Quite a few ME/CFS patients experience bad reactions from taking prebiotics — reactions such as significant gut pain, stomach bloating, diarrhea, constipation, or a worsening of ME/CFS symptoms. A poll showed that 48% of ME/CFS patients cannot tolerate prebiotic supplements like inulin or FOS (although 52% are fine with prebiotics). Patients have often assumed that these bad reactions are caused by the effect of prebiotics on the gut microbiota. However, in addition to their effects on the microbiota, prebiotics exert a direct stimulating effect on the immune system, and specifically the complement system, a part of the innate immune system. This post explores whether this direct activation of the immune system by prebiotics might explain (at least in part) the prebiotic sensitivity that occurs in many ME/CFS patients, and considers an approach that may mitigate prebiotic sensitivity. Inulin And FOS Directly Activate The Immune System Prebiotics inulin and fructo-oligosaccharide (FOS, aka oligofructose) have direct effects on the immune system, independent of their action on gut bacteria: More info on complement receptor 3 can be found here: Macrophage-1 antigen So inulin and FOS may be directly modulating immune function by their effects on the carbohydrate receptors. And in the book Atlas of Immunology, it says that inulin is known to activate the alternative pathway of the complement system. Interestingly, inulin-derived adjuvants (immune stimulants) have been examined as possible replacements for the standard aluminum hydroxide vaccine adjuvant: It may also be of relevance that coxsackievirus B, a virus strongly associated with ME/CFS, is known to activate the alternative pathway (but not the classical pathway) of the complement system (ref: here). So the presence of a chronic coxsackievirus B / enterovirus infection in the stomach or intestines (which Dr Chia found in 82% of ME/CFS patients) may be constantly activating the alternative complement pathway, and then when prebiotics are consumed, this activation may be further increased. Reducing the Activation of The Alternative Complement Pathway As we have seen, possibly the bad reactions that some ME/CFS experience with prebiotic supplements like inulin and FOS may arise through the direct effect that these prebiotics have on the immune system, and specifically their activation of the alternative pathway of the complement system. If activation of the alternative pathway is the cause of the bad reactions some ME/CFS patients experience when taking prebiotics, then possibly inhibitors of the alternative pathway might prevent or mitigate these bad reactions. Alternative pathway inhibitors include: rosmarinic acid, which is found in Melissa officinalis (lemon balm) essential oil and Rosmarinus officinalis (rosemary) essential oil (ref: here), the herb Ephedra sinica (ref: here), heparin (ref: here), and fucans (sulfated polysaccharides) from brown seaweed such as Ecklonia cava (ref: here). See also page 74 of this paper: Therapeutic Inhibition of the Complement System. Note that olive leaf extract is a potent inhibitor of the classical pathway of the complement system, but not the alternative pathway. So possibly taking say Ecklonia cava, or several drops of lemon balm essential oil (diluted in 15 ml of cooking oil) might mitigate the bad reactions from prebiotics, and might even be generally helpful for gut health in ME/CFS patients with such prebiotic sensitivities. Prebiotics In Foods: A Paradox An intrigue about ME/CFS patients' intolerance to prebiotic supplements is that, as far as I am aware, prebiotic-sensitive ME/CFS patients do not generally experience problems with high-prebiotic foods like onions, leeks, garlic, asparagus, chicory, wheat flour and Jerusalem artichoke (ref: here). If you consider leeks for example, these contain 3 to 10% inulin (ref: here). A couple of large leeks weighs around 400 grams, so if you were to eat two large leeks, you would be getting 12 to 40 grams of inulin. That's quite a bit of inulin, probably more than you would take if you were supplementing with pure inulin power. (One heaped teaspoon of pure inulin power weighs around 5 grams). So this is something of a conundrum: why should prebiotics in food cause no issues, but when the same prebiotics are taken in pure supplement form, they trigger bad reactions in quite a few ME/CFS patients? One possible speculative explanation is that pure prebiotic powders like inulin may be more immediately accessible or bioavailable than the inulin naturally found in food items (the prebiotics in foods may be released more slowly). This may mean that the inulin and FOS naturally found within foods do not activate the complement system as much as when these prebiotics are taken in purified supplement form, and this might perhaps explain why foods high in prebiotics are tolerated by ME/CFS patients, but pure prebiotics often cause bad reactions. However, this is just a guess. Though if high prebiotic foods are not causing any problems for prebiotic-sensitive ME/CFS patients, this suggests that eating more of these foods may be a good way to increase prebiotic intake for such patients — and thereby feed their friendly bacteria — but without precipitating the bad reactions that prebiotic supplements can create.