"Anti-Candida albicans IgG antibodies in children with autism spectrum disorders"

The quote titling this post - "Anti-Candida albicans IgG antibodies in children with autism spectrum disorders" - reflects the title of the paper by Paul Ashwood & Heather Hughes [1] who set out to "determine if children with ASD [autism spectrum disorder] exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species." Such work is based on the still developing idea that "individuals with ASD have significant aberrations in the composition of their gut microbiota, known as dysbiosis" and part of that dysbiosis might also stretch to fungal as well as bacterial species.

Candida albicans also known as C. albicans is described as a 'opportunistic pathogenic yeast' quite readily observed in quite a large proportion of 'healthy adults'. For most people, this yeast does not cause any issues. On occasion however, C. albicans can lead to problems, particularly among those who are described as 'immunocompromised'. This is not the first time that C. albicans has been examined in the context of autism. Granted, the studies so far have been relatively small scale [2] and in requirement of follow-up [3] but this topic is no stranger to the peer-reviewed science literature. The Ashwood & Hughes paper should also be viewed in the context of other science discussions from this authorship group [4]; indeed several [5].

So: "We measured anti-C. albicans immunoglobulin (IgG) in plasma from eighty children enrolled in the UC Davis MIND Institute CHARGE study." IgG antibodies, represent 'immune status' with regards to a history of encountering specific pathogens. So, being positive to "anti-C. albicans immunoglobulin (IgG)" means that someone has been exposed to C. albicans at some point in their lifetime and retained something of an 'immune memory' to it. This subsequently means that your immune system is 'primed' in case that specific pathogen is encountered once again.

Results: "Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28)." I'm sure that you can see the disparity between the groups, bearing in mind that this was not an 'all-or-nothing' finding in relation to the separation of the groups. I should also mention that researchers also reported that gastrointestinal (GI) symptoms, also examined in this cohort, did not seemingly play a role in C. albicans antibody positivity.

Where next for this area of investigation? Well, alongside perhaps taking these results into consideration with other findings from this research group (see here), the authors mention that "exploring fungal composition within the gut as well as metabolic byproducts of yeast species such as d-arabinitol and ethanol, and identifying associations these might have with behaviors in ASD" could be one direction. In light of other independent research (see here), I'd say that was a sensible next step to take.

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[1] Ashwood P. & Hughes HK. Brief Report: Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front. Psychiatry. 2018. Nov 26.

[2] Ekiel A. et al. Intestinal microflora of autistic children. Med Dosw Mikrobiol. 2010;62(3):237-43.

[3] Iovene MR. et al. Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders. Mycopathologia. 2017 Apr;182(3-4):349-363.

[4] Hughes HK. et al. The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. Curr Neurol Neurosci Rep. 2018 Sep 24;18(11):81.

[5] Hughes HK. et al. Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Front. Cell. Neurosci. 2018.

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Sex-specific immune response to Candida albicans in schizophrenia and beyond

I have quite a bit of time for the various members of the Stanley Division of Developmental Neurovirology at Johns Hopkins on this blog. Not least because of the interesting work of one researcher in particular - Emily Severance - as a name behind some potentially very important research on how food, infection and immune function might come together in complicated conditions such as [some] schizophrenia and [some] bipolar disorder (see here and see here).

Continuing their 'gut-brain' theme (oh, yes) new research from Prof/Dr Severance and colleagues [1] has been published observing that "sex-specific C. albicans immune responses were evident in psychiatric disorder subsets." C. albicans refers to Candida albicans, a fungus that I'm sure most people will have heard of at one time or another if not only as a function of those TV adverts for preparations to combat C. albicans when tied into yeast infection.

On this most recent occasion, researchers were testing the idea of "C. albicans as a new candidate infectious disease target for studies of schizophrenia and bipolar disorder" as a extension of other research talking about 'bacterial dysbioses' potentially contributing "to C. albicans overgrowth by failing to provide the competition needed to keep the fungus in check." If you're furrowing your brow about the thought that the trillions of wee beasties that call us home (the gut microbiome) might exert an effect on behavioural or psychiatric presentation, relax yourself slightly: interest is growing in this area [2] following on from other investigations in other areas (see here).

So, researchers: "measured and compared IgG antibodies directed against this fungus in two psychiatric cohorts: one composed of 261 people with schizophrenia, 270 with bipolar disorder and 277 individuals without a history of psychiatric disorder; the other cohort was composed of 139 people with first-episode schizophrenia, 78 of whom were antipsychotic naive." They also examined cognitive symptoms and took into account various factors that might act as confounders onwards to the idea that IgG antibodies to C. albicans *might* be considered a risk factor for either schizophrenia or bipolar disorder.

Results: well it wasn't as straight-forward as blanket saying that the presence of IgG antibodies (seropositivity) or quantitative levels of these antibodies to C. albicans equals schizophrenia or bipolar disorder (or not-schizophrenia or not-bipolar disorder). There was nothing statistically significant between the various groupings in the cohorts included for study. But... when the groups were categorised according to sex (gender), researchers reported "significant elevations of C. albicans IgG in males with schizophrenia and bipolar disorder compared with male controls."

Further analyses suggested that there may be some 'associations' with other variables examined across the sexes when it came to those IgG antibodies ("females with schizophrenia who were C. albicans IgG-seropositive performed more poorly on these [cognitive] tests than did females with schizophrenia who were C. albicans IgG-seronegative or than female controls") and it appeared that antipsychotic medication use did little to impact on the findings. The bottom line: "antibodies directed against the opportunistic fungal pathogen, C. albicans, were elevated in distinct subsets of individuals with psychiatric disorders" and minus any sweeping generalisations, a research agenda incorporating brain, immune function, gut and also contents of the gut could be indicated in future study. This of course set among the idea that schizophrenia might be better represented by the more plural 'schizophrenias'.

Some of the media around this study and its findings are perhaps a little 'sensational' as per the headline asking: Is a sexually transmitted yeast infection making people mentally ill? I perhaps wouldn't go as far as that at the moment given that C. albicans is present in everyone(?) and overgrowth of such a yeast is not necessarily due to sex or related activities. Yes, certain sexual diseases can manifest as psychological symptoms but an important basis of the Severance study is that intrinsic factors such as gut dysbiosis might start a chain reaction whereby C. albicans is able to flourish and becomes rather more systemic and pathogenic linked to the presentation of behavioural symptoms. Or at least that is part of the hypothesis requiring further testing...

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[1] Severance EG. et al. Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. npj Schizophrenia 2016; 2: 16018.

[2] Dinan TG. et al. Genomics of schizophrenia: time to consider the gut microbiome? Mol Psychiatry. 2014 Dec;19(12):1252-7.

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Severance, E., Gressitt, K., Stallings, C., Katsafanas, E., Schweinfurth, L., Savage, C., Adamos, M., Sweeney, K., Origoni, A., Khushalani, S., Leweke, F., Dickerson, F., & Yolken, R. (2016). Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder npj Schizophrenia, 2 DOI: 10.1038/npjschz.2016.18

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