A gluten-free diet for "schizophrenia positive for antigliadin antibodies (AGA IgG)"

Short post alert...

"This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder."

So said the findings reported by Deanna Kelly and colleagues [1] as the conference abstract [2] of their study finally hits the peer-reviewed science literature (see here).

As per my previous musings on this study, this was the "first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA [anti-gliadin antibodies] IgG." Results were interesting insofar as "participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale... and in negative symptoms." Net result: encouraging findings with the need for more study; also with a nice focus on effect sizes too...

'Nuff said.

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[1] Kelly DL. et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019 Mar 27;44(3):1-9.

[2] Kelly D. et al. Randomized double-blind feasibility study of a gluten-free diet in people with schizophrenia and elevated antigliadin antibodies (AGA IgG). Schizophrenia Bulletin. 2018; 44: S190.

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Gluten, mimicry and schizophrenia

The findings reported by Daniela Čiháková and colleagues [1] provide the rather long blogging fodder today, and some interesting observations on how the immune system 'reacting' to gluten in some cases of schizophrenia might have some pretty far-reaching consequences when it comes to other proteins with a similar chemical structure.

OK, first things first, gluten is a protein. It's made up of long chains of amino acids; the building blocks of proteins. As gluten is digested in the gastrointestinal (GI) tract, various enzymes get to work on the protein to break it down into it's constituent amino acids, forming peptides (short chains of amino acids) along the way. The protein gluten and its components like gliadin has a characteristic shape like every protein has. For reasons that aren't yet completely understood, the immune system of some people can sometimes 'mark' normally fairly harmless proteins like gliadin as something that needs dealing with. It does this via the production of antibodies. Antibodies usually mark pathogens like bacteria or viruses, and by doing so, set off a cascade of biological processes to [try and] ensure that such invaders don't take hold and also to remind the immune system of what to look out for. Marking something like gliadin out (which is neither bacteria nor virus!) probably means that the body is detecting gliadin in places it shouldn't be; something that I'll come back to in a minute.

It's not beyond the realms of possibility that when the immune system marks a specific protein as something to keep an eye on, it can make mistakes. If for example, two proteins 'look' similar to each other in a chemical arrangement sense, despite being different proteins with different functions, the immune system can sometimes become a little confused and start to mark both as being an invader on the basis of one already having 'special interest' status. Several descriptions describe such a process: "cross reactivity or mimicry." This accidental marking can sometimes have important repercussions, where such a process is thought to be a basis for autoimmunity.

Čiháková et al detail findings suggesting that just such a process - mimicry - could well be pertinent to some cases of schizophrenia. As already mentioned, they started with the observation that some people diagnosed with schizophrenia have high levels of specific antibodies to gliadin (see here and see here). This follows quite a lot of history linking gluten and schizophrenia together (see here). They wanted to see if as well as presenting with antibodies to gliadin, a cohort of people diagnosed with schizophrenia might also present with elevated antibodies to something called GRINA - Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1. They focused in on GRINA because it has a "similar protein structure to gliadin representing a potential target for cross reactivity or mimicry." GRINA also links into glutamate system functioning, something which has also already been mentioned with schizophrenia in mind (see here).

There's another detail about the Čiháková study which relates to a point I touched upon earlier, on the possible hows-and-whys of gliadin antibodies being found in cases of schizophrenia: enhanced gut permeability a.k.a leaky gut. Researchers also analysed serum samples for the presence of something called Anti-Saccharomyces Cerevisiae antibodies (ASCA) which they say are "related to gut permeability." This follows other research in a similar vein (see here) and the suggestion that something like abnormal gut permeability *could* be implicated in some cases of schizophrenia.

Results: looking at serum samples of 160 people diagnosed with schizophrenia and 80 not-schizophrenia controls, researchers observed "a higher prevalence of positivity to ASCA IgA... and IgG" in those with schizophrenia. This tallies with the leaky gut hypothesis. They also reported that "GRINA IgG was higher in schizophrenia patients than in healthy controls." Putting these results together, they concluded that the mimicry hypothesis might well be pertinent to some schizophrenia.

There is a lot more work required in this area for sure. This will need to involve further investigation of the hows-and-whys of any such mimicry, and whether such a process could be a potential target for intervention. Indeed, in that intervention vein, I'm wondering whether use of a gluten-free diet for some with schizophrenia who have such antibodies (to gluten and other things like GRINA) might be an option. There's also merit in looking further at the issue of gut permeability and schizophrenia; whether again adoption of a gluten-free diet (which can positively affect gut permeability measurements) might be indicated, perhaps alongside other therapeutic targets.

But this area of research is interesting, and adds to the quite long research history linking food components and some behavioural / psychiatric labels...

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[1] Čiháková D. et al. Gut permeability and mimicry of the Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) as potential mechanisms related to a subgroup of people with schizophrenia with elevated antigliadin antibodies (AGA IgG). Schizophr Res. 2019 Jan 23. pii: S0920-9964(19)30007-6.

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Antibodies against gluten in autism don't correlate with leaky gut markers

The paper by Jan Józefczuk and colleagues [1] provided some intriguing observations pertinent to quite a few topics previously discussed on this blog. Not only was there mention of anti-gliadin antibodies (AGA) and more specifically the finding that increased IgG-AGA was found in a quarter of their 77 participants with autism included for study, but also the important point: "An increased production of antibodies related to gliadin and neural TG6 [neural transglutaminase 6] in ASD [autism spectrum disorder] children is not related to serological markers of an impaired intestinal barrier."

It's worthwhile breaking down some of the details of the Józefczuk findings and what they might mean. I'll warn you that this is likely to be a bit of a long-read blog post so please, get comfy and read on...

So, AGA and more specifically, IgG-AGA represent the immune system 'recognising' gliadin, an important part of the protein gluten. IgG-AGA are typically found in many people diagnosed with the archetypal gluten-related autoimmune condition called coeliac (celiac) disease (although this measure is not considered diagnostic) but also alongside other more 'non-coeliac' gluten sensitivity conditions too (see here). The finding of elevated IgG AGA in cases of autism is by no means a new one (see here) (yes, this data came from the AGRE program [2] so no quibbling about the diagnosis of autism or anything like that). Other data has indicated that the presence of such antibodies seems to be a good reason to attempt a gluten-free diet (see here) which is music to my autism research ears (see here) and a good evidence-based reason to quiet down those who might 'challenge' such dietary intervention in the context of [some] autism. Then also is the idea that the presence of IgG AGA in conditions not totally unrelated to autism (see here) *might* play an important role in something like 'peripheral' inflammation [3] and whether the same could be true for [some] autism...

Next: "antibodies against neural transglutaminase 6 (TG6)" described by the authors as present in about 5% of their cohort is also an important finding. Turning up in a variety of different conditions [4] (although not yet considered 'mainstream' in certain quarters), some of the most interesting, and potentially relevant, labels where TG6 might be present include something called gluten ataxia [5], a neurological 'sign' characterised by a 'lack of voluntary coordination of muscle movements that includes gait abnormality.' Again, the data is compelling insofar as the use of a gluten-free diet as an intervention option [6] where gluten ataxia is diagnosed. With specific regards to autism and TG6 antibodies, I think the Józefczuk paper provides the first research outing for the two together (at least in a PubMed search). Other transglutaminase antibodies however, have been reported in the context of autism (see here for example) with the need for lots more investigations including with reference to the overlap between autism and coeliac disease (see here). At this point, I'll also note that gluten ataxia has not yet been linked to autism despite ataxia potentially showing some connection to some cases [7].

Moving on and we have the finding that: "Mean levels of zonulin and I-FABP [intestinal fatty acid binding proteins] in ASD [autism spectrum disorder] patients were similar to those found in healthy controls." Further: "Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity." OK, zonulin is another topic of interest to this blog particularly in light of other recent findings with autism in mind (see here). Still the topic of considerable debate, zonulin has been described as "a biomarker of impaired gut barrier function for several autoimmune, neurodegenerative, and tumoral diseases" [8]. The data so far seems to indicate that gliadin - that component of gluten - 'induces' zonulin release [9] hinting that diet may be an important variable when it comes to 'impaired gut barrier function' otherwise known as intestinal hyperpermeability (or more imprecisely, leaky gut). I-FABP is something I'm a little less sure about in any context. It has been mentioned in the peer-reviewed research arena with autism in mind [10] but I can claim not expertise on this specific marker.

The Józefczuk findings report that zonulin levels in their cohort with autism were similar to "to those found in healthy controls" which is contrary to those previous findings in autism published by Erman Esnafoglu and colleagues [11]. They (Esnafoglu et al) concluded that: "Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). " Forgetting (but not excusing) the incorrect use of 'healthy controls' in that paper, there is something of a difference between the Esnafoglu and Józefczuk results. One could argue that this is simply reflective of 'conflicting' autism research more generally (see here) but one might also question things like the analytical ways-and-means of assaying for something like zonulin too (see here).

The observation that zonulin (and I-FABP) levels showed 'no statistically significant association with antibody positivity' whilst informative is something I've been thinking about quite a bit. I don't have any easy answers as to why they found what they found aside from assuming that such data is evidence for how "increased immune reactivity against gluten" might not be specifically related to "the effect of intestinal barrier abnormalities" in relation to autism. This relationship assumes that abnormal gut permeability is the route through which gluten fragments (peptides) gain access to the wider central nervous system (CNS) which then elicits that immune response. It is a little surprising that no relationship was found given that one of the ways that zonulin is released is ingestion of gliadin and the assumption that gluten needs to be present in the diet for antibodies to be formed against it. But there you go. I suppose one might entertain the possibility that zonulin as a biomarker of impaired gut barrier function might not be the optimal way of measuring gut barrier function and including other more direct measures [12] could be the way forward to resolving this issue further.

Either way, research on immunological responses to gluten and notions of atypical gut permeability in the context of 'some autism' are seemingly not going away any time soon. Indeed, even medical professionals are seemingly not adverse to prescribing a gluten-free diet in the context of [some] autism [13]...

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[1] Józefczuk J. et al. The Occurrence of Antibodies Against Gluten in Children with Autism Spectrum Disorders Does Not Correlate with Serological Markers of Impaired Intestinal Permeability. J Med Food. 2017 Oct 26.

[2] Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155.

[3] Kelly DL. et al. Anti Gliadin Antibodies (AGA IgG) Related to Peripheral Inflammation in Schizophrenia. Brain Behav Immun. 2017 Oct 23. pii: S0889-1591(17)30476-2.

[4] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Jun;72(6):676-81.

[5] Hadjivassiliou M. et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008 Sep;64(3):332-43.

[6] Hadjivassiliou M. et al. Dietary treatment of gluten ataxia. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;74(9):1221-1224.

[7] Ahsgren I. et al. Ataxia, autism, and the cerebellum: a clinical study of 32 individuals with congenital ataxia. Dev Med Child Neurol. 2005 Mar;47(3):193-8.

[8] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

[9] Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218-23.

[10] Pusponegoro HD. et al. Maladaptive Behavior and Gastrointestinal Disorders in Children with Autism Spectrum Disorder. Pediatr Gastroenterol Hepatol Nutr. 2015 Dec;18(4):230-7.

[11] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. Journal of Pediatrics. 2017; 188: 240-244.

[12] Bischoff SC. et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology. 2014;14:189.

[13] Rubenstein E. et al. The prevalence of gluten free diet use among preschool children with autism spectrum disorder. Autism Res. 2017 Nov 20.

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"a gluten-related subgroup of schizophrenia"?

A quote to begin this post: "this preliminary study demonstrates that altered AGDA [antibodies against gliadin-derived antigen] levels in the circulation are associated with schizophrenia and could serve as biomarkers for the identification of a schizophrenia subgroup that may need an alternative therapy or precision treatment."

So said the findings reported by McLean and colleagues [1] (open-access) looking at an area of some interest to this blog (see here) on how dietary gluten might show something of an important relationship to at least some cases of schizophrenia. Just in case you weren't aware, there is quite a history when it comes to gluten and schizophrenia (see here) as per the very forward-thinking of people such as Curt Dohan and Karl Reichelt.

Researchers on this latest occasion set about looking in a little more detail at the suggestion that circulating anti-gliadin antibodies (AGAs) reflective of an immune response to a component of dietary gluten might show some connection to schizophrenia. Indeed they note that "all the tests for circulating AGAs in schizophrenia have been developed with mixtures of full-length native gliadins consisting of ~300 amino acid residues" suggesting that such a scatter gun approach may have included epitopes "that are unlikely to survive digestion in the gut." So, they instead "measured plasma levels of IgG and IgA against indigestible peptide fragments derived from γ- and α-gliadins" in archived plasma samples from "169 patients with schizophrenia and 236 control subjects."

The results - based on the use of an "In-house ELISA for antibodies against gliadin-derived antigens" - were rather intriguing. So: "There was no significant difference in the levels of plasma antibodies against native gliadins between the patient group and the control group." If I'm reading this right, this finding is in contrast to other independent research occasions [2]. Indeed, when it came to looking at both IgA and IgG plasma anti-gliadin antibodies, there was no significant difference between the schizophrenia and non-schizophrenia participants as groups.

But... when it came to a specific gliadin (γ-Gliadin) derived fragment  - AAQ6C - with the amino acid sequence HPKCSIMRAPFASIVAGIGGQYRD - researchers reported on something potentially important to see: "patients with schizophrenia had significantly higher levels of plasma anti-AAQ6C IgG than control subjects." Importantly too, authors also noted that anti-psychotic medication did not appear to influence their antibody results. This was important given that seemingly all of the participants diagnosed with schizophrenia were taking one or more of this class of medicine. In line with the opening quote to this post, the authors make a preliminary foray into the possible 'biomarker' usefulness of the various anti-gluten antibodies for schizophrenia. I have to say on this point however, that the data is not that impressive as things currently stand.

There is more to do when it comes to the possible effects of dietary elements containing gluten (and casein) in relation to cases of schizophrenia. This work adds something to the idea that diet can affect psychiatry/behaviour/development but what is perhaps missing is the recognition that schizophrenia is probably a heterogeneous and plural condition (see here and see here for examples) and as such, not every case is going to be gluten and/or casein-related. I do agree with the authors that more research is needed in this area alongside the idea that intervention via either dietary changes [3] and/or other options might also be on the research agenda...

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[1] McLean RT. et al. Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational Psychiatr. 2017. May 9.

[2] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[3] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophrenia Res. 2012;140(0):262-263.

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McLean RT, Wilson P, St Clair D, Mustard CJ, & Wei J (2017). Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia. Translational psychiatry, 7 (5) PMID: 28485731

Candida albicans triggering coeliac disease?

Will the bafflement around coeliac (celiac) disease ever stop?

I want you to cast your eye over the paper from Marion Corouge and colleagues [1] (open-access) and the interesting hypothesis that: "CI [Candida albicans infection] may trigger CeD [coeliac disease] onset in genetically-susceptible individuals."

Continuing a theme of 'bafflement' when it comes to the autoimmune condition known as coeliac disease (see here), Corouge et al reported that a protein, hyphal wall protein 1 (Hwp1) present in C. albicans, 'required for hyphal development and yeast adhesion to epithelial cells' "presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase." Further a: "suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset."

Just in case you aren't au fait with all-things coeliac disease, my training post on the condition might come in useful (see here). Gliadin is a type of protein found in wheat and other cereal produce which together with the glutenins make up gluten. Gluten is the stuff that those with coeliac disease have to avoid as a consequence of the peptides that it eventually is metabolised into meeting a specific (geno)type of immune system. Transglutaminase reflects enzymatic alterations to said gluten peptides and a sort of 'super-charging' of them (deamidation) with reference to that 'coeliac immune system' and the processes it starts/continues.

There is quite a bit of chemistry included in the Corouge paper but the main results were:

• "using recombinant Hwp1" the authors reported "serological cross-reactivity in humans between this C. albicans antigen and gliadin." This translates into Hwp1 and gliadin - peptides from gliadin - potentially having something of a shared ability to invoke an immune response or be involved in immune processes pertinent to coeliac disease.
• Looking at serum samples from participants diagnosed with coeliac disease or presenting with "systemic CI" researchers also reported that: "CI and CeD patients had higher levels of anti-Hwp1... and anti-gliadin... antibodies" than asymptomatic control specimens. Interestingly, they couldn't [significantly] differentiate between the coeliac and CI samples on these parameters .
• When plotting Hwp1 levels and anti-gliadin antibodies "during the course of C. albicans infection" they found that the expected increase in anti-Hwp1 antibodies was also accompanied by an "increase in anti-gliadin antibodies that paralleled the anti-Hwp1 response."
• Finally: "The decrease in levels of anti-gliadin antibodies in GFD [gluten-free diet] -adherent compared to non-adherent CeD patients further validates the clinical classification used." That being said: "the relative independence of anti-Hwp1 antibodies from a GFD" hints that the gluten-free diet might do many things but not necessarily everything in this suggested relationship.

A final quote from the paper is worthwhile reproducing: "This study has revealed immune cross-recognition between two substrates of the potential auto-antigen transglutaminase, namely the fungal “invasive” protein Hwp1 and the dietary ‘innocuous” vegetal protein gliadin. Together our data, obtained from a translational comparative analysis of an infectious and an auto-immune disease, support the hypothesis... that the former may trigger the development of the latter."

Independent replication is the name of the game when it comes to the Corouge results before anyone gets too carried away with the possible implications. That being said, the idea that in those possessing the risk genotype of coeliac disease a bout of Candida albican infection might have the ability to set the biological wheels in motion in a journey towards the condition (or even perpetuating the condition) represents a potentially important finding [2]. One might also question whether similar cross reactivity (molecular mimicry?) might also be transferable to other autoimmune conditions and whether the agent of choice has to necessarily be just a fungus [3]?

Music: Kings Of Leon - The Bucket.

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[1] Corouge M. et al. Humoral Immunity Links Candida albicans Infection and Celiac Disease. PLoS One. 2015 Mar 20;10(3):e0121776.

[2] Nieuwenhuizen WF. et al. Is Candida albicans a trigger in the onset of coeliac disease? Lancet. 2003 Jun 21;361(9375):2152-4.

[3] Cabrera-Chávez F. et al. Maize prolamins resistant to peptic-tryptic digestion maintain immune-recognition by IgA from some celiac disease patients. Plant Foods Hum Nutr. 2012 Mar;67(1):24, 30.

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Corouge M, Loridant S, Fradin C, Salleron J, Damiens S, Moragues MD, Souplet V, Jouault T, Robert R, Dubucquoi S, Sendid B, Colombel JF, & Poulain D (2015). Humoral Immunity Links Candida albicans Infection and Celiac Disease. PloS one, 10 (3) PMID: 25793717

Stopping gliadin peptides in their tracks?

A micropost if you will, to bring to your attention the paper by Marco Sarno and colleagues [1] and their suggestion of "a novel effect of probiotics in the prevention of undigested gliadin peptides toxic effects".

Knitting on't Moors @ Wikipedia 

The probiotic in question is something called Lactobacillus paracasei CBA L74, which if I'm not mistaken is connected with a certain '57 varieties' company. The authors (which included one Alessio Fasano) indicated that said probiotic appeared to inhibit two gliadin peptides, P31-43 and P57-68, entrance in Caco2 cells, a model of the intestinal barrier [2]. Given that the entrance of such gliadin peptides into the gut mucosa (well the lamina propria) is part of the autoimmune condition known as coeliac (celiac) disease (see here), one might reasonably assume that use of Lactobacillus paracasei CBA L74 (LP CBA L74) might hold some potential as a possible treatment strategy outside of the standard gluten-free diet. At the very least, assuming some further investigations are indicated, it might be added to the list of other compounds being tested with coeliac disease in mind (see here).

I note that this is not the first time that LP CBA L74 has come under the peer-reviewed research spotlight as per the paper by Elena Zagato and colleagues [3] (open-access here). On that occasion the authors reported that: "fermented products of Lactobacillus paracasei CBA L74 act via the inhibition of proinflammatory cytokine release" and "could protect against colitis and against an enteric pathogen infection". With those statements in mind, I wonder whether coeliac disease might just be the tip of the iceberg when it comes to the applications for LP CBA L74 as per the work of a distant relation?

Speaking of tracks, here's Smokey and the Tracks of My Tears.

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[1] Sarno M. et al. Lactobacillus paracasei CBA L74 interferes with gliadin peptides entrance in Caco-2 cells. Int J Food Sci Nutr. 2014 Jul 17:1-7.

[2] Sambuy Y. et al. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005 Jan;21(1):1-26.

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Sarno M, Lania G, Cuomo M, Nigro F, Passannanti F, Budelli A, Fasano F, Troncone R, Auricchio S, Barone MV, Nigro R, & Nanayakkara M (2014). Lactobacillus paracasei CBA L74 interferes with gliadin peptides entrance in Caco-2 cells. International journal of food sciences and nutrition, 1-7 PMID: 25030417