm – an ME/CFS Perspective

December 18, 2018

Our guts are teeming, just teeming, with bacteria that provide many useful functions. They break down food, knock down pathogens, regulate the immune system and hormone release, and even affect brain functioning. Several serious diseases including cancer, diabetes and rheumatoid arthritis have been associated with what are considered unhealthful assemblages of gut bacteria.

probiotics

These studies indicated that pounding the gut with probiotics isn’t always a good idea.

Studies suggest that something is off, though, in the guts of people with chronic fatigue syndrome (ME/CFS). Pro-inflammatory and anaerobic species are more dominant and diversity -an important component of a healthy gut –  is low.  Plus bad gut bacteria may be gnawing away at our gut linings when we exercise, allowing the bacteria to spill into our blood, causing systemic inflammation.

The solution seems clear – pound the gut with good bacteria, get it back into balance, turn the immune activation off, and who knows, maybe even conquer ME/CFS and fibromyalgia (FM). Certainly it’s worked for some people but for many others it hasn’t. That’s really no surprise, nothing works for everyone in these diseases, but some people have experienced really negative effects from good bacteria. How could that have happened?

We’re beginning to learn how. Two studies that are turning upside down our notions of using probiotics to replenish our gut flora are indicating that the gut, like every other part of the body, is more complex than we knew, it seems.

The Studies

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, Kotler E, Zur M, Regev-Lehavi D, Brik RB, Federici S, Cohen Y, Linevsky R, Rothschild D, Moor AE, Ben-Moshe S, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Shapiro H, Pevsner-Fischer M, Sharon I, Halpern Z, Segal E, Elinav E. Cell. 2018 Sep 6;174(6):1388-1405.e21. doi: 10.1016/j.cell.2018.08.041.

These Israeli researchers did something rather simple – at least in design – which, in retrospect, should have been done long ago. They took 25 healthy people, used endoscopy and colonoscopy to assess the bacteria found in their upper and lower guts, then gave them a standardized dose of probiotics twice a day (Lactobacillus acidophilus, L. casei, L. casei sbsp. paracasei, L. plantarum, L. rhamnosus, Bifidobacterium longum, B. bifidum, B. breve, B. longum sbsp. infantis, Lactococcus lactis, and Streptococcus thermophilus) and measured the bacteria in their guts. Their stools were sampled throughout the study.

Resisters and Persisters

Two groups emerged: the persisters – a group whose guts accepted the new bacteria and changed in a positive way, and the resisters whose guts rejected the bacteria and didn’t change at all.

Their interest piqued, the researchers then transferred the bacteria from the resisters and persisters into mice with no gut bacteria, and then gave probiotics to them. The same thing happened – indicating that the bacterial makeup of a person’s gut, at least in part, determines whether probiotics will help them or not. Something about the ecological makeup of the resisters’ bacterial populations made it impossible for the good bacteria to catch hold.

That was an intriguing finding, but the Israeli researchers didn’t stop there. Adding the participants’ gene expression – which genes were active or not in the blood – into the mix, they hit a home run.  Even though they were healthy, the resisters had something extra going on – an autoimmune gene signature – that was somehow not allowing their gut to accept good bacteria.

If you’re not benefiting from probiotics, then, both your immune system and your gut bacterial makeup may be keeping the probiotic bacteria from taking hold. The problem may be worse than that, though.

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.

Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E.Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047.

When gut problems are suspected, a standard protocol among some doctors is to wipe the slate as clean as possible by killing the bacteria with antibiotics and then re-populating the gut with probiotics. Of course no probiotic combination can approach the immense diversity found in our guts, but anecdotal reports suggest the protocol does seem to work in some people.

This study suggested, though, that there are much better ways to go about replenishing one’s gut after a nuclear attack by antibiotics. The researchers wiped out the guts of three sets of people, then recolonized one group with fecal transplants of their own gut bacteria, another with probiotics, and the last they let recover naturally.

The guts of the participants recolonized with transplants of their own fecal material recovered at lightning-speed: within a week their gut composition was back to normal. The participants whose guts were allowed to heal naturally took about three weeks to return to normal, but the people taking probiotics took up to six months for their gut composition to return to normal, and some of them were still not normal even then.

Any ecologist  (the gut is an ecological system) probably wouldn’t have been surprised at this result. Trying to reinstitute a complex ecosystem by giving a few species a boost can allow them to block others from establishing themselves, resulting in a low diversity ecosystem. That’s basically what happened. Even months later the guts of probiotic-receiving participants had low bacterial loads and dysregulated gut ecosystems. It turned out it was far better to let mother nature take its course and allow the gut ecosystem to repopulate naturally.

It’s possible, then, that taking probiotics when you have a dysregulated gut ecosystem could help, but it could also throw things off. One wonders if some of the negative responses to probiotics result from adding good bacteria into the wrong ecosystem.

Laboratory studies suggest that factors secreted by the Lactobacillus species often found in yogurt preparations might actually be inhibiting other bacteria from colonizing. The probiotic species found in store-bought preparations, it should be noted, are not necessarily the ones that are needed – they’re the ones easily grown in the lab.

“We’re talking about an entire rainforest in the gut that’s being affected in different ways by different antibiotics, and you can’t just patch that up by giving a probiotic. Because, let’s face it, a probiotic has maybe seven or eight strains. There’s a lot in the literature about some of these bacteria being beneficial, and it’s interesting, but they are really some of the few microbes in the gut that are fairly straightforward to culture. And I think that drives the probiotic industry more than it would like to admit.” Allen-Vercoe

The Poop on Stool Samples

But then came some more bad news. Putting stool samples in your body may not be your idea of fun, but at least it’s easy to do and relatively inexpensive. However, despite the fact that stool samples are regularly used to assess gut bacterial composition, they provide a pretty inaccurate snapshot of what’s going on in the gut.  The bacteria actually found in the gut (obtained through endoscopies and colonoscopies) were markedly different from those found in stool samples.

Lactobacillus bacteria

Factors secreted by some Lactobacillus bacteria may prevent other bacteria from colonizing

Finding the probiotics you took via your mouth in your stool was supposed to be a sign of success, but this study found that wasn’t necessarily true.  It’s quite possible for probiotics to show up in your stool without recolonizing your gut at all.

The stool samples failed at predictiveness as well. While the gut mucosal samples (and the gene expression results) could be used to determine whether someone was a “resister” or “persister” – the stool samples could not.

It turns out that the most widely used snapshot of the gut – the stool sample – is the least representative. Gut mucosal sampling – a sampling of the bacteria found in the gut lining via two invasive procedures (endoscopy and colonoscopy) is the only way to truly determine the state of your gut, because the samples are obtained from where the gut bacteria actually reside.

There are, of course, other less invasive ways to assess the effectiveness of probiotics or fecal transplant. Improvement in symptoms: gut issues, fatigue, mood, etc. could indicate that whatever gut manipulation you’re doing is working.

The news in these studies wasn’t all bad, though. The fact that the probiotics were better able to colonize the guts of the healthy controls who had lower levels of good gut bacteria suggested that people with poor gut flora – such as people with ME/CFS – have a better chance of benefiting from probiotics. (That has to be considered alongside the fact that people with autoimmune tendencies tended to resist probiotic colonization.)

Still, the fact that probiotics may be more effective in those with more impaired guts wasn’t really a surprise. There is certainly a place for probiotics in medicine. A recent review of two ME/CFS probiotic studies concluded that probiotics had a “significant effect on modulating the anxiety and inflammatory processes “. Repeated studies have found them helpful in irritable bowel syndrome (IBS), metabolic syndrome, diabetes and obesity. The situation is just a bit more complex now.

That we’re not at the prescriptive phase of treating most diseases with probiotics isn’t exactly shocking, either.  ME/CFS researchers Ian Lipkin and Maureen Hanson, a member of Simmaron Research’s Scientific Advisory Board, have been tackling the gut, and both have been wary about providing any prescriptions for gut manipulation in ME/CFS yet. Given the huge differences in gut bacteria from person to person, a personalized approach – matching personal gut weaknesses with specific probiotics – was always probably going to be necessary.

Ian Lipkin alluded to this earlier:

As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

The good news is that gut research is exploding in ME/CFS. Ian Lipkin introduced an  gut-associated subset (ME/CFS patients + IBS) with unique metabolic problems, and remarkably enough, found that differences in gut bacteria were more effective than metabolites in differentiating people with ME/CFS from health controls.  Derya Unutmaz – whom Lipkin is now collaborating with – has found strong evidence that T-cells  associated with bad bacteria are playing a role in ME/CFS.  Plus, a recent hypothesis put forth by Jonas Blomberg proposes that leaky gut may set the stage for ME/CFS. Finally, Maureen Hanson is overseeing the first fecal transplant trial in ME/CFS.

“The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset

Simmaron Research is an active collaborator in microbiome and immune-related studies with Dr. Lipkin, Dr. Hanson, Dr. Mady Hornig, Dr. Elizabeth Unger, and others to deepen the field’s understanding of disease subsets and to identify and study treatment options for patients.

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44 Comments

  • dejurgen

    December 18, 2018 at 9:02 pm - Reply

    “an autoimmune gene signature – that was somehow not allowing their gut to accept good bacteria”

    In people with an autoimmune disease or leaky gut, we could expect a far stronger immune activity of the body in the gut. It would be reasonable to find that some bacterial strains can better withstand that additional pressure then others.

    If so, the added good bacteria will probably be wiped out at a faster rate then the few resilient leftover bacteria that will repopulate the gut.

    It may be helpful to know what the baddies and the goodies eat by preference so we can shift the odds. Extensive in vitro growth of mono cultures could be tested for growth rate when fed pre-digested food.

    Thanks for another well written blog Cort!

    • Cort Johnson

      December 19, 2018 at 8:38 pm - Reply

      Thank you sir!

      Interesting about the autoimmune condition possibly attacking the good bacteria. Somehow this autoimmune response – which can’t be too strong – as these were all healthy people – was associated with lack of colonization.

      It just shows how everything is tied together!

    • Beca

      December 30, 2018 at 2:33 am - Reply

      The problematic areas of histamine inflammation /intolerance (due to DAO gene snp messup or and environmental exposure of some type or both) and a tendency toward much oxalate crystal formation (can be IDd through the Organic Acids/OAT test, very comprehensive and telling re: digestive byproducts; they give followup consult too, and is covered by Medicare) are both very necessary to finding one’s unique self-designed gut healing protocol. There are online websites through medical professionals and associated support groups to support gut healing protocols along these lines. Dr. Ben Lynch of Seeking Health has himself struggled with a lot of the above due to a rough snp hand; he has found many solutions and shares them online. Some of readers’ comments above hint at the issues addressed with the MD-formulated gut healing product Restore, which has been clinically tested at UVA at Charlottesville. Another fulvic/humic earth product is Raw Materials, the humic/fulvic concentrate specially formulated for Senergy Medical Institute/Dr. Jerry Tennant in Texas.

      Go low and slow; no one size fits all; “all healing is voltage” (the quality and strength of the microcurrents charging up cells and their self-healing functions, according to Tennant’s amply documented groundbreaking work, which joins both Western and Eastern medicine).

  • tatt

    December 18, 2018 at 10:29 pm - Reply

    Personally I find prebiotics (specifically Bimmuno) do provide some benefit while I take them – but it’s not a cure and I have to take them all the time. Since they are expensive and I fear I may stop getting the benefit I only take them from time to time.

    I also find digestive enzymes beneficial, again too expensive to take continuously.

    • Rhonda

      December 19, 2018 at 1:14 pm - Reply

      Have you looked at resistant starch? Before processed foods, people routinely consumed 30-50 grams of resistant starch/day (from unprocessed whole grains, green bananas, beans, raw starches and cooked and cooled starchy foods), but now we’re only getting about 5 grams/day. It ferments slowly, so you do not get a lot of gas, and makes more of the short-chain fatty acid butyrate than other types of fermentable fibers. I work with green banana resistant starch, which is just starting to become available to consumers, but raw potato starch and resistant corn starch are other options.

  • Waiting

    December 18, 2018 at 11:11 pm - Reply

    So great to hear that Lipkin and Unutmaz are working together on this! Also, a personalized solution would be a great trial intervention for ME.

    • Cort Johnson

      December 19, 2018 at 8:35 pm - Reply

      I agree! I love that collaboration 🙂

  • Daniel B.

    December 19, 2018 at 5:15 am - Reply

    I have been disabled for some 20+ years due to CFS/ME, and have had a lot of gut problems. Resolving those hasn’t been a cure, but I think it is worth the effort. For me at least, largely resolving my gut problems reduced the severity of my “crash” symptoms a little, and when I am able to control the gut problems for a few weeks at a time, seems to correlate with a reduction in my joint & muscle pain quite a bit. Here is what I have discovered after years of experimentation.

    1 – Probiotics can help, but don’t expect ALL probiotics to help. There is a great deal of variation in people’s gut biomes, immune variation, and digestive ability even for normal and healthy people. Being sick adds more variation, and you have to find what works for you.

    Don’t expect that what works best will be what is most acclaimed. Kefir for example, is probably the most renowned traditional yogurt or cultured food from a curative standpoint, but not only did it not work for me, but it actually seemed to provoke my CDS/ME somewhat. This was a consistent effect incidentally. I tried the kefir at different times more than a year apart, with the same negative results. Viili on the other hand, for me at least, works very well. Those are traditional cultured foods that you normally will have to make yourself, but the same is true of supplements and yogurts you buy at the store. Do realize that individual STRAINS of probiotic culture vary in their results incidentally, even when the scientific species is the same, so you should expect different brands of yogurt, or different product lines, to have different results, even if the label lists the same species of bacterial in the culture.

    2 – You will need to give your probiotic a chance to work, but you also have to listen to your body. What this means in practice is that you will have to take a probiotic or yogurt for a few days just to see whether or not it is harmful, because just the change can disturb your digestion.

    This does not however, mean that you should keep taking a probiotic for a long time when it seems to make you ill. I would recommend trying the supplement or food for three or four full days. At that point, if it seems to make things worse, give it up, let your body return to its normal state, and try something else. If however, you notice a minor improvement after three or four full days, you will often have to keep taking the probiotic a couple of weeks at least before you reap the full benefits. If your gut heals, or if autoimmunity is dampened down, you won’t see full results right away.

    3 – If you have gut symptoms, try an elimination diet. I especially recommend the FODMAPS system, because sensitivities of that type are quite a bit more common than celiac disease or say, egg allergies, but you can easily include any other possible risks while testing for FODMAPS intolerances. As it happens, I have FODMAPS category of intolerance to fructans in particular, and while probiotics are indeed helpful to me, there is no probiotic that will allow me to eat onions and garlic and remain healthy.

    4 – If you have difficulty eating food that has either protein or lipids (fats and oils) experiment also with enzymes like betaine hydrochloride, if protein rich foods give you trouble, or pancreatin, if fats are the problem.

    Hopefully this will help some of you, and you can improve your health, at least somewhat. Every little bit helps!

    • Cort Johnson

      December 19, 2018 at 8:57 pm - Reply

      Thanks Daniel for those excellent suggestions. This really is a trial and error area and you gave IMO some good guidelines to that.

      Did FODMAPS diet help you the most with your gut?

      For those who don’t know about FODMAPS diet – here’s a link to information on it on Health Rising – https://www.healthrising.org/forums/resources/could-a-diet-reduce-the-pain-in-fibromyalgia-a-fodmaps-study-suggests-yes.462/

      • Daniel B.

        December 20, 2018 at 7:29 pm - Reply

        I would say that the FODMAPS diet is either the first or second most important change that helped to get my gut problems under control, the other being the use of digestive enzymes.

        It is worth noting by the way, for anyone who is put off by the seeming restrictiveness of a FODMAPS diet, that the most restrictive aspect is only for a couple of weeks, and you will typically be able to reintroduce some of the foods because very few people are strongly sensitized to everything containing FODMAPS at the same time. Some foods which you are sensitive to you will probably also be able to eat somewhat, although not in unlimited quantities. For myself as an example, I am very sensitive to fructans, but not very sensitive to milk sugars. My fructan sensitivity is too great to allow me to eat onions or garlic (except for the green portion of green onions or leeks) which is pretty inconvenient in terms of the processed, convenience, and restaurant foods that I can eat, and since there are fructans in wheat, I cannot eat whole wheat bread or bran flakes. On the other hand, I am not so sensitive that I cannot eat normal pastas or non-whole grain baked goods. Getting rid of the gut symptoms, and cutting down on the muscle & joint pain is a pretty big benefit too….

  • ElizabethKay

    December 19, 2018 at 6:52 am - Reply

    This begs the question of looking at old studies that tested antibiotics as treatment for ME/CFS/Fibro. Is it possible that some of the people who have benefited from antibiotics did so because their gut flora got wiped out and re-colonized? Apparently in some of those antibiotic studies, some patients improved and — of course — many did not. We’re talking people being on antibiotics for 6 months, or more! That certainly would create a gut that is stripped of flora, wouldn’t it? Here’s a report from June 2014, but there are also some older ones out there. https://www.healthrising.org/blog/2014/06/28/drug-repurposing-antibiotics-reduce-microglial-activation-mecfs-fibromyalgia/

    • Cort Johnson

      December 19, 2018 at 9:03 pm - Reply

      I think its quite possible.

  • Lilpink

    December 19, 2018 at 10:27 am - Reply

    Has anyone considered the role of mast cells wrt these phenomena? It would seem to be a very sensible area to investigate.

  • Rhonda

    December 19, 2018 at 1:11 pm - Reply

    Nice article. I appreciate the explanations. I always thought that prebiotics, or the food for the good bacteria, were a major missing piece. The bacteria are only part of the equation, because if you are not feeding them fermentable fibers, they cannot produce the short-chain fatty acids and other biochemicals that trigger numerous health effects. You need both the bacteria and the fermentable fibers to get the health-promoting fermentation.

    • Cort Johnson

      December 19, 2018 at 9:02 pm - Reply

      Yes, we forget about prebiotics. I looked up foods that are good prebiotics. They were kind of strange but they did include green bananas and onions! (as well a raw garlic, jerusalem artichokes and raw asparagus)

      https://www.health.com/digestive-health/prebiotic-foods

      https://www.prebiotin.com/foods-containing-prebiotics/

      • dejurgen

        December 19, 2018 at 10:15 pm - Reply

        Don’t forget that many people with ME/FM have food intolerances and often multiple. Near all of the prebiotic foods listed on both above links make me either more ill or a lot more ill.

        Cooked and cooled down potato is about the only source of good bacteria food I have found to be safe so far. It’s not a real prebiotic but resistant starch. Thanks Rhonda for bringing that to mind again as upping that and starting with expensive hand rolled oats should be good for me. Green bananas are a clear no for me. Raw potatoes very likely are a no too. Maybe small quantities of potato starch may do. I’m still in the slow trial and error phase as me knowing to have food intolerances is recent.

        • Daniel B.

          December 20, 2018 at 7:51 pm - Reply

          I have to second this sentiment. Most of the prebiotics except for resistant starch in food like potatoes and bananas are VERY problematic for me. The thing to realize is that prebiotics go to feed some types of bacteria and yeasts in your gut on the assumption that doing so helps bacteria and yeasts that are GOOD for you. If the bacteria that grow are NOT good for you for whatever reason, then you are likely to need to avoid prebiotics, although you do not need to avoid all PROBIOTICS which are SOMETIMES a different thing.

          Quite a few of the more expensive probiotic supplements and yogurts are also “enhanced” with prebiotics and if you are not careful, that can throw off your assessment of what types of probiotic bacteria are helpful to you. As an example, most of the strains and types of Bifidobacterium seem to be fairly compatible with me, although some are more so than others. I thought that Bifidobacteria made me sick for a while however, because when I first started experimenting with probiotics, I tried a supplement that included a big dose of prebiotics. In fact, it was the prebiotics and not the strain of the bacteria in the supplement that I was intollerant of.

          • dejurgen

            December 21, 2018 at 11:45 am -

            Thanks for the warning Daniel!
            I had bought 4 months worth of brand probiotics on a sale to try later. And yes, the first ingredient is fructo-oligosaccharide. As I have such a stock I’ll try them but rather careful. Starting with half a tablet every other two days will do while carefully observing my gut.
            The tablets are 1.5 grams a piece only so taking in half should yield about 0.5 grams a dose. But given how aggressive onions are I’d rather be careful. On a plus, it offers me a chance to estimate what quantities I can tolerate ;-).

          • gh

            December 29, 2018 at 9:05 am -

            It could be that d-lactate is a problem for you. Bifidobacterium do not produce d-lactate.
            https://www.fxmedicine.com.au/blog-post/d-lactate-producing-probiotic-strains-chronic-fatigue-syndrome

        • Rhonda

          December 21, 2018 at 1:21 pm - Reply

          Thanks for the reminder. Fermentation of any kind can be problematic for some. Resistant starch actually is a real prebiotic. The biggest difference between soluble prebiotics (inulin/FOS) and insoluble prebiotics (resistant starch) is that resistant starch ferments more slowly. The FODMAP diet does not exclude resistant starch foods because they can be better tolerated. I am also encouraged by studies like http://www.sciencedirect.com/science/article/pii/S1931312818305912 that show resistant starch improved autoimmune manifestations in an animal model of lupus while probiotics worsened them. It is most likely because resistant starch helps heal a leaky gut and helps to stop translocation of the bacteria and other chemicals into the bloodstream.

  • Donna

    December 20, 2018 at 6:56 am - Reply

    I have always said it was the gut, 22yrs of CFS/MCS, brought on after a dose of the drug FLAGYL, never been the same since…..And because I lived in a sugar cane growing area (lots of chemicals), CFS quickly , nose dived into MCS , and never recovered. The chemicals in the area you live, at the time you have your gut damaged, also has alot to do with it, AND , NO ONE….EVER…..LOOKS…..AT ……THAT…..

    • Matt

      December 28, 2018 at 11:29 am - Reply

      Donna: The origin of my CFS may have been similar to yours. I was living in a poor tropical country many years ago and given alot of Flagyl for stomach parasites along with other anti-biotics for bacterial infections which I was getting from dirty water (I was using a shallow well with very dirty water at the time) and dirty food. And, it was an agricultural area too with lotsa chemicals used. There were some other things going on as well, including a case of mononucleosis and my first Ebstein-Barr Virus positive result, and getting dengue fever twice. That was over 30 years ago and I have never really recovered.

    • Vic

      January 20, 2019 at 3:35 pm - Reply

      Yes, Flagyl was very destructive to my body also – my arms and legs went numb and I had liquid diarrhea almost immediately – but doctors and nurses acted like I must be nuts, that no one *ever* had such a reaction.

  • Simas

    December 20, 2018 at 12:49 pm - Reply

    Cort, thanks so much for writing this. I always thought that, at least for me, it has always been about the gut. I actually got sick after using probiotics!! I’m not exaggerating. I wish everyday that I hadn’t taken them. I had issues since I was 15, but they were relatively mild compared to my current problems. I had high blood pressure some brain fog, etc, but I was more or less functional. I could do whatever I wanted, minus exercise.

    Fast forward 7 years, I had some constipation and skin issues when I was 22 and I bought some proobiotics (Theralac) thinking it can’t hurt… I only took them for a week or two, but that was enough. I began loosing weight and had horrible malabsorption manifesting with what I call constipated diarrhea, plus terrible malaise, fibromyalgia-like muscle pain, confusion, etc. Since then, I have ME/CFS (or I think I do, because nobody diagnoses it where I live). I can’t work, I can’t socialise and so on.. you know the story.

    So it certainly seems to me that I was already predisposed long time ago, probably already had significant intestinal permeability and when I challenged my gut with probiotics it was a tipping point with no way back, unfortunately.

    Initially, I was able to improve my symptoms with SCD diet, which I think has some evidence of increasing bacterial diversity. Unfortunately, it doesn’t really work anymore and oftentimes, anything that feeds bacteria, including vegetables, carbs that are difficult to digest and anything that cab remotely irritate intestinal mucosa (even honey) are just aggravating the symptons and there’s just no way out.

    I’m now thinking that fecal transplant may be something that could help me, because anything that changes gut composition has a very noticeable effect on me. My only fear is that it could make things worse and I just couldn’t handle it. I’m already on the edge.

    Anyone knows where I could go in Europe for this?

    • dejurgen

      December 20, 2018 at 4:06 pm - Reply

      Hi Simas,

      “had horrible malabsorption manifesting with what I call constipated diarrhea”

      How do you observe malabsorption, how does it manifest itself? I’m asking because I believe the most likely cause of my fructose intolerance is fructose malabsorption.

      I have no way of observing this directly because I wouldn’t know how to, but when I eat even moderate quantities of food that have a fructose-to-glucose ratio significant higher then 1, I get really severe gut problems plus instant fatigue, feeling down…

      Having a ratio of 1 or higher seems to be as important or more important then absolute fructose content and that seems to be a feature of fructose malabsorption so that is why I suspect that to be the cause. As long as the ratio is smaller, fructose absorption is a lot better then when it becomes bigger then 1. Then (when it is bigger) fructose enters the large intestine and is like rocket fuel allowing some bacterial species to multiply very rapidly. I think it is that that sets up the balance in my gut by letting 1 or a few species that grow very well on fructose to vastly out-compete other species that use slower food sources. Honey has a ratio of 1. Most ripe fruits have a ratio significantly higher then one.
      -> Have you ever tried to strictly reduce fruit and other sources of fructose? Works pretty well with me.

      When I eat too much fructose at once, I get alternating diarrhea and constipation and significant amounts of blood in the stool. I learned that I have fructose intolerance after eating 2 small apples the size of 1 regular apple and nothing else as a breakfast (I reduced fruit consumption in the year before a lot because it was also full of natural sugars). That too should make fructose intolerance worse as I did not eat starch (rich in glucose) to offset the very high fructose-to-glucose ratio apples have. Result: a strong diarrhea about a day after doing so and plenty of blood in the stool, blood in the stool for 2 weeks, alternating diarrhea and constipation each during 2 to 3 days for 1 month and 1 more month of getting my gut only as before with a far stricter diet then before.
      -> Would that resemble (maybe minus the blood in the stool) what you call constipated diarrhea?

    • Cort Johnson

      December 21, 2018 at 4:07 pm - Reply

      Isn’t that something! Wow.

      I had never heard of a specific carbohydrate diet – http://www.breakingtheviciouscycle.info/

      For me I wonder if home fermented foods such as sauerkraut and pickles (non-pasturized) have a different or wider array of probiotics in them than say yogurt?

      • Yocheved

        December 25, 2018 at 11:39 pm - Reply

        I’ll let you know. I’m working on my first batch of fermented cabbage right this moment.

      • Vic

        January 20, 2019 at 3:55 pm - Reply

        The specific carbohydrate diet worked very well for my husband and me, gave us both more energy and I was finally able to think clearly. It did have lasting benefits, although neither of us could remain on the diet – we were able to do it for 3 weeks, and that was helpful, but then ended up adding some carbs and sugars beyond just honey back in. I’d believed I have a bacterial overgrowth for a long time, but as soon as I started having foods outside the SCD, all of that came back. But lowering carbs in general went a long way in clearing my brain fog, and that benefit remained.

        I don’t have ME but have a lot of things that border on it, gut issues, immune issues, including HHV-6, sick all the time, etc. I was doing the SC diet because of having the Alzheimer’s gene, APOE4. In the book “The End of Alzheimers”, Dr. Bredesen makes a series of recommendations and talks a lot about how closely connected diabetes is to Alzheimers. I recommend it to anyone who has the APOE4 gene. And if you don’t know, I recommend finding out – the choices you make about things like taking hormones, your diet, etc., can make a big difference.

        I’ve gone off my probiotic after hearing about this study and so far I’m not noticing any difference – the last time I stopped I got intense stomach cramps, but not so, this time. I’ve been a lot more vigilant about avoiding every possible source of gluten, and discovered there were some I hadn’t realized, like in soy sauce out at restaurants. I had read “Autoimmune Fix”, which was also really helpful in understanding the damaging role gluten can have.

  • Sarah R.

    December 20, 2018 at 2:34 pm - Reply

    Another excellent review of important literature, Cort. Thanks for this.

    I’ve tried multiple probiotics over the years, plus prebiotics at one point. I couldn’t see a positive effect from any of them except Align (Bifidobacterium 35624). It’s expensive in the context of all of the different meds and supplements I take (about 75 cents apiece), but I take it every day. The benefit I get from it sounds sort of weird, but it definitely makes me feel like I’ve fallen back into my body, instead of hovering right above it. I believe it must work somehow to calm at least one aspect of my neurological hyperactivity.

  • RAGHAVAN SANTHANAGOPALAN

    December 20, 2018 at 5:34 pm - Reply

    I could never tolerate probiotics or colostrum. But when I add them to kefir wait for 4 hours or so and then take it it is very useful. It does not cause my iBS to flare up. Instead it helps with eating trigger foods.

    • Cort Johnson

      December 21, 2018 at 4:02 pm - Reply

      Interesting! Thanks for passing that on.

      I find that home manufactured kefir is FAR superior to the pasturized stuff you get in the store. It’s almost a completely different production and much more potent.

    • dejurgen

      December 22, 2018 at 9:51 am - Reply

      That may relate to what Daniel said: some probiotics also contain fructans for them to feed on. When you are intolerant to fructans, that can be problematic. After his post, I was thinking about ways to “let the good bacteria in the probiotics eat the fructans” before I take the probiotics that contain fructans. Fermenting was one of the options but it sounded troublesome.

      Dropping in Kefir may just do that: consume the troublesome fructans and let them grow. Thanks for the idea RagHavan!

  • Dakota

    December 21, 2018 at 12:20 am - Reply

    Another awesome article Cort! Thanks for all that you do 🙂

    Question – on the Maureen Hanson mention at the end regarding overseeing a FMT Trial, has that trial started / do you know timing of the start date by chance?

    • Cort Johnson

      December 21, 2018 at 4:01 pm - Reply

      I’m pretty sure the trial has started but am not positive. As I remember she’s doing it in conjunction with a group in Europe.

  • dejurgen

    December 22, 2018 at 6:35 pm - Reply

    When looking at the blog and the comments of Rhonda, Daniel B. and Raghavan there seems to emerge a significant subgroup of people with fructan/FODMAP/fructose intolerance who do poorer then most on some sort of prebiotics. It resembles that for these people there may be a combination of:
    * more FODMAPs then usual end up in their large intestine due to less absorption in their small intestine.
    * they seem to have bad bacteria in their gut that grow very well on these FODMAPs
    * many of the good bacteria feed on food filled with FODMAPs
    => It seems reasonable to believe these bad bacteria largely feed on the same food as the good bacteria, but the bad ones have a faster rate of multiplication and outgrow the good ones. As bacteria evolve very rapidly it would be reasonable that the bad ones evolve to multiply even quicker under these hypothetical conditions. Mothers vulnerable to this would hence pass more virulent strains of bad bacteria to their newborn children.

    Potential solutions under this hypothesis:
    A) replace fiber with resistant starch hoping the bad bacteria like it less; problem can be that some foods high in RS are also high in FODMAPs or that increasing RS has other GI problems
    B) use what I would call “post biotics”; end products such as lactic acid or acetic acid do decrease multiplication rates of competing bacteria; using the wright end products can help shifting the odds in favor of the good bacteria; think of people using natural vinegar for health; problem is to determine the wright and tolerated mix
    C) fasting and keto diet???

    Let me explain C):
    Every living thing can invest more of it’s energy in either rapid growth or increased longlivity. Call it a general form of “Dauer’s law”: if we can hunker down to survive harsh conditions longer at the cost of reduced energy/renewal then it should work in reverse too. As mitochondria and much of basic building blocks of humans resemble a lot bacterial life, bacterial life should have it’s own sort of Dauer and reverse Dauer.

    => In short: if the bad bacteria can outcompete the good one by growing faster and hence start each day with high numbers favoring their further survival, then bacterial famine caused by fastening or keto diet (very low in FODMAPs and fiber) should help the good bacteria by allowing them to die less fast during famine then their more virulent bad competition.

    => In the case of the keto diet, the very low amount of “fast fuel” would favor the good bacteria. Over time this should reduce the need for the gut to have a strong immune response against the bad bacteria. As the gut is a very big part of the immune system, that should result in both better gut functionning (despite lower absolute bacteria counts) and lower immune activation.

    • Rhonda

      December 24, 2018 at 1:33 pm - Reply

      I think it is bigger than just the bacteria. It is more about the leakiness of the gut. If the gut is damaged and letting the contents of the intestinal tract into the bloodstream, lots of bad things happen. A new study might be helpful here. It showed that probiotics made lupus symptoms worse but resistant starch improved them in animals. It is a very technical paper, but very well done. They showed that resistant starch decreased the translocation of toxins across the intestinal barrier and reduced the inflammation and autoimmune responses of lupus. In short, it increased the effectiveness of the intestinal barrier, improving whole-body health. From this paper: “Overall, we demonstrate that RS fermentation to SCFAs and its effects on gut microbial communities improved outcomes in TLR7-dependent lupus models. RS decreased the abundance of L. reuteri, gut leakiness, type I IFN and proinflammatory responses, pDC infiltrations, and organ pathology, thereby preventing the development of systemic autoimmunity and decreasing mortality.” https://doi.org/10.1016/j.chom.2018.11.009.

      Resistant starch’s fermentation produces more of the short-chain fatty acid butyrate than other types of fibers. http://ajcn.nutrition.org/content/73/2/415s.short. Butyrate is the preferred food for colon cells. Colon cells are one of the few cells in the body that gets its food from the contents of the intestinal tract (not the blood). Without fermentable fibers AND bacteria to ferment them, the short-chain fatty acids do not get produced. Without butyrate, colon cells shrink and get leaky.

      • dejurgen

        December 31, 2018 at 12:55 pm - Reply

        Hi Rhonda,

        Thanks for the insightful comment. I too believe leakiness of the gut is important, but looked more at it from the “gut destruction by aggressive bacteria angle” then the “lack of gut restoration due to shortage of SCFA”.
        I believe in the strong benefits of SCFA. It’s just that I seem to produce them. Depending on what I eat I can have only moderate flatulence, odorless flatulence, sulfur-like flatulence, flatulence smelling like something I believe is buteric acid and flatulence having sour stable smell. When having “probably buteric acid filled gas” it seems the SCFA are largely expelled rather then taken up by the gut. But that’s truly but a “gut feeling”.
        The other reason why I mainly looked at the gut destruction rather then lack of restoration angle is because most keto diets should be very low in RS or fiber and hence produce low SCFA amounts. Yet, they seem to often improve symptoms including gut symptoms. That’s why I added at the end of my post on the keto subject “that should result in both better gut functioning (despite lower absolute bacteria counts) “.
        I also am conservative going quickly to full RS diet as for some it fires back too thegutinstitute.com/2014/10/dont-take-raw-potato-starch-rps-temporarily-if-you-have-an-autoimmune-disorder-part-5.html. The plan is to reduce fructose, FOS and inulin as likely the biggest causes of bacteria-gut related problems in my case (creating toxic products attacking gut lining and preventing SCFA to be produced and reaching gut lining sufficiently in my guess). For temporarily reduced gut bacteria counts I hope the keto-diet thing having probably low gut bacteria count helps me through this transition. I already shifted to eat potatoes cooked and cooled for RS. I prefer “natural food” remedies and I tolerate this low but increased quantities well. Next follows replacing oat with hand rolled oat containing more RS too. Then we’ll see where to go next. It’ll be a very slow process, but as long as I slowly progress I prefer that over the risk of a huge fire-back. I had a few very destructive ones in the past. I dread the idea of a new one.
        I have learned a few things from your post:
        * “Starch diet-derived short-chain fatty acids suppress L. reuteri in vitro and in vivo” from your first link. I suspected it might be suppressing competing bacteria, but it’s nice to have this confirmed. Can help me to balance my gut microbiome. In the future more RS might do but for now some butter will do nicely too. I tolerate diary well. Butter is often part of keto diets too.
        * From the second link you provided: “oligofructose yields predominantly acetate”. As I have problems with mainly fructos, FOS and inulin it is interesting to see that they (at least FOS) yield predominantly acetate. I was using natural vinegar as a “gut antibacterial” that reduces growth of non acetate producing bacteria in favor of acetate growing bacteria as they are supposedly good ones. There is no guaranty that mine are predominantly acetate producing too, but it seems wise to cut back on acetate intake to hopefully reduce their dominance. Going with that may be many fermented foods like sauerkraut or sourdough bread. On the other hand these are probably reducing FOS and inulin content in the raw product. But it may be better to avoid them and their unfermented base product altogether.

      • dejurgen

        December 31, 2018 at 2:12 pm - Reply

        I’ve been wondering for quite some time if that flatulence that smells like buteric acid is indeed high in buteric acid that is excreted. If so, it didn’t make much sense to me. But now I suddenly look at it different.
        We know from recent research that bacteria can interact with the brain and signal (via the nerve system) that they like a certain food increasing our wish or cravings to eat it. They also produce chemicals like serotonin that let us feel good, probably if they are fed something they like. What if some bacteria learned the reverse too? Could the dominant microbiome send a signal to the brain if it dislikes the current food in the gut so much that it entices it to flush it (causing diarrhea)? Could they create a strong feeling of not being well if they sensed a new competing species wants to take over? Could they produce toxic stuff creating a strong immune reaction in the gut towards all bacteria and creating strong GI symptoms and diarrhea in the process? It sounds complicated but a large ecosystem of different interacting simple species can demonstrate a surprising amount of perceived intelligence.
        Causing diarrhea would cause their numbers to be reduced as much as those of competing new species but it could give the dominant species a strong competitive advantage by denying the competing species to establish a foothold. And the dominant species could not grow much on that food anyways.
        It could help explain why increasing fiber or RS from lowish to average in a single step can cause an outspoken upflare in GI symptoms. Given the exponential growth rate of bacteria, even with the dominant species creating chemicals reducing the growth rate of competing species, any species that grows well on that fiber or RS is already present and should be able to cope with for example a 60% increase of preferred food no problem IMO. So there may be more going on then just competitive growth rate reduction by producing stuff (like natural antibiotics, acetate, SCFA…) by one type of bacteria that directly modifies the growth rate of competing bacteria. Enticing and modulating the gut immune system and emptying may help doing the trick.

  • Yocheved

    December 25, 2018 at 11:42 pm - Reply

    Do you know if there are any ME doctors in Israel? I see a lot of doctors who know a little bit about some things, but nobody who gets the whole picture. I know we have so much research here, it’s very frustrating to not be able to see someone! I would gladly travel halfway across the country and eat some poop if it would make me feel better.

  • gh

    December 29, 2018 at 8:43 am - Reply

    I’ve had some improvement in brain symptoms lately from taking Pediococcus acidilactici. (In Jarrow EPS).
    Pediococcus acidilactici suppresses Autoimmune Encephalomyelitis:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217013/

  • Nansy Mathews, CRNP

    January 1, 2019 at 6:32 pm - Reply

    I cannot resist adding one more confusing element to this discussion: for those of us with CFS who were not breastfed taking Bifidobacterium 35624 should be helpful. Do you agree?

  • mark roth

    February 12, 2019 at 9:17 pm - Reply

    To piggyback on these last 2 comments, Pediococcus Acidilactici increased my IgA levels and is also relieving some of my brain fog. I also noticed almost total relief of my recently new experiences with inflammation pain. And I’ve just ordered Visbiome, aka VSL#3, which is supposed to act at MANY inflammatory sites (including cd38). One of its 8 probiotic strains is Bifidobacterium Infantis 35624. Fingers crossed

  • lisa d

    April 16, 2019 at 4:26 am - Reply

    I found all of this information very interesting and helpful. I wanted to share my response to L. Reuter. After only two doses I became extremely more fatigued, weak, and tired. My food sensitivities came back, and a weird head sensation when drinking carbonation returned as well. Not soda, something about carbonation. I have no idea why, but for years it would create an awful wavy feeling in my brain.