Milk opioid peptides and dipeptidyl peptidase-4 (DPPIV) linked to autism

So: "we have concluded that milk-derived opioid peptides and DPPIV [dipeptidyl peptidase-4 (DPPIV)] are potentially factors in determining the pathogenesis of autism."

That was the quite sweeping statement made in the paper published by Beata Jarmołowska and colleagues [1]. It continues a quite a long running research topic in autism circles (see here and see here) on whether the chemical arrangement of certain dietary components *might* have an important biological effect on at least some people diagnosed as being on the autism spectrum.

The Jarmołowska paper is open-access so there is no real need for me to go over the suggested hows-and-whys of some diets being potentially related to (some) autism. If you need some further reading on the topic, I'll direct you to other posts on this blog where I've discussed this 'gluten and casein' issue (see here) and onward, my professional interest in it for quite a few years.

The aim of the Jarmołowska study was to determine "BCM7 [β-casomorphin-7] influence on DPPIV functioning in children with ASD in comparison to healthy children." 'Healthy children' is the term for the control group used by the authors by the way, not me. They "examined content and activity of serum DPPIV, content of BCM7 in serum and urine, and studied the effect of hydrolysed bovine milk, as a source of opioid peptides, on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in both groups."

Results: "We found that the content of BCM7 in serum was significantly higher (p < 0.0001) in ASD than in the control group." Urine concentrations of BCM7 were not significantly different among those with autism compared with controls. Also: "Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01)."That was about the sum of the differences noted by researchers.

Caveats? Well some. So: "ELISA test enabled identification of BCM7 contents in the serum and urine from patients, as well as in tested peptide extract obtained from hydrolyzed bovine milk." Authors do mention how the testing was carried out "in triplicate" following a previously published protocol. I don't dispute the results they got but am not exactly enamoured with the ELISA method used. I'd much rather see the analysis undertaken using something like mass spectrometry or similar technology, given the precision that comes with such methods (see here) based for example, on the use of internal standards. Perhaps if the authors still have their samples, they might consider further analyses if available to them?

Although researchers provide quite a bit of information about their participant groups, I also noted one important detail to be missing: were any of their participants - diagnosed with autism or not - following any special dietary regime? Y'know, they talk about casein (milk) free diets and how such diets are supported by "numerous scientific reports." So I guess in a cohort of 86 children diagnosed with autism, at least a few of them might be following such a dietary intervention? I've searched their paper but couldn't find anything to say that they were or weren't.

Putting such issues to one side, I don't want to take anything away from the Jarmołowska findings. As they end their paper: "this issue requires further investigation." I wouldn't disagree.

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[1] Jarmołowska B. et al. Role of Milk-Derived Opioid Peptides and Proline Dipeptidyl Peptidase-4 in Autism Spectrum Disorders. Nutrients. 2019 Jan 4;11(1). pii: E87.

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Dipeptidyl peptidase (DPP) IV and autism: supporting opioid-excess?

Serum levels of dipeptidyl peptidase (DPP) IV were found to be lower in children with autism compared to asymptomatic controls according to the study by Shahid Bashira & Laila AL-Ayadhi [1]. Based on analysis by ELISA, researchers concluded that "alterations in the plasma level of DPP IV play a role in the pathophysiology of autism".

A sailor went to sea, sea, sea... @ Wikipedia 

Anyone who has followed the autism research scene for any length of time might have already heard about DPP-IV and autism. The paper by Hunter and colleagues [2] (open-access here) and subsequent response [3] highlights some of the discussions in this area relating to the use of the opioid-excess hypothesis [4] as a means to potentially explain some autism. The idea stemming from some earlier work (see here) being that a defect in the functioning of DPP-IV with regards to its ability to degrade proline-rich proteins such as gliadin (gluten) might account for the build-up of gluten derived opioid peptides suggested as part of the opioid-excess theory. Earlier accounts of issues with DPP-IV in relation to the classic gluten-related autoimmune condition coeliac disease (see here for an overview) kinda set the tone [5] for some analysis with autism in mind. Indeed, at least one trial of enzyme-based therapy has also talked about the potential involvement of DPP-IV in some cases of autism [6].

The Bashira paper did not specifically set out to look at the relationship between DPP-IV and dietary elements potentially linked to autism. Instead their focus seemed to be on the involvement of this peptidase in brain physiology and "its possible link to neuroinflammation in autism". DPP-IV has, for example, been discussed with cerebral ischemia in mind as per the results from Röhnert and colleagues [7] although I hasten to add that I am not equating autism and brain ischemia.

I personally feel that quite a bit more research effort is needed in the area of DPP-IV. Lower plasma levels of DPP-IV have been noted in cases of other conditions such as depression [8]. The recent results from Simone Peters and colleagues [9] which talked about "Short-term exposure to gluten specifically induced current feelings of depression" in their cohort (see this post) could fit well with the reduction in gluten peptide degrading abilities potentially present as a consequence of something like lower DPP-IV levels. Indeed, one might also speculate that the suggestion of non-coeliac gluten sensitivity (NCGS) may actually reflect involvement of opioid peptides on the basis of such a correlation...

I'm also taken back to some work by Vojdani and colleagues [10] which talked about anti-CD26 autoantibodies being present in a "significant percentage of children with autism". CD26, a surface glycoprotein used synonymously with DPP-IV, was suggested to show involvement as a function of "dietary peptides, bacterial toxins and xenobiotics bind[ing] to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism". Their follow-up study [11] further added to the literature in this area and how "Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity" in relation to autism. Autoimmunity and autism y'say?

As per the cycles of scientific research, where research areas fall in and out of favour, it does appear that there is a resurgence of interest in elements of the opioid-excess theory with a specific focus on the role of food-derived peptides in relation to at least some autism. The Roy review looking at naltrexone for autism (see here) is one element given the opioid antagonistic effects of this pharmaceutic. The Sokolov paper (with its flaws) looking at beta-casomorphin - the opioid peptide derived from the casein protein - in relation to autism is another. The Trivedi paper (see here) on exogenous opioid peptides and DNA methylation levels adds to the research bundle. Dare I even mention the camel milk and autism connection also being made in the research literature too as a function of different milks and different protein/peptide configurations?

Music to close. Epic by Faith No More.

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[1] Bashir S. & AL-Ayadhi L. Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study. Neurology, Psychiatry and Brain Research. 2014; 20: 41-44.

[2] Hunter LC. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8.

[3] Shattock P. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2004 May;46(5):357.

[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] Smith MW. & Phillips AD. Abnormal expression of dipeptidylpeptidase IV activity in enterocyte brush-border membranes of children suffering from coeliac disease. Exp Physiol. 1990 Jul;75(4):613-6.

[6] Brudnak MA. et al. Enzyme-based therapy for autism spectrum disorders -- is it worth another look? Med Hypotheses. 2002 May;58(5):422-8.

[7] Röhnert P. et al. Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia. J Neuroinflammation. 2012 Feb 28;9:44.

[8] Maes M. et al. Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatr Scand. 1996 Jan;93(1):1-8.

[9] Peters SL. et al. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory clinical study. Aliment Pharmacol Ther. 2014 May;39(10):1104-12.

[10] Vojdani A. et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

[11] Vojdani A. et al. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

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Bashir, S., & AL-Ayadhi, L. (2014). Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study Neurology, Psychiatry and Brain Research, 20 (2), 41-44 DOI: 10.1016/j.npbr.2014.03.001