Thursday, September 3, 2015

Gluten Research Update: Cesarean Section, Breast Feeding, Noocebo Effects and the ‘Right’ & ‘Wrong’ Bacterial ‘Poop’

As read on the SV Facebook: Baking makes gluten resilient to digestion, the presence of protein does the opposite. The food matrix makes the difference.
In view of the fact that "gluten" is or isn't (literally) in everyone's mouth or tummy, I thought that it may make sense to keep you up-to-date on the latest interesting research in the area of non-celiac gluten sensitivity and celiac disease.

Don't worry I am not going to bother you with the typical Internet bogus about how cancer, obesity and everything else we are or are not suffering from (yet) is triggered by gluten. What I will do, though, is to summarize and discuss the results of two recent studies and one review on the connection between our microbiome and our very individual susceptibility to gluten-related health problems
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Is Gluten Intolerance Real?
  • Celiac disease and non-celiac gluten sensitivity may be all about the microbiome and begin at the very moment you're born via cesarean section and worsen when you're not breastfed - In a soon-to-be-published review in Nutrients Cenit et al. try to elucidate whether gluten intolerance and celiac disease are consequences or triggers of significant imbalances in the bacterial composition of the human microbiome and how one or the other may eventually come about..

    As the authors point out, there are in fact studies which suggest that the early colonization of the infant’s gut in conjunction with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of our kids' oral tolerance to gluten.
    Figure 1: Proposed model for celiac disease (CD) pathogenesis. Specific host genetic makeup and environmental factors could promote the colonization of pathobionts and reduce symbionts, thus leading to dysbiosis. Dysbiosis may contribute to disrupting the immune homeostasis and gut integrity, thereby favoring CD onset and aggravating the pathogenesis (Cenit. 2015).
    In that, the early colonization of the intestinal tract is of particular importance, because it programs a normal or abnormal immune reaction to gluten (and other potential allergens). It is thus no wonder that celiac disease and a whole host of other autoimmune diseases have been linked to a lack of, or an improper early colonization of the intestinal tract and the consequential misprogramming of the immune cells. In that, it has been suggested that the resulting dysbiosis may affect autoimmunity by altering the balance between tolerogenic and inflammatory members of the microbiota and, therefore, the host immune response.

    Needless to say that the increased risk of autoimmune diseases is a standalone problem. It is after all not a mere reaction to the bacteria, but a bacterially induced phenomenon that involves the epigentic reprogramming of a whole host of genes. This process is however (unfortunately) so complex that we haven't yet fully understood the individual bacteria-gene and gene-gene interactions. Everyone, who tells you otherwise is lying - probably to sell his snake oil or snake oilish lifestyle advise.
    Figure 2: While there's one outlier, 3/4 studies on the effects of breastfeeding when the first gluten containing foods are introduced show significantly reduced risks of developing celiac disease (Akobeng. 2006).
    Among the few things we do know, though, is that breastfeeding and the way it promotes the early colonization of the gut with Bifidobacterium spp. is associated with a reduced risk of gluten intolerance. This is particularly true, if gluten containing foods are introduced while the kids are still breastfed (-52% according to a meta-analysis by Akobeng et al. 2006).
Breast milk contains a gliadin specific anti-body - What does that mean? Özkan et al. were the first to describe the presence of gliadin-specific IgA antibodies in breast milk (Özkan. 2000). The presence of significant amounts of this anti-body in the breast-milk (and even more in the colostrum) of 105 healthy mothers (aged 17 – 36 years) is generally understood to be one of the potential pathways by which breast milk and colostrum can protect children from celiac disease by educating the immature immune system of newborn children.
  • The fact that these benefits do not apply for every breastfed child may be explained by (epi-)genetic polymorphisms of the mother, such as the altered concentration of several immune markers that have been observed by several researchers in the breast milk of mothers with celiac disease (Olivares. 2014). If that's in fact the case, it's hardly astonishing that the number of celiac patients began to rise when the use of formula peaked and is exploding now that more and more women with celiac disease (or non-celiac gluten sensitivity) are feeding their children with "non-protective" breast milk. We must be careful, though, not to jump to conclusions. There are, after all, as Cenit et al. point out "no robust prospective studies revealing how differences in breast milk composition and intestinal microbiota acquisition and evolution early in life might ultimately protect or contribute to CD onset" (Cenit. 2015).

    A similar healthy skepticism is necessary with respect to the link of cesarean sections and an increased susceptibility to gluten sensitivity (Dominguez-Bello. 2010). While it would appear logical to assume that the lack of exposure to the vaginal microbiome may contribute to the previously mentioned misprogramming of the immune system, it would be overtly simplistic to assume that gluten wouldn't be a problem if we were all breastfed and born the natural way.
    Figure 3: Increases in risk of full-blown celiac, intestinal inflamation and the presence of markers of celiac disease in the blood in subjects with previous exposure to antibiotics; in all fairness it must be said that the risk increase decreased when individuals who were exposed within the last 24m were excluded - even then the reduced 30% increase was statistically significant and practically relevant, though (Mårild. 2013)
    In conjunction with the indisputable link between the (early) use of antibiotics (Mårild. 2013 | see Figure 3) and the first successful efforts to ameliorate the chronic inflammation in celiac guts with prebiotics, there is yet little doubt that the "right" microbial make-up may be what distinguishes celiacs from patients with non-celiac gluten insensitivity and the still large number of people who don't appear to react to gluten at all.
  • Study in healthy subjects, celiacs and their relatives suggests that the way your bacteria metabolize gluten may make you sick - From the first study, or rather review, I've analyzed in this feature article we've already learned that the inability to digest or handle gluten may be transmitted via certain immune factors in the breast milk from mother to child. It is thus particularly interesting that scientists from the Universidad de Léon in Spain who compared the stool of sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten found that significant differences in how celiac disease patients metabolized gluten.
Good news for celiacs: With the increasing awareness of celiac disease and gluten intolerance and the ever-increasing market shares of gluten-free products, it has become relatively easy to eat gluten-free, these days. Against that background it is all the more important that a recent study shows remission rates of 37% and general improvements in more than 50% of the patients in a recent study investigating the efficacy of gluten-free diets in celiacs over a four-year period (Newnham. 2015). The only potentially "bad" news is that all subjects gained significant amounts of body fat - specifically in the first year. The lean body mass indices, which did also improve, on the other hand, improved only very slowly and irrespective of status at diagnosis.
  • Table 1: Cultivable bacteria involved in gluten metabolism isolated from faeces of healthy subjects, active coeliac disease patients and firstdegree relatives (Caminaro. 2015).
    In contrast to healthy volunteers, their feces showed a significantly higher glutenasic activity (FGA), tryptic activity (FTA), SCFA, but lower levels of faecal gluten. That's interesting, yet counter-intuitive. After all, we've previously thought that one of the main problems of celiac disease and non-celiac gluten sensitivity is that the proteins are not broken down. Rather than that the results of the study at hand suggest that celiacs harbour bacteria that generate immunogenic peptides or pro-inflammatory metabolites which are the actual triggers of the problem (otherwise they'd have to poo out at least as much gluten as the other subjects on the gluten-free diets).

    Needless to say that this result does, once more, point toward fecal transplants or prebiotics as potential future treatment options celiac disease and non-celiac gluten sensitivity... with the only problem being: We don't know yet which bacteria we want to support and which to annihilate to solve the problem. If you look at the data in Table 1, though, killing the Clostridium and promoting the Lactobacillus population could be a first step to reinstalling a less celiac-prone gut microbiome.
  • More 60% of non-celiac gluten patients don't react to gluten in randomized clinical study - That's certainly an impressive number Zanini et al. report in their latest paper in Alimentary Pharmacology and Therapeutics (Zanani. 2015).

    Let's hope aspergillus niger does not produce the wrong proteins when breaking down gluten otherwise it would make NCGS worse not better. Thus, further studies are needed. 
    In the corresponding study the researchers studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures of the study from the University and Spedali Civili of Brescia in Italy were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores (criteria & results see Figure 4).

    In contrast to what the Internet experts are trying to make you believe, only 12 and thus hardly more than 34% of the allegedly highly gluten-intolerant patients were able to tell when they were fed gluten-containing flour based on increases in pain, reflux, indigestion, diarrhoea, and constipation.
    Figure 4: Increased severity of symptoms according to whether subjects were able to distinguish whether they were fed a gluten-containing or gluten-free diet (Zanani. 2015).
    Seventeen participants (49%), on the other hand, swore black and blue that they had been fed the gluten-containing flour when they were on the gluten-free diet (and if you look at the data in Figure 4, they even felt worse than those who were actually sensitive ;-).

    Now, what's most intriguing about this is that the study proves that there's a non-negligible noocebo effect involved, when it comes to non-celiac gluten sensitivity. One that's powerful enough to have people experience real increases in pain, reflux, indigestion, diarrhoea, and constipation... that tells you something about how infections reading too much bogus on the internet is, right?
Is Noneliac Gluten Sensitivity Legit? A Recently Published Review of the Latest Scientific Evidence on NCGS by Alex Leaf (Guestpost) May Help You Decide Whether you Even Want to Do the Painstaking Test | more
Bottom line: By including yet another study that puts a huge question mark behind the allegedly ever-increasing prevalence of non-celiac gluten intolerance into this write-up I am not trying to suggest that this pathogenesis does not exist. I am just trying to remind you that there is good evidence that it can also be triggered by the mere assumption that you have NCGS.

With that being said, the actual topic of this feature article is not the noocebo effect of the aggressive gluten-free propaganda, but rather the evidence of the existence of a physiological link between "dysbiosis" (in the broadest sense), the subsequent mal-metabolism of gluten by the "wrong" bacteria in your gut and the occurence of gluten sensitivity and full-blown celiac disease.

As bad as this may sound, the potential existence of this link between the gut microbiome and gluten sensitivity is actually good news: If the influence of your current gut bugs is in fact as huge as some of the scientists speculate, it should be possible to ameliorate, if not annihilate, the symptoms by reinstalling a "corrected" gut microbiome that helps celiacs and individuals with non-celiac gluten sensitivity metabolize gluten "correctly". This in turn could eventually even reverse the epigenetic changes that are causally involved in the inflammatory immune response to gluten and thus alleviate at least the nasty problems that occur if celiacs consume really small amounts of gluten incidentally. Whether it will fully reverse celiac disease, though, appears more than just questionable to me | Comment on Facebook!
  • Akobeng, Anthony K., et al. "Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies." Archives of disease in childhood 91.1 (2006): 39-43.
  • Caminero, et al. "Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives." British Journal of Nutrition (2015): Ahead of print.
  • Dominguez-Bello, Maria G., et al. "Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns." Proceedings of the National Academy of Sciences 107.26 (2010): 11971-11975.
  • Mårild, Karl, et al. "Antibiotic exposure and the development of coeliac disease: a nationwide case–control study." BMC gastroenterology 13.1 (2013): 109.
  • Newnham, Evan D., et al. "Adherence to the gluten‐free diet can achieve the therapeutic goals in almost all patients with coeliac disease: A five‐year longitudinal study from diagnosis." Journal of gastroenterology and hepatology (2015).
  • Olivares, Marta, et al. "Human milk composition differs in healthy mothers and mothers with celiac disease." European journal of nutrition 54.1 (2014): 119-128.
  • Özkan, T., T. Özeke, and A. Meral. "Gliadin-specific IgA antibodies in breast milk." Journal of international medical research 28.5 (2000): 234-240.
  • Zanetti, et al. "Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity." Alimentary Pharmacology and Therapeutics (2015): Ahead of print.