Scientists make gut-brain connection to autism
An article, more of a press release really, suggests that Scientists have made a connection between the gut, brain, and autism. One might read that to mean that they've discovered a connection but I prefer the more literal interpretation. They've made a connection where one may or may not exist.
Now don't get me wrong, I'm completely open to the idea that there is significant communication between the Central Nervous System(CNS) and the Enteric Nervous System(ENS) but how that interplay might (if at all) contribute to autism is largely unknown. These researchers have an hypothesis, or at least a vague outline, of the mechanism(s) that might be involved. Essentially, certain foods are metabolized by certain gut bacteria in such a way as to release high concentrations of Propionic Acid which may travel to the brain causing one to be autistic.
So how did they test their hypothesis? Did they measure blood or cerebrospinal fluid concentrations of proionic acid? Did they isolate and culture unique bacteria form the guts of autistic children to see if they are more likely to convert culprit foods into propionic acid?
No. They injected PPA into the brains of mice and observed their behaviors. Surprise!
"They immediately engaged in bouts of repetitive behaviour, hyperactivity and impaired social behaviours which had close similarity to what parents are seeing with autism," MacFabe said.
Note the reference to parent anecdote. Here it is again:
UWO researchers investigated the "gut-brain" connection after many parents of autistic children reported significant improvements in the behaviour of their autistic children when they modified their diet, eliminating dairy and wheat products, Dr. Derrick MacFabe, the director of a research group at UWO in London, Ont., told CBC News Thursday.
So how does this show a connection between the gut-brain and autism? Easy. Parents tell the scientists that removing certain foods from their children's diet cause improvements in their behavior. Scientists say, "Ah-Ha! We think we know what's causing that." There's the connection.
Expect to hear more 'connections' from the thimerosal/mercury folks since it's well know that mercury kills the good gut bacteria allowing the PPA producing bugs to thrive, or something like that.
Below is the abstract of the research published in January.
Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders
Derrick F. MacFabe, Donald P. Cain, Karina Rodriguez-Capote, Andrew E.
Franklind, Jennifer E. Hoffman, Francis Boon, A. Roy Taylor, Martin Kavaliers
and Klaus-Peter Ossenkopp
Abstract
Clinical observations suggest that certain gut and dietary
factors may transiently worsen symptoms in autism spectrum disorders (ASD),
epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a
short chain fatty acid and an important intermediate of cellular metabolism. PPA
is also a by-product of a subpopulation of human gut enterobacteria and is a
common food preservative. We examined the behavioural, electrophysiological,
neuropathological, and biochemical effects of treatment with PPA and related
compounds in adult rats. Intraventricular infusions of PPA produced reversible
repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion,
caudate spiking, and the progressive development of limbic kindled seizures,
suggesting that this compound has central effects. Biochemical analyses of brain
homogenates from PPA treated rats showed an increase in oxidative stress markers
(e.g., lipid peroxidation and protein carbonylation) and glutathione
S-transferase activity coupled with a decrease in glutathione and glutathione
peroxidase activity. Neurohistological examinations of hippocampus and adjacent
white matter (external capsule) of PPA treated rats revealed increased reactive
astrogliosis (GFAP immunoreactivity) and activated microglia (CD68
immunoreactivity) suggestive of a neuroinflammatory process. This was coupled
with a lack of cytotoxicity (cell counts, cleaved caspase 3′ immunoreactivity),
and an increase in phosphorylated CREB immunoreactivity. We propose that some
types of autism may be partial forms of genetically inherited or acquired
disorders involving altered PPA metabolism. Thus, intraventricular
administration of PPA in rats may provide a means to model some aspects of human
ASD in rats.
Keywords: Locomotor activity; Seizures; Dystonia; Kindling;
Animal model; Oxidative stress; Neuroinflammation; Glutathione; Clostridia
Interesting ideas but absolutely nothing beyond a proposed rodent model and a pet hypothesis.
Martha Herbert has this to say about the groundbreaking research:
Dr. Martha Herbert, assistant professor in neurology at Harvard Medical School, told CBC News that the study opens up a new way of thinking about the disorder.
Really? How's that exactly? Martha has made it clear that she see autism as the result of any number of environmental insults, including thimerosal and even toxic mold, so how many more ways of thinking can there be. Inject bad stuff, observe neuroinflammation and antisocial behaviors, Et Viola! Autism. It's a pretty simple formula and one that can be applied to just about anything at the right concentration.
Herbert strongly advocates a balanced diet, consisting of all food groups, not just "bread and cheese."
Wow. Sage advice.
"If you have foods that child is sensitive to in their immune system, that can set up processes that can impact brain function, and it can do so in a negative way. And if you remove those foods, that negative impact can stop."
Brilliant. At least they didn't ask her why a fifth of Americans can't locate the US on a world map.
posted by notmercury @ 7:35 AM
16 comments
16 Comments:
"Clinical observations suggest that certain gut and dietary
factors may transiently worsen symptoms in autism spectrum disorders (ASD)"
Clinical observations? They are kidding right?
I saw that article also, NM. I arrived the same results - that it was awfully rash to make a stew of parents' anecdotal reports and rats' behaviors and pronounce that they have solved a mystery of autism.
It occurs to me that, if gluten and casein are so wrapped up in determining autistic behaviors, wouldn't societies with extremely low dietary intake of those proteins have notable mower prevalence figures for autism? Maybe Japan? Or Indonesia?
To follow up on what Steve said, we should also see higher figures in Europe, where more dairy and gain is eaten, but we don't.
It's just plain foolish to try and draw conclusions about a complex and poorly defined cognitive difference based animal models. These guys are going from "When you inject this stuff into rats brains, they act weird. And I've heard that autistic folks act weird, too," to arrive at, "This stuff must be what causes autism." For heavens sake.
Even better, they said, well, some people have injected this stuff into baby rats or mice peritoneal cavities, but no one has injected it straight into their brains, so that's what we decided to do.
AND they were adult rats. AND they tried to connect what they saw in adult rats with what might happen to human fetuses if exposed to too much PPA from their moms??? or something, following injestion of Valproate.
These were adult rats! I want to see what happens to an adult from Japan or elsewhere who never has had much or any wheat or dairy, if you start feeding him wheat and dairy does he become autistic, or does he need to have certain bacteria in his gut to do that?
How about we inject PPA into these scientists' brains to see if it can make an adult human autistic. And if it does, does changing their diet undo the damage done by the PPA injection into the brain?
Martha Herbert is her usual brilliant self, isn't she?
Ohmigosh!
I think if my brain were chucked into a blender and hmomogenized it might show some signs of Oxidative Stress after coming out too.
But I suggest an alternative to direct injection to the 'wherever the heck' they are putting it.
At least inject the whatever substance they want to point the finger at this time into the bloodstream/limyphatic system to show it can even cross the blood/lymphatic brain barrier, as if whatever substance we are pointing the finger at this time can't get into the brain then how can we blame it for making brain malfunctions.
(Or would that just be too simple and reduce the $Funding$?)
Interesting post NM. It's amazing how much the press accounts differ from the actual study. This may be interesting, if you're into rodent research, but it's otherwise underwhelming.
Free Full-Text
Seems to me they created a mouse model of propionic acidemia. See excerpt from paper below.
"There are a number of genetic and acquired conditions with
CNS involvement where elevated levels of PPA are known to
exist. Most notable is propionic acidemia, a genetic neurodevelopmental
disorder of amino and fatty acid metabolism resulting
in developmental delay, seizure development, movement disorder
and gastrointestinal symptoms."
I think this also illustrates one of the downfalls of some research.
Researchers (like politicians) are always looking for money. And one way of getting money is to hitch yourself to a "hot topic" in research. People don't necessarily want to pay for basic science mouse research. But put in your research proposal that you're looking at curing AIDS, breast cancer, or now, autism, and there's a bigger potential money pot to be had.
So researchers "stretch" what their present research shows in order to get publicity, name recognition, and further funding.
You would think other scientists wouldn't fall for something like that. But it's not just scientists controlling the purse strings. And so it goes.
Joe
From a quick read of the paper--
Take away the introduction and the conclusion and this paper has very little to do with autism. Very little.
Under abnormal behaviors they list:
In addition to the results described above, 14 of the 15 rats given PPA injections displayed a variety of abnormal behavioural responses, in some cases associated with single epileptiform spikes or short, distinct bouts of epileptiform spiking that were not accompanied by limbic convulsion behaviours. Four prominent abnormal behaviours occurred: retropulsion dorsiflexed spine with repeated forelimb extension, pushing the body backward), snake like posture (hyperextension of body parallel to the floor, usually with paddling motions of the limbs), turning (full body turning in a continuous rotating motion in place or in a limited area of the test box; 1 turn = 360◦ of body rotation), and limb dystonia (dystonic movement of forelimb or hindlimb contralateral to the injection, usually with repeated adduction and extension).
The rest of it is "we dump a lot of this chemical into the brain and the rats have siezures".
Most of the discussion and analysis is on siezures
Hi Not Mercury -
"Did they isolate and culture unique bacteria form the guts of autistic children to see if they are more likely to convert culprit foods into propionic acid?"
Why do what has already been done? Several studies have shown that autistics are much more likely to harbor larger, and more diverse populations of Clostridia than non autistics. Among the known byproducts of Clostridia are propionic acid, ammonia, and others.
An excess of propionic acid (i.e., propioinic acidemia) is associated with several clinical findings that correlate well with autism; including increased ammonia, and a reduced level of carnitine. If I am not mistaken, there are others, including some behavioral similarities.
As I'm sure you are aware, it has been found that autistics are much more likely to have greatly reduced amounts of carnitine when compared to controls, as well as greatly increased amounts of ammonia. Whats more, placebo studies involving carnitine and autistics showed that symptoms improved when carnitine was administered when compared to placebo. Treatment for propionic acidemia also frequently involves carnitine supplementation.
Also observed in the model were increased markers for oxidate stress, lipid peroxidation, and glial activation, all of which are likewise observed in autism.
This doesn't prove that propionic acid causes autism by any stretch, but you sure seem to have chosen some odd parts of the paper at which to target your arrows.
Do you have any particular problems with the clinical correlations found between an excess of propionic acid and autism? You are, of course, free to be critical of whatever you would like, but it does give one pause to see so much significant information left out of a review only to focus on the low hanging fruit.
Take care!
- pD
pD: "Several studies have shown that autistics are much more likely to harbor larger, and more diverse populations of Clostridia than non autistics."
Citations please.
"As I'm sure you are aware, it has been found that autistics are much more likely to have greatly reduced amounts of carnitine when compared to controls, as well as greatly increased amounts of ammonia."
Citations please.
"Whats more, placebo studies involving carnitine and autistics showed that symptoms improved when carnitine was administered when compared to placebo."
Citation please.
This doesn't prove that propionic acid causes autism by any stretch, but you sure seem to have chosen some odd parts of the paper at which to target your arrows."
No it doesn't. Not by any stretch. I'm not really taking issue with the paper so much as the conclusions presented in the press release. If you disagree and think that this study in any way does "make a gut-brain connection to autism" please feel free explain.
Hi Not Mercury -
Microflora differences between autistics and controls
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16157555&ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum - Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15528506&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus - Real-time PCR quantitation of clostridia in feces of autistic children.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12173102&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus - Gastrointestinal microflora studies in late-onset autism.
Carnitine deficiency and incresed ammonia
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15679182&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum - Relative carnitine deficiency in autism.
Oops, l-carnosine was placebo tested. My bad.
"I'm not really taking issue with the paper so much as the conclusions presented in the press release. "
The following statement has nothing to do with how the paper was presented, but rather, your feelings on the quality of the paper and/or the methodology used.
"Inject bad stuff, observe neuroinflammation and antisocial behaviors, Et Viola! Autism. It's a pretty simple formula and one that can be applied to just about anything at the right concentration."
What's more, you cannot get increased ammonia, reduced glutathione levels, or increased lipid peroxidation markers by injecting 'just about anything at the right concentrations'. Perhaps you have a citation showing otherwise?
"If you disagree and think that this study in any way does "make a gut-brain connection to autism" please feel free explain."
What this study does is provide evidence of potential gut / brain interactions. The press release is quite clear on this:
"Compounds produced in the digestive system have been linkedto autistic-type behaviour in laboratory settings, potentially demonstrating that what autistic children eat can alter their brain function, say scientists from the University of Western Ontario." (my emphasis)
You are the one who uses the description of ground breaking.
Unless you have citations showing that these compounds are not produced in the digestive system, why shouldn't we accept this statement at face value?
Take care!
- pD
(blogger was not allowing me to enclose href tags. (?))
pD: From your first study --
Fifty-eight children diagnosed with ASDs participated in the study (48 males and 10 females, between 3 and 16 years of age). Many of the children had undertaken numerous courses of antibiotic treatment from an early age and suffered from common GI disorders (the most frequent complaints being diarrhoea and/or constipation). Most of the children were on GF/CF diets and many were taking probiotics/prebiotics and other supplements prior to entering the study. Two control groups were included: a non-autistic sibling group (seven males and five females, from 2 to 10 years of age) and an unrelated healthy group (six males and four females, from 3 to 12 years of age). Inclusion in the unrelated healthy control group required that volunteers had not used functional foods (such as probiotics and/or prebiotics) for at least 6 months prior to the study. The healthy sibling group was included to examine any impact of host genetics, environment and/or lifestyle. Written informed consent was obtained from each individual, their parent or guardian prior to inclusion in the study. In addition, a written questionnaire was used during recruitment of volunteers to assess GI habit, dietary characteristics and antibiotic usage, and to look for any correlation between the characteristics of individuals and bacterial profiles. This study was carried out under the guidance of the Ethics and Research Committee of the University of Reading.
Given the differences in diet, supplement and probiotic intake, history of antibiotc use, etc. I'd be more surprised to learn that there were no differences between the ASD and control groups.
OK, lets's say some autistic kids do harbor unusual levels of clostridium strains compared to other children. Why should I suspect that these gut flora are responsible for converting gluten or casein to propionic acid which, in turn, reaches high enough concentrations in the brain to cause a person to be autistic?
Let's start there and then we'll move on to your next cite.
Finegold is convinced that Ellen Bolte's son improved while taking Vancomycin and he's been looking for a gut bug to fit his hypothesis for a very long time now. Isolating a few unique bacteria hasn't exactly proven his hypothesis.
"Unless you have citations showing that these compounds are not produced in the digestive system, why shouldn't we accept this statement at face value?"
I'm not arguing that they aren't produced in the digestive system, they probably are. Your point being?
Wouldn't Pica easily explain differences in gut flora? They need to control for that if they want to take that hypothesis further. I suppose dietary differences could also explain it.
BTW, the l-carnosine study (not related to this discussion) has not been replicated. I always thought it was odd that no improvement was seen with placebo in that one study.
Pd may not wish to take issue with the paper but I will. Propionic Acid (it's really propanoic acid) is a medium organic acid - not weak as the paper says. It's corrosive and the exposure limit for humans is 10 PPM. The paper says that there is evidence that in disorders of PPA metabolism levels in the serum can reach the millimolar level. So these guys injected what level - the low dose was 52 millimolar and the high does was 500 millimolar. The reason they chose those levels apparently had nothing to do with what might correlate with real time levels found in serum let alone CSF. Nope , they chose them on behavioural grounds. In plain language they knew what level would produce the 'right' reaction before the experiment. Injecting a corrosive substance at 100 times the level set for safe exposure directly into the brain will get you some very nice reactions. Those they duly documented in great detail. So, the lab techs got plenty of practice in histochemistry and brain imaging. What they did not do was add one iota to the sum of human knowledge of autism. This is truly awful Science and enough to make me question the statement on their website that this research earned to approbation of the Canadian Research Council.
Your "commentary" is vague and wordy.
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