Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?

Today’s post allows me to cross off several topics from my to-blog list, since I can link them all together.

N = 1 or N > 1

If you are the parent of one of more children with autism, you will have a very specific view of autism, since your kind is the only kind that affects you.  This is natural and so for most readers it is case of N = 1.

When it comes to everyone else, and what they (should) teach medical students, it is the big picture that matters.  So large clusters of people behaving in a certain way is more significant that any outliers.  If you are the outlier, this is not much consolation.

In the world of autism, rather strangely, it is the very rare types that have an established medical therapy.  This ranges from the types caused by rare metabolic disorders to the more common PANDAS/PANS.

The large cluster that is classic autism remains untreated.

Polypill N = 3

To date I am aware of only a handful of people who have implemented the majority of my suggested Polypill for classic autism.  Three parents found major improvements and one found no impact; but the no impact case was not classic autism, it was very late regressive autism, later diagnosed as mitochondrial disease.

Many parents have implemented 1-2 elements of the Polypill with good results; these usually are elements that are the non-prescription drugs.

Three is not many, but it is more significant than one; and three out of four is a pretty good success rate.

As it stands, the Polypill will be a therapy for some children whose parents happen to be doctors, or own a pharmacy.

What does this have to do with antibiotics?

The other day I wrote a post about a recent 6 month clinical trial of Minocycline, an antibiotic.  The hope was that drug would reduce microglial inflammation and improve autism; but it did not.

Then I received a comment from Seth, a regular reader of this blog, to say that in his son tetracycline antibiotics really do improve autism.

I just read about John, another Dad, who found his child’s autism improved greatly while on antibiotics.  He has started his own charity N of One (N = 1) to raise funds for autism research and published an account of what he noticed.

An n=1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean

There are many other accounts of certain antibiotics improving certain people’s autism.

In the case of PANDAS/PANS antibiotics are just the initial part of the therapy, but unless you live in the US you are unlikely to get diagnosed with PANDAS/PANS, let alone treated for it.

I will not be able to solve this puzzle today, but I will make my observations, for what they are worth.

First of all, Seth is talking about tetracycline-class antibiotics, one of which is Minocycline, the subject of that six month autism trial.  Now as we saw in a recent post, that trial was deemed a failure, but that was a trial of 10 children with regressive autism.  

Note that what people mean by "regressive autism" varies widely; most autism has some degree of regression.  In classic autism, the person is born different and then gradually becomes more evidently "autistic" during early childhood. Regressive autism, as defined by Chez, is when things are normal for at least the first 12 months.  Language can be normal or abnormal and then lost.  

I should also highlight that are other reports of Minocycline being beneficial in Schizophrenia and other neurological disorders.

Minocycline: therapeutic potential in psychiatry.

Abstract

Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialed in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.

Minocycline is not just an antibiotic; it has several other known modes of action.

Minocycline is the most lipid-soluble of the tetracycline-class antibiotics, giving it the greatest penetration into the prostate and brain, but also the greatest amount of central nervous system (CNS)-related side effects, such as vertigo.

In various models of neurodegenerative disease, minocycline has demonstrated neurorestorative as well as neuroprotective properties

Minocycline is also known to indirectly inhibit inducible nitric oxide synthase (NOS).

As an anti-inflammatory, minocycline inhibits apoptosis (cell death) via attenuation of TNF-alpha, downregulating pro-inflammatory cytokine output.

Early research has found a tentative benefit from minocycline in schizophrenia

Amoxicillin

The antibiotic that John (from N=1) found to have magical properties was Amoxicillin, a very common type of penicillin.  Amoxicillin is a standard therapy for a strep throat.

Streptococcal infections are the initial trigger for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

Amoxicillin seems to be have just one mode of action, that of an antibiotic.  This means it is a type of antimicrobial used specifically against bacteria, and usually used in medical treatment of bacterial infections. Antibiotics may either kill or inhibit the growth of bacteria.

          From the US National Institute of mental Health  (NIMH):-

Can penicillin be used to treat PANDAS or prevent future PANDAS symptom exacerbations?

Penicillin and other antibiotics kill streptococcus and other types of bacteria. The antibiotics treat the sore throat or pharyngitis caused by the strep by getting rid of the bacteria. However, in PANDAS, it appears that antibodies produced by the body in response to the strep infection are the cause of the problem, not the bacteria themselves. Therefore one could not expect antibiotics such as penicillin to treat the symptoms of PANDAS. Researchers at the NIMH have been investigating the use of antibiotics as a form of prophylaxis or prevention of future problems. At this time, however, there isn't enough evidence to recommend the long-term use of antibiotics.

However, a quick “google” will show more n=1 cases, of people claiming their child’s autism/PANDAS improving on Penicillin and then regressing again afterwards.

  

Vancomycin

The other antibiotic that has been researched in autism is Vancomycin.  This drug is not absorbed from the intestine, so for systemic therapy it has to be taken by injection.  

When given orally it is used for things like treating bacterial infections of the intestines that cause colitis.  Orally administered vancomycin is recommended as a treatment for intestinal infection with Clostridium difficile, a common side effect of treatment with broad-spectrum antibiotics.

Vancomycin was first isolated in 1953 at Eli Lilly, from a soil sample collected from the interior jungles of Borneo by a missionary.

.

Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism

Abstract

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism

What is going on?

The truth is that nobody knows for sure what is going on.  That also applies to PANDAS & PANS, which is why most of the world does not recognize them as genuine diagnosable conditions.

It would seem to me that various different processes are likely involved.  It would not be so hard to do some detective work, on a case by case basis.

For example, both Seth and John were using broad spectrum antibiotics.  If they gave Vancomycin a quick trial, they would find out if the problem was in the intestines, since that is the only place oral Vancomycin can have an effect.

John has written in his paper all about possible changes to the gut microbiome and how repeated antibiotic use early in life could set the stage for the development of autism in some children.  It is very easy to test this hypothesis, just try some Vancomycin.

We know that ulcerative colitis is comorbid with autism.  We know that this will lead to a permeable gut and the flow of unwanted substances to other parts of the body.  We see that Vancomycin is used for treating bacterial infections of the intestines that cause colitis.

So it is no surprise that in some people with autism, Vancomycin will improve behaviors.  You just need to identify which people.

Once apparent that Vancomycin is indeed effective, at least you know where the problem is.  Then it is a question of finding long term solutions to manage the problem.

We already know much about the so-called “leaky-gut” and the many GI problems in autism.  This is very well covered on the SFARI site and blog, so here are some highlights from there.

'Friendly' bacteria treat autism-like symptoms in mice

The new study is the first to show that maternal infection alters the microbiome in the offspring. The finding is significant for autism, as many children with the disorder are plagued by gastrointestinal problems, including diarrhea, vomiting and stomach discomfort. 

Leaky gut is also reported in children with autism and is associated with several other disorders, such as inflammatory bowel disease and Crohn’s disease, and perhaps with Alzheimer’s and Parkinson’s diseases, says Sarkis Mazmanian, professor of biology at the California Institute of Technology.To diagnose leaky gut in the mouse pups, the researchers fed them a carbohydrate molecule attached to a fluorescent molecule. The molecule later turned up in their blood, showing it had escaped through the gut wall. The mice also showed elevated gut levels of an immune molecule called interleukin-6 (IL-6) — a prime suspect in mediating the effects of maternal infection

The researchers then treated the mice with B. fragilis. This strain of bacteria isn’t commercially available, but exists naturally in about 20 percent of the human population. 

Mice treated with B. fragilis at 3 weeks of age don’t have a leaky gut five weeks later, their levels of blood 4EPS and gut IL-6 plummet, and the assortment of bacterial species in the gut reverts to something closer to that of control mice. And the mice do better behaviorally: They stop obsessively burying marbles in their cages, become as vocal as controls and are less anxious.

Probiotic curbs autism features in mouse model

• Guest blog: The case for using 'prebiotics'

• A probiotic therapy for autism

Sarkis K. Mazmanian, Ph.D.California Institute of Technology

Most research into autism spectrum disorders has focused on genetic, behavioral and neurological aspects of the illness, but people with autism also show striking alterations in immune status.

What’s more, a significant subset of children with autism spectrum disorders show chronic intestinal abnormalities, such as loose stool and altered bacterial microbiota (the collection of beneficial bacteria within the intestine). Antibacterial treatments are reported to provide behavioral improvements in some cases.

In addition, many children with autism have been diagnosed with food allergies and are on special diets. Societal advances (including 'Western' diets and antibacterial products) may have paradoxically compromised human health by reducing our exposure to health-promoting gut bacteria.

The connection between gut bacteria, intestinal disease and autism is a promising area of investigation. Sarkis Mazmanian and his team at the California Institute of Technology used mouse models that show autism-like features to evaluate the efficacy of probiotics.

They found that specific probiotic bacteria ameliorate autism-like behaviors in both environmental models of ‘induced’ disease (by mimicking viral infection of the mother during gestation), as well is in two genetic models of autism spectrum disorder.

These studies are an important step in furthering research that addresses the connection between the gut microbiome and altered behaviors, a link suggested by studies in humans. Finally, Mazmanian’s findings may help validate the use of probiotics as a safe and effective treatment for autism when it is accompanied by gastrointestinal abnormalities.

   

What it means?

It certainly appears that some people with ASD and GI problems have a something similar going on to my case of “N=1” (ASD + pollen allergy).  An allergic reaction has caused mast cells to degranualate releasing histamine and  IL-6.  That histamine causes further release of IL-6 elsewhere.  IL-6 is a pro-inflammatory cytokine and “public enemy number one” in the case of autism flare-ups.

It does appear that some people with autism + GI problems improve somewhat with supplemental digestive enzymes, like Creon/Kreon.  This does appear to be the basis of CM-AT, the long awaited therapy from Curemark.

However, based on feedback from this blog, it appears that blocking the calcium channel Cav1.2 with Verapamil may be even better.  It will certainly be much cheaper.

The standard treatment for this type of allergy related GI problem, is Cromolyn Sodium, a mast cell stabilizer.  Verapamil is also a mast cell stabilizer, among other properties.

Interestingly, some people “do grow out” of some allergies.  I myself, as a child, was prescribed Intal (Cromolyn Sodium) for GI problems of unknown origin.

You will find countless reports on the internet of children with “autism” who, on various diets, “recovered”.  You will hear plenty of people saying that young children will “grow out of” their autism.  It is generally accepted that most people’s autism does moderate as they become adults, just like many people’s asthma.

There is some sense in all of this.  Allergies can seriously aggravate autism.  So if you have someone with very mild autism, but a severe allergy, when you control the allergy you will see dramatic behavioral improvement.

Some readers of this blog have found that common allergy treatments like Zyrtec (cetirizine), have a profound behavioral improvement on their child, who was supposedly allergy-free.

In “my” subgroup of classic autism one underlying problem appears to be a channelopathy (Cav1.2); this might be genetic, or it might be an “epigenopathy”.  In either case, you could detect it, with existing technology, if you really wanted to.

Conclusion

The clever people at the NIMH think that PANDAS/PANS is a kind of Rheumatic Disease, where an autoimmune disorder (triggered by strep throat infections) causes the body to produce antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. However in a rheumatic disease, the antibodies mistakenly recognize and may attack the heart valves, joints, and certain parts of the brain.  When they attack the joints it is called Rheumatic Arthritis, when they attack the brain it is now called PANDAS.

The NIMH thinks that PANDAS/PANS is distinct from autism.

If you regularly read the research in this blog, you may disagree with the NIMH and see that PANDAS/PANS is just another autism variant.  Likely many things, other than strep infections, can also trigger this over-active immune system.

Many strange things occur in autism, one being that adults apparently cannot have PANDAS.  Of course they can; it just would have to be called ANDAS.

If an adult with autism wants to check for some rare for metabolic disorders leading to “autism” he/she may need to get referred to a children’s hospital, like Arkansas Children’s Hospital.  All the while, some of their diagnoses/treatments continue to be regarded as quackery by many other clinicians.

Some people with Schizophrenia, who improved on Minocycline, should try Vancomycin.  If the benefit is lost (as I suspect, it will be), then we would know that the effect was elsewhere than in the intestines.

Having established that Minocycline had no benefit in children with regressive autism, perhaps Johns Hopkins and NIMH should trial it in early-onset autism (classic autism).  It is Johns Hopkins after all, who believe that regressive autism is primarily mitochondrial disease.  The research indicates that mitochondrial disease is but one feature of classic autism.

Vancomycin is a useful diagnostic tool, rather than a long term therapy, but if Vancomycin improves behaviour, then you have plenty of choices:-

·        Cromolyn Sodium

·        Verapamil

·        Digestive enzymes like Creon/Kreon and, eventually, CM-AT

·        Probiotics & Prebiotics  (one day even Bacteroides Fragilis)

·        Exclusion diets

So if your child improves after taking antibiotics, or anything else, my suggestion is to investigate it yourself, rather than found yet another autism charity.

There is actually plenty of existing research and clever people, like those at the Simons Foundation, are funding further work on a prolific basis.

Other than readers of the SFARI blog and the Questioning Answers blog, is anyone actually reading (nearly) all this research? (let alone applying it)   Evidently not.

The academic researchers just read narrowly around their very focused area of interest.  The majority of clinicians read almost none of the research.

If you want to solve a complex problem, collect all the available data, look for connections and then think about it.

You should not have to do this for yourself, but with autism you do.