Neurotensin, intestinal inflammation and autism?

"Elevated peripheral pro-NT [neurotensin] levels reflect more severe forms of active celiac disease, indicating a potential role of NT in intestinal inflammation."

The suggestion, from Caroline Montén and colleagues [1], that the neuropeptide called neurotensin might play a role in paediatric coeliac disease is an interesting one that caught my eye recently. Interesting not only because of the potential implications for the archetypal 'gluten-causing' autoimmune condition called coeliac disease, but also because neurotensin might have some rather important links to [some] autism too [2].

OK, a quick recap is perhaps useful. Neurotensin when it comes to autism typically means one name, Theoharis Theoharides, he of mast cells fame (see here). The idea is that neurotensin (NT) is, among other things, quite a 'potent trigger' of mast cells and when activated these mast cells can release their inner contents that include quite a few substances linked to allergic inflammation. At least some of the talk linking 'inflammation' and autism might include a role for mast cells [3]  and so hey presto, a potentially important chain of biological events might therefore be linked.

Going back to the original Montén paper on NT and coeliac (celiac) disease, researchers set about investigating "if plasma pro-NT levels correlated with the degree of intestinal mucosal damage and tissue transglutaminase autoantibody (tTGA) levels in children with celiac disease." They did find elevated levels of one of the NT precursor fragments in a coeliac disease group (n=96) compared with controls (n=89) and there did seem to be something of a possible connection between pro-NT levels and tTGA. On these basis, they concluded that NT might indeed be linked to the intestinal inflammation noted in cases of coeliac disease. Mast cells might also be important to coeliac disease too according to recent findings.

Accepting that coeliac disease is not autism (even though in some individual cases they may be linked [4]), there are a few further studies that might be required on this topic with autism in mind. As I've already mentioned, inflammation - particularly inflammation of the gastrointestinal (GI) tract - is not something unheard of in autism research/practice circles (see here). I know furrowed brows can be associated with this area of discussion but I'm talking about peer-reviewed science not anecdote and speculation. One might for example, see an investigation whereby those with autism and GI-related issues (including an inflammatory component) might be more closely inspected for something like NT to see if it is something important. You could even include those potentially falling into the grey area of non-coeliac gluten sensitivity (NCGS) if you so wished (see here). Given also related findings for some on the autism spectrum in relation to tTGA too (see here) and the possibility of another link there with NT, some brave research team might also wish to inspect this parameter. I might also suggest that looking at gut motility patterns in relation to NT levels could be another area ripe for further investigation with autism in mind (see here) given some previous discussions on the effects of NT.

Just a few suggestions for how a little more work in this area might prove illuminating.

Insofar as what to do about a possible link between NT and autism, well someone it seems has already started that conversation [5] and discussions are seemingly continuing in the peer-reviewed domain [6]...

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[1] Montén C. et al. Role of pro-neurotensin as marker of paediatric celiac disease. Clin Exp Immunol. 2016 Sep 10.

[2] Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010 Aug 23;7:48.

[3] Theoharides TC. et al. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016 Jun 28;6(6):e844.

[4] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

[5] Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7:58.

[6] Patel AB. et al. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A. 2016 Sep 23. pii: 201604992.

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Montén C, Torinsson Naluai Å, & Agardh D (2016). Role of pro-neurotensin as marker of paediatric celiac disease. Clinical and experimental immunology PMID: 27612962

Neurotensin, autism and tail-chasing Bull Terrriers?

I'm not kidding.

The paper by Tsilioni and colleagues [1] (open-access) did indeed look at serum levels of neurotensin and corticotropin-releasing hormone (CRH) in a cohort of children diagnosed with an autism spectrum disorder (ASD) alongside levels in tail-chasing Bull Terrier dogs as compared to unaffected [non tail-chasing] Bull Terriers (BTs) and Labrador Retriever dogs. You may well smirk or even laugh at such research but, as per the recent [preliminary] broccoli chemical - autism study (see here), unusual research may yet offer some interesting insights into some of the biology of at least some of the autism spectrum.

Meg's gravy is famous.

Mention of neurotensin and autism really can only mean the involvement of one researcher: Prof. Theoharis Theoharides and his continuing interest in this area [2]. Indeed, the only thing seemingly missing from the Tsilioni paper is some analysis of another of Prof. Theoharides' interests: mast cells and autism (see here); although I do note that the authors mention how: "NT [neurotensin] is a vasoactive peptide isolated from the brain and is implicated in immunity. It is increased in the skin following acute stress, triggers skin mast cells (MCs) and increases skin vascular permeability in rodents through MC activation".

The Tsilioni paper is open-access but a few pointers might be in order:

• Greek children diagnosed with an ASD (N=40) fulfilling quite a few inclusion criteria provided a fasting blood sample. Similar samples were also provided by "normotypic" controls (I assume this means asymptomatic for ASD).
• "Serum from unaffected (n=18) and affected BTs (n=14) and unaffected Labrador retriever dogs (n=6) was collected at various facilities accessible to the owners and was sent to the senior Author’s laboratory on dry ice". Apparently a behavioural survey was used to classify Bull Terriers into affected and unaffected groups.
• Analysis for NT and CRH levels was completed on samples based on ELISA preceded by some clean-up steps. Results were presented to also include: "whether there is any relationship between the number of ASD children with GI [gastrointestinal] symptoms and high serum NT levels and whether it is more than expected by chance".
• So: group serum NT levels were significantly elevated in the cohort of children with ASD compared to controls (see here). As per the scatterplot shown in that last link however, this elevation was not noted for every child with autism; by my count about 11 children in the ASD group showed results above the upper 95% confidence interval (CI) for that particular group. The presence of GI symptoms also seemed to moderate this relationship: "There is a strong correlation between the number of ASD children with GI symptoms and high serum NT levels".
• Group serum CRH levels were also elevated for the ASD group compared to controls (see here) (12 of which seemed to show a similar pattern to that previously described).
• Bull Terriers affected by that tail-chasing behaviour - "reminiscent of stereotypic spinning exhibited by autistic children" - also showed group elevations in the levels of serum NT and CRH when compared to control dogs. The authors suggest that this: "supports the premise that these dogs could represent at least an autism endophenotype" from an animal model point of view (see this table for further information).

Outside of trying to model autism or more precisely behaviours associated with autism in another animal model other than rodents (see here) or monkeys (see here), the authors provide other clues for their report of a [potential] canine model: "This dog breed may be useful in the investigation of the diagnosis, pathogenesis and treatment of ASD. NTR and/or CRHR-1 antagonists, as well as MC blockers, could provide possible therapeutic approaches for stress-induced ASD. For instance, the natural flavonoid luteolin is known to inhibit mast cell-mediated allergic inflammation, and a dietary supplement containing luteolin was recently reported to significantly benefit children with ASD". That last sentence on luteolin as a potential intervention option for autism comes from other work published by the authors [3] in need of further, controlled study.

The evidence is starting to stack up suggesting that there may be more to see when it comes to NT and CRH levels in relation to at least some cases of autism (the autisms?). That GI symptoms (which are becoming much more readily accepted as being elevated in frequency when it comes to autism) might be a moderating variable of the presence of those peptide hormones is another potentially important feature in terms of how such pathology seems to interplay with behavioural symptoms (see here). I would like to see a little more focus on how other behavioural signs and symptoms (autism+) might also be affecting NT and/or CRH levels when it comes to cases of autism, and indeed, how this work overlaps with other reports of NT for example, in other conditions [4] potentially acting as "an endogenous antipsychotic drug" and more [5]

Music then. The Sound of Silence by S & G.

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[1] Tsilioni I. et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Transl Psychiatry. 2014 Oct 14;4:e466.

[2] Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010 Aug 23;7:48.

[3] Theoharides TC. et al. A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders. Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):317-23.

[4] Boules M. et al. Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol (Lausanne). 2013 Mar 22;4:36.

[5] Boules MM. et al. Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders. Behav. Sci. 2014; 4: 125-153.

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Tsilioni I, Dodman N, Petra AI, Taliou A, Francis K, Moon-Fanelli A, Shuster L, & Theoharides TC (2014). Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Translational psychiatry, 4 PMID: 25313509

Neurotensin and autism

I've been trying to catch up with the various articles published this summer (2012) whilst I was on vacation which might be of interest to this blog. There is quite a list of papers which I will hopefully try and get through but for now I've settled on this paper by Angelidou and colleagues* (open-access) on the topic of autism, babies, brains and inflammation.

Corbita @ Wikipedia 

I'll state from the outset that the Angelidou paper is a talky-talky review paper and as per quite a few review papers, there is a healthy sprinkling of speculation also included. In this case it is the suggestion that a premature birth combined with a specific pattern of 'susceptibility' genes might predispose an infant via various triggers to mast cell activation (see my previous post on this topic) onwards to brain inflammation and autism.

I've already covered autism and SEN and prematurity in previous posts (see here for example), so won't dwell too much on that for now aside from directing you to another relevant paper in this area by Leavey and colleagues** recently published, quote confirming "the role of shortened gestation in ASD risk". As to the susceptibility genes side of things, well once again the ENCODE project really suggests that we should be looking a little further and a little wider when it comes to all things genetics but I'm going to leave that for now.

One specific part of the paper by Angelidou was however of particular interest to me: neurotensin (NT) and the evidence base with relation to autism. A quick description first: neurotensin is a peptide found in various tissues including brain and gastrointestinal (GI) tract. Originally categorised as a hypotensive (lowering blood pressure) by Carraway & Leeman*** it appears that this peptide has quite a few potential functions and relations as per the work on its neuromodulatory action on dopamine release (see this paper by Fawaz and colleagues**** open-access) and the lessons which could be learned for various pharmacotherapies such as the neuroleptics which may be of relevance to quite a few conditions. Other, seemingly quite diverse areas, also seem to have been linked to neurotensin chemistry including alcohol metabolism and some cancers. Indeed some pretty strong evidence of involvement for neurotensin and diseases associated with premature death was recently published.

With autism in mind, the current science base for neurotensin is a little bit limited. There are however some key papers to point out:

• The mast cell activation theme runs through a lot of the research starting with this paper by Angelidou (again!) and colleagues***** (open-access). Out of several peptides that are potentially able to stimulate mast cells (including beta-endorphin), the authors reported that only levels of neurotensin were found to be significantly elevated in their cohort of children with autism compared with controls. Having said that, with participant group numbers of n=19 (autism) and n=16 (controls), there was a very preliminary air to this data.
• Next on the list is this paper by Zhang and colleagues****** (open-access) again with some familiar names on the authorship list. This paper extends the previous findings of elevated neurotensin levels in cases of autism to suggest that such elevations might also have the propensity to influence the "release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger". In case you want to read more about mitochondrial DNA and 'anti-mitochondrial antibody Type 2' take a look at these pages (here and here). I'll probably do a super-post on autism and mitochondria at some point given this and the growing literature in this area.
• And continuing the story, this paper by Asadi and Theoharides******* (open-access). Not too much more to say here aside from some indication "that stress and infection-mimicking extracellular mitochondrial components augment allergic inflammation that may be involved in the early pathogenesis of ASDs".
• Finally, Ghanizadeh******* (open-access), who seems to have a whole stream of ideas relating to autism and related conditions (see here), offers a brief but interesting opinion piece about how targeting neurotensin levels in cases of autism might have some interesting therapeutic advantages, bringing into play everyone's favourite excitatory amino acid and neurotransmitter, glutamate (and its receptors and signalling), alongside the calming effects of GABA. 

And rest.

There's not too much more to add at the moment to this body of work on neurotensin and autism. I've not for example talked about the neurotensin receptors (see here) nor the genetics of neurotensin (see here) despite there probably being some important connections to be made. Complementary to the mast cell activation investigations in cases of autism, there does appear to be some good reasoning to continue research in this area.

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* Angelidou A. et al. Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC Pediatrics. 2012; 12: 89.

** Leavey A. et al. Gestational age at birth and risk of autism spectrum disorders in Alberta, Canada. The Journal of Pediatrics. September 2012.

*** Carraway R. & Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. Journal of Biological Chemistry. 1973; 248: 6854-6861.

**** Fawaz CS. et al. Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function. BMC Neuroscience. 2009; 10: 96.

***** Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. Journal of Neuroinflammation. 2010; 7: 48.

****** Zhang B. et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. Journal of Neuroinflammation. 2010; 7: 80.

******* Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7: 58.

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Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, & Theoharides TC (2012). Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC pediatrics, 12 (1) PMID: 22747567