Microbes passing traits to host babies?

The paper by Clara Moon and colleagues [1] has garnered a lot of headlines with their findings suggesting that [mouse] mothers pass on bacteria to their [mouse] offspring. Their results reported in Nature, focused on a bacterium not unfamiliar to this blog, Sutterella (see here) and how, through the transmission of Sutterella via their poo(p), a specific trait might also be passed on. In this case, low levels of immunoglobulin A (IgA) (something else that has cropped up on this blog) were noted in offspring. The idea being that Sutterella might have an effect on IgA production and low IgA is a factor in quite a few conditions not least the inflammatory bowel diseases [2] and other autoimmune related conditions.

I have to say that I did a bit of double-take when reading this study and some of the accompanying media given the potential implications. "When we study mice, we have to account for the possibility that inherited bacteria and their genes could be influencing the trait we're trying to learn about," is a quote from one of the researchers involved in this work. Certainly this is the most pressing issue to come from the Moon study but the results are potentially much more profound than just where you house mice in a research setting. First though, I'd like to see some independent confirmation of these findings please.

Although there is quite a bit of hype around the microbiome these days, and particularly those trillions of beasties which reside in our gastrointestinal (GI) tract, there is something of a greater appreciation that their role(s) appears to extend well beyond just helping us digest food and producing the odd nutrient or two. My coverage of the 'poo transplant [potentially] made me obese' paper (see here) kinda hints at one possible alternative action for our gut bacteria or some other, related component of the gut. I'd also draw your attention back to the paper by Desbonnet and colleagues [3] talked about in this post, which brought the concept of 'psychobacteriomics' (my definition!) to the world and how gut bacteria might also impact on [mouse] social behaviour too.

Going back to the the Moon paper, I'm also drawn to the possible implications for a wide range of issues and diagnoses based on their findings. Genetics, more traditional structural genetics, based on investigations of how the structural differences of the genome might confer elevated/reduced risk of good or adverse health issues, is undergoing a bit of a revolution at the moment. Not only are we talking more about the epigenome (see the Nature special on this and a very informative video here) but as per some other comments from the paper authors, science is potentially thinking of an: "expanded model of heredity to produce a more complicated but also much more insightful picture of how human, bacterial and viral genes influence human health." This is all the more important when you consider how many bacterial genes there are vs. 'human' genes alongside the idea that just as viruses have a history of passing genes to humans (think HERVs) so bacteria may also be able to 'transfer' genes to us too. I wonder if the Moon findings might also account for those peculiar 'elevated levels of autoimmune conditions in the spouses of those with coeliac disease' findings [4] too?

Given that Sutterella is the starting point for this possible association, and with something of a potential role for this bacteria in some cases of autism [5] replicated even [6], one might entertain the idea that autism should perhaps figure in follow-up work in this area. I'm not suggesting that autism as a label (or labels) is somehow the product of Sutterella but as per the discussions linking Sutterella to potential bowel pathology in some cases of autism, whether the mechanism talked about by Moon and colleagues might also apply to humans too.

Then there is the tantalising idea of 'altering' the microbiome to alter specific traits...

So then, it missed out on an Oscar but the song is still awesome...

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[1] Moon C. et al. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature. 2015 Feb 16.

[2] Ludvigsson JF. et al. Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol. 2014 May;34(4):444-51.

[3] Desbonnet L. et al. Microbiota is essential for social development in the mouse. Mol Psychiatry. 2014 Feb;19(2):146-8.

[4] Emilsson L. et al. Autoimmune Disease in First-degree Relatives and Spouses of Individuals with Celiac Disease. Clin Gastroenterol Hepatol. 2015 Jan 30. pii: S1542-3565(15)00112-3.

[5] Williams BL. et al. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio. 2012 Jan 10;3(1).

[6] Wang L. et al. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013 Nov 4;4(1):42.

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Moon C, Baldridge MT, Wallace MA, Burnham CA, Virgin HW, & Stappenbeck TS (2015). Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature PMID: 25686606

ALV003 glutenase and more

Today's post is a bit of mash-up but hopefully containing some common threads. If you're also reading the title of this post and wondering what it might have to do with autism research, stay with me...

For mash get smash... @ Wikpedia 

The chopping up duties of ALV003
To start, we have the paper by Lähdeaho and colleagues [1] who reported results based on the "ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury". Those with their ear to the coeliac (celiac) disease research ground will probably have heard something about ALV003 from Alvine Pharmaceuticals before. This glutenase mix - a protease compound designed to degrade gluten - comprising cysteine endoprotease B-isoform 2 and prolyl endopeptidase has already started to make some scientific waves following the results of a couple of studies reporting tolerability [2] and initial efficacy [3] in cases of coeliac disease (CD). The theory behind it being that chopping up those dastardly gluten proteins/peptides might break an important link in the chain of biological events observed in coeliac disease.

The data from Lähdeaho et al suggest that "the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten". In other words, taking ALV003 together with a gluten-supplemented meal seemed to have some protective effect on the state of the gut mucosa compared to the effects of a placebo.

With my autism research hat on, and particularly the green beret marked gluten and casein-free (GFCF) diets, I did wonder whether there may be something to be potentially learned from these results. I'm not for one minute implying that ALV003 should be indicated for autism nor am I suggesting that autism is coeliac disease despite some potential overlap. But I did wonder in light of something like the opioid-excess theory of autism [4] and some continued interest in all-things digestive enzymes and autism (see here), whether there may be some investigations to do in this area.

IgA deficiency and autoimmunity
Next up is the paper by Ludvigsson and colleagues [5] who observed that: "Individuals with IgA deficiency have a higher prevalence of several other autoimmune disorders". IgA deficiency is something that has cropped up on this blog before, again with an autism slant (see here). Harking back to some potentially important work by the late Reed Warren [6] suggestive that some on the autism spectrum may present with an IgA deficiency, extrapolating the results from Ludvigsson (yes, he of the 'not quite coeliac disease but something close in cases of autism' study) might have some important implications.

In particular, Ludvigsson et al  report quite a dazzling connection between IgA deficiency and the risk of various autoimmune conditions, such that there was: "a 35-fold higher PR [prevalence ratio] for celiac disease and 10-fold higher for type 1 diabetes". I'm only an amateur statistician but even I understand that a frequency of CD in IgA deficient vs. non-deficient population controls amounting to 6.7% and 0.2% respectively, is something potentially very important. Outside of the fact that IgA deficiency can affect the serological diagnosis of CD [7] I find these results to be interesting. That some people on the autism spectrum presenting with IgA deficiency may similarly find themselves in the cycle of greater risk of autoimmune conditions potentially offers some important lessons for screening and management of such issues. Also noted in a fairly recent presentation from one Alessio Fasano (see here for the video), science could do a lot worse than look to something like gluten as also being one of the important [modifiable] drivers in this autoimmunity relationship too.

I've probably bored you enough with this post and the speculations contained within. As per my recent ramblings on disappearing anti-gliadin antibodies following use of a gluten-free diet (see here) the important point to get across is that alongside a diagnosis of autism (and other comorbidity) there may be some important biochemistry that needs to be examined at least for some on the autism spectrum. Looking past the presented behavioural symptoms to see the person first and the autism label second is a pretty important part of this strategy so as to ensure that such health issues if present for some on the autism spectrum, don't disadvantage individuals further.

Now, how about some light reading paralleling pathogens and gluten peptides in CD [8] with suitable musical accompaniment by Sheryl Crow. Have some fun!

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[1] Lähdeaho ML. et al. The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology. 2014 Feb 25. pii: S0016-5085(14)00242-X.

[2] Siegel M. et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012 Feb;57(2):440-50.

[3] Tye-Din JA. et al. The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol. 2010 Mar;134(3):289-95.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Ludvigsson JF. et al. Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. J Clin Immunol. 2014 Mar 2.

[6] Warren RP. et al. Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord. 1997 Apr;27(2):187-92.

[7] Shahnaz A. et al. Tissue transglutaminase antibody levels predict IgA deficiency. Arch Dis Child. 2013 Nov;98(11):873-6.

[8] Bethune MT. & Khosla C. Parallels between Pathogens and Gluten Peptides in Celiac Sprue. PLoS Pathog 2008; 4(2): e34.

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Lähdeaho ML, Kaukinen K, Laurila K, Vuotikka P, Koivurova OP, Kärjä-Lahdensuu T, Marcantonio A, Adelman DC, & Mäki M (2014). The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology PMID: 24583059



Ludvigsson JF, Neovius M, & Hammarström L (2014). Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. Journal of clinical immunology PMID: 24584841

Serum IgA, humoral immunity and autism

The important contribution of the late Reed Warren to autism research has been discussed previously on this blog. The findings from Warren and his team in relation to the C4B null allele in autism (and other conditions) were interesting and quite influential in opening the door to questions about the genetics of the immune system being implicated in some cases of autism. In light of the focus on epigenetics in recent years, I perhaps do question whether genomic differences might be the only influence on such gene function, but that's beside the point.

Another of Warren's astute observations on autism featured in this paper* from 1997 discussing a subset of people with an autism spectrum condition also presenting with a deficiency in immunoglobulin A (IgA). Indeed bringing things right up to date, another research group have reported similar findings as per this paper by Jolanta Wasilewska and colleagues** (full-text) specifically in relation to a group of children defined with regressive autism. A small additional point before progressing, Dr Wasilewska and other authors are no strangers to autism research as per their involvement with another interesting area related to oxalates and autism (see blog post here).

Let's just back up slightly and define IgA deficiency. A selective deficiency of IgA  represents an immunodeficiency and implies low or absent levels of IgA specifically tied into protection being afforded to various mucus membranes such as the airways or digestive tract. Described as being relatively common, selective IgA deficiency seems to be more apparent in conditions like coeliac (celiac) disease (here) and lupus (here) stressing the connection with autoimmune disease as per this review by Wang and colleagues*** (full-text).

A summary of the findings from Wasilewska et al:

• The primary objective of their study was to ascertain whether tests of humoral immunity - immunity tied into secreted antibodies - might be able to identify children with autism, particularly those presenting with a regressive aspect to their symptom onset. A secondary objective relates to the examination of gluten-specific IgG antibodies in cases of autism which has been of some interest to this blog already (here).
• Twenty-four children diagnosed with autism (and regression defined by a loss of previously acquired skills) were compared against 24 asymptomatic controls matched on various factors including age and importantly, gender.
• Morning blood samples were drawn and collected from participants and serum IgA, IgG and IgM levels measured alongside various other measures including serum C-reactive protein (CRP) levels, lymphocytes and other measures of blood morphology.
• Results: not too much significant group difference among quite a lot of the measures being looked at including CRP and white blood cell (WBC) counts. Interestingly, IgG anti-gluten antibodies were also not significantly different between the groups. 
• Serum IgA levels were however significantly lower in autism as a group compared to controls; IgE levels just escaped being significantly elevated in the autism group compared to controls (p=0.08) with one spectacular outlier reported whose IgE levels were over double the amount of the second highest level seen across the groups. Also interestingly, eosinophilia - previously discussed in this post - seemed to be more prevalent in the autism group over controls despite no significant overall difference reported in blood eosinophils (p=0.08). Elevations in CD19 / CD23 - proteins found on the surface of B cells - were also noted in the autism group compared to controls (p=0.0134) confirming a role for humoral immunity (at least in some cases).
• Some exploratory data on the usefulness of the various immunoglobulins measured were carried out to see how predictive they may be to regressive autism but unfortunately AUC values were not as stunning as other work in other areas.

Bearing in mind the small participant group included as part of this trial and how one defines regression, this is quite a comprehensive paper with some potentially important findings. The area of immunoglobulins in relation to autism is full of contrasting findings probably reflective of the fact that any issues with the immune system are probably not uniform in cases of autism and also focused on its nature according to the environment it works in. The mucus link to IgA is particularly interesting given that both airways and gut have cropped up more than once in autism research circles (here and here). That and the associations that have been made between certain medications - certain antiepileptic pharmacotherapy - inducing IgA deficiency for example, makes for some interesting speculations.

The IgE "nearly" findings take me back to the previous work done in this area and in particular that rather interesting area of research looking at mast cell activation in relation to autism. Of course there could be lots of reasons to account for the nearly findings in this recent trial and one should not perhaps speculate too much. I do however think that the eosinophilia data in the current study is an important finding given the links in other conditions between IgE, mast cells and eosinophilia; also adding to the previous (limited) literature on this topic with autism in mind, including another paper produced by Dr Wasilewska and colleagues.

I should finally comment on the CRP results obtained by Wasilewska and colleagues in light of my recent post on the paper by Khakzad and colleagues. Wasilewska reported no significant difference in CRP levels between the groups (means: autism = 0.1 mg/L vs. controls = 0.05 mg/L). Khakzad and colleagues reported  mean group CRP levels of 540.1 ng/L (autism) vs. 1.3 ng/L (controls). Noting the differences in concentration units (milligrams vs. nanograms), a quick re-calculation (using this handy tool 'cos I was too lazy to just divide by 1000) suggests that Khakzad was reporting CRP levels as quite a lot higher in their participant group (0.5401 mg/L) than in the Wasilewska participant group. Whether this is reflective of the different participant groups, differing ethnicities or geographical locations or other factors remains to be seen.

The growing (and growing) focus on the immune system and autism continues at a pace. Accepting a degree of individuality in how the immune system, different sides of the immune system, are positioned in cases of autism, it strikes me that once again, another set of parameters potentially reveal themselves which have been shown to be ripe for further tantalising endophenotype studies that are already starting to be done with autism in mind.

To finish, 'The Boss' is in town today so get your guitar and flag ready.

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* Warren R. et al. Brief report: Immunoglobulin A deficiency in a subset of autistic subjects. JADD. 1997; 27: 187-192.

** Wasilewska J. et al. Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Archives of Medical Science. 2012; 9: 324-331.

*** Wang N. et al. Selective IgA deficiency in autoimmune diseases. Molecular Medicine. 2011; 17: 1383-1396.