What is autism
Autism is classified as one of the pervasive developmental disorders of the brain. As such, it’s not a disease but rather a disorder.
How prevalent is this disorder? Estimates of the incidence of autism in the general population vary greatly, depending on the diagnostic criteria used. Some estimates show that autism affects as few as 5 of every 10,000 people, but others put the incidence as high as 1 in 80. In reality, the incidence of autism may be several times higher than previously thought. Autism strikes males four times more often than females.
People with classical autism have three types of symptoms: impaired social interaction, problems with verbal and nonverbal communication, and unusual or severely limited activities and interests. More specifically, people with autism may be self-absorbed and unable to interact socially; they may also have behavior problems and language dysfunction (such as echolalia). These symptoms can vary in severity. In addition, people with autism often have abnormal responses to sound, touch, and other sensory stimulation.
The symptoms of autism usually appear during the first three years of childhood and continue through life. In many children, the symptoms improve with intervention or with age. Some people with autism eventually lead normal or near-normal lives. However, the onset of adolescence can worsen behavior problems in some children, and parents should be ready to adjust treatment for the child’s changing needs.
The accumulated symptoms of autism are sometimes categorized as autism spectrum disorders, or ASD. This categorization fits with theories suggesting that people with autism have several maladies. About one third of the children with ASD eventually develop epilepsy. This risk is highest in those with severe cognitive impairment and motor deficits. Despite this range of symptoms, people with autism have a normal life expectancy.
What causes autism
While the exact cause of autism remains elusive, considerable advances have been made in recent years. These advances have come from study of the geographic localization, biological, and psychological aspects of the disease. From these studies, several theories have emerged.
One theory is that some people have a genetic predisposition to autism; researchers are looking for clues about which genes contribute to this increased susceptibility. Other studies of people with autism have found abnormalities in several regions of the brain, which suggests that autism results from a disruption of early fetal brain development. In some children, environmental factors also may play a role. Additionally, due to the timeframe of when the disease is initially observed (that is, in infancy), there has been an association between autism and childhood vaccination.
Other theories point to diet as playing a major role in the development of autism. It’s thought that opioid-type peptides (or exorphins) are produced due to maldigestion of casein and gluten. Casein and gluten are proteins commonly found in dairy and wheat, respectively. (This will be discussed in more detail in the final section of this chapter.)
Several previous notions about the nature and causes of autism have been disproved. For instance, it was once commonly believed that autism resulted from a lack of parental affection, and mothers, in particular, were blamed for being cold toward their children. (They were sometimes referred to by the medical profession as “refrigerator mothers.”) As silly as it sounds, this theory went unquestioned, at least publicly, until about 1970. Another popular theory about the so-called savant tendencies of autistics was popularized by the mass media through such movies as Rain Man. While it’s true that some individuals with autism have amazing abilities in certain areas such as recognizing and repeating strings of numbers and music and having extraordinary artistic abilities no clear relationship has been established between these skills and autism.
How is autism treated
There is currently no cure for autism, but appropriate treatment may bring about relatively normal development and reduce undesirable behaviors. Different types of therapies are designed to remedy specific symptoms. For instance, educational/behavioral therapies emphasize highly structured and often intensive skill-oriented training. Doctors also may prescribe a variety of drugs to reduce symptoms of autism. Other interventions are available, but few, if any, scientific studies support their use.
The prevailing nutritional therapies attempt to remedy autism in three ways, used either singly or in combination: diet restriction (avoiding dairy and wheat), supplementation with exogenous enzymes, and supplementation with probiotic bacteria. Until recently, none of the therapies addressed the molecular mechanisms that may be at work in the development and progression of autism.
The following section will look at the molecular and cellular mechanisms that are possibly related to autism and discuss how they can be used to treat the disease through the use of various nutrients. The link between autism and unusual immune and inflammatory responses will also be explored in the context of probiotics.
What is the probiotic solution
Pioneers in the field of autism first observed the significant correlation between the symptoms of autism and an impaired ability to adequately digest peptides/proteins from dairy (casein) and wheat (gluten). During digestion, preopioid-type compounds in the diet, typically from casein and gluten, seem to be activated due to an incomplete breakdown of proteins. These partial proteins or peptides, which are called exorphins (that is, casomorphins and gluteomorphins or gliadorphin), are then easily transferred across the lumen of the gut into the bloodstream; they are carried to the brain, where they exert an opioid-type action.
The transfer of peptides across the lumen of the gut is thought to occur at a high level in someone with autism because of the leaky nature of his or her gastrointestinal (GI) tract. According to the exorphin theory of autism, the attenuated level of a gut enzyme called Dipeptididylpeptidase IV (DPPIV) could manifest as autistic symptoms. DPPIV is one of the enzymes that specifically digests exorphins so they don’t interact with the body’s own natural neural signaling.
Ingesting probiotics can help repair this leaky gut by providing a physical barrier that prevents bad bacteria (or pathogens) from attaching to and then moving across from the lumen to the inside of the body and causing bacteremia (or bacteria in the blood). Not only do the probiotics physically keep the bad bacteria at bay, but they also allow the body to recover from the physical distress those bacteria can cause. This allows the body to heal itself, to a large extent. In short, ingesting probiotics helps repair the GI tract of the autistic individual.
Another level at which probiotics are functional and beneficial to people with autism goes back to the exorphins in the diet. Recently, my own lab published findings on the use of enzymes and probiotics in the treatment of autism. A distinction was made between the two, but in reality, the line between probiotics and enzymes is not that clear cut at least, not for a discussion of autism. The reason is that the probiotics contain very high levels of a variety of enzymes, several of which may be important for people with autism.
While other studies have been undertaken on the use of enzymes to treat autism, none have been reported in the literature at this time. And while my lab’s study is similar to these others in structure, we used a unique enzyme formulation. In addition to adding several new enzymes, my lab’s study is the first to report the therapeutic potential of genomeceuticals, which are designed to stimulate the body’s own production of both the DPPIV enzyme and probiotics.
An important element of that formula is galactose, which is a simple sugar. It’s almost identical to glucose, but the body doesn’t use it in the same way. Galactose is believed to function at two levels. The first is as a genomeceutical, in which it is believed to increase the gut expression of the DPPIV gene present in the body. This allows for a greater level of DPPIV enzyme in the enterocytes (gut cells), promoting the more thorough breakdown of any exorphins produced by the proteases.The second and equally interesting possibility is that galactose serves as a fuel source of the beneficial microflora (that is, probiotics) in the gut. This is important because the probiotic organisms themselves contain enzymes capable of breaking down such exorphins.
Research has shown that the probiotic organisms currently used as health supplements contain analogues of the DPPIV enzyme (for example, PepX), which is known to be able to digest exorphins. With over 10 trillion microorganisms in the gut, their contribution of enzymatic activity can far exceed that of the enterocytes. It is well documented that galactose is a prebiotic (that is, it stimulates the growth of probiotics) and can therefore increase the number of probiotics in the gut.
Thus, it seems that increases occur both in the level of DPPIV in the gut and in the level of DPPIV-type activity (contributed by a large increase in the bacterial flora). And due to the rapid formation of any exorphins from the high level of acid stable protease, the result is that the levels of absorbed exorphins drops below the threshold required for manifestation of the parameters measured. To test this hypothesis, future studies are planned to assay urinary polypeptide levels on retained samples both before and after treatment. Future studies will also look at blood peptide levels both before and after treatment. Additionally, research is planned to determine how genomeceuticals contribute to the formula. Again, increasing levels of galactose will be assessed against all the parameters measured in the present study, along with blood levels of exorphins and stool levels of various probiotic species.
The only known contraindication for the use of galactose is in a fairly rare metabolic disorder called galactosemia. However, the amount of galactose in the formula (100 milligrams) is far less than the amount consumed in drinking a glass of milk. A typical glass of milk contains around 12 grams of lactose, which, when broken down, would contribute 6 grams of galactose to the diet or approximately 60 times the amount in a single capsule of one of the products used.
As an uncontrolled pilot clinical study, work in my lab has had tremendous value in treating people with autism. The overwhelming majority of parameters measured show significant benefits from the enzyme blend, and very few negative reactions were associated with it. In addition, this is the first time a genomeceutical approach has been therapeutically applied not just to autism but to any disorder. While the relationship between autism and ASDs still remains elusive, clearly, the present study advances the knowledge base for improving treatments.
One of the things that’s observed in treating people with autism (and in a variety of other situations in which probiotics are used) is that over time, the same strain seems to have less and less positive effects on the body. Recently, I addressed this with the Brudnak method of pulsing and rotating probiotics, as I conceived of this theory and first wrote about it. (This is discussed in more detail later in this section and also in Chapter 10.)
Ten years ago, most probiotic products contained either Lactobacillus acidophilus or Bifidobacterium lactis (bifidum). If someone was really lucky, he or she could find a combination of the two and possibly a couple of yogurt strains (Lactobacillus bulgariucus) thrown in. Many of these contained only a few 100 million viable cells at the time of manufacture. While that may sound like a lot of organisms, especially when we are conditioned to think of bacteria as being bad, current data show that those numbers were probably far too low to have done very much good. This was true at least in the short-term therapeutic application of probiotics.
What’s changed in the past 10 years? As more and more data have come in, it has become apparent that at least 1 billion organisms per dose are needed to achieve any real clinical significance. In a recent study, 10 billion Bifidobacterium were given per day in milk and the immune markers were measured. A significant increase in phagocytic activity of granulocytes was observed.
Another study looked at the preventive effect that probiotics have in warding off infections in cancer patients. Thirty patients (35 episodes) were included. Lactobacilli were given as two capsules, three times a day for 30 days, starting at the initiation of the patient’s chemotherapy. Each capsule contained a 50/50 mix of Bifidobacterium lactis and Lactobacillus acidophilus, 4 billion organisms per capsule. The occurrence of fever was significantly postponed from a median time of 8 days to 12 days. Clearly, probiotics can play an important role in treating even the most serious conditions, such as cancer.
The level of ammonia in the blood of people with autism is another research concern. The use of probiotics can easily assist with the reduction of circulating ammonia. One study used 5 billion organisms of either B. lactis or B. breve in caecal contents (or feces). In this study, researchers also observed a corresponding drop in the pH of the caecal contents. This lends support for the use of probiotics in detoxification protocols.
The whole area of detoxification of the body is very popular in the autism community. Doctors use things such as DMSA, EDTA, and other such chelating agents. (To chelate means to grab or surround something.) Detoxification is relevant to treating autism because it has been suggested that environmentally acquired mercury ingested through causal contact or through vaccination is the culprit behind autism and ASDs.
An area related to detoxification but yet unexplored is the body’s own endogenous enteric bacteria: probiotics. The rationale is that the gut associated lymphoid tissue (GALT) serves as a sort of lynchpin in the establishment and/or progression of autism. It’s known that bacteria can detoxify methyl mercury (organic) using the mer genes. The mer genes are required to detoxify organic mercury compounds by converting them to volatile and much less toxic elemental mercury and in organomercurials.
The mer genes are organized in a regulated operon, which may be genomically or extra chromosomally housed. The group of mer genes consists of mer R, which codes for Hg(II)-sensing, DNA-binding, regulatory protein; mer A, which codes for the mercuric-ion-reducing protein; and one or more of the genes mer P, mer T, and/or mer C, which code for proteins involved in moving the mercuric ions into the cytoplasm.
There is growing interest in the bacteria that harbor these genes, as they may be able to detoxify the body of mercury. This is a very hot topic now; in fact, it received a congressional review in April 2000. Since ordinary probiotics have been shown to detoxify mercury and have a long history of safe use, it seems a natural fit to use them to support proper functioning of the GALT, which is linked with immunity and overall health of a person.
Obviously, as the probiotics take up the mercury, more will be needed to replace those that pass through the system. The goal is not to provide constant circulation but rather to flush out the mercury in the probiotics along with the other waste.
Probiotic supplementation has been demonstrated to be safe and effective for a wide variety of conditions, including antibiotic side-effects, diarrhea and constipation, lactose mal-absorption, and cholesterol reduction. Dosages ranging from 1 to almost 500 billion organisms have been used without complications. Current trends seem to indicate that a range of 10 to 100 billion live organisms is most effective in treating the variety of conditions just mentioned.
At least two different companies have high-dose products on the market, containing 20 and 30 billion organisms per capsule. Interestingly, both of these products were originally designed for use in different markets: people who are environmentally challenged and those who have autism (and Down syndrome), respectively. In terms of marketing, two conclusions seem obvious here: There is a need for high dose probiotics to treat selective conditions, and there is also a need for a variety of products.
Thus, it seems that while a low-dose, run-of-the-mill L. acidophilus (providing it’s well produced) can be great for a general maintenance program, often times, a much higher dose is needed to achieve clinical significance. Additionally, it’s becoming more and more apparent that including other strains, such as Lactobacillus rhamnosus or Lactobacillus plant arum (an exciting up-and-coming star), can have a dramatic effect. The inclusion of multiple strains is beneficial for the specific conditions and may also play another important role in the application of probiotics.
I recently had a conversation with Dr. Stephanie G. Hoener, a naturopathic physician based in Portland, Oregon. She specializes in assisting children with special needs, such as those with autism, and frequently speaks in the medical community on issues such as autism and detoxification. Dr. Hoener had this to say about using high-dose probiotics to treat children with autism: We often have to start patients on 20 to 60 billion organisms per day in order to get the beneficial effects. The majority of children with autism have severely compromised intestinal function and large numbers of pathogenic yeast and bacteria, so dosing this high is often what is needed in order to begin the process of normalizing digestive function. Usually, we can dose even higher than this with even better results—as high as 100 billion organisms per day or higher, depending on the child’s age. In addition to supporting GI function, these high doses of probiotics also help to strengthen these children’s immune systems, which are often significantly compromised.
Increasingly, the use of mono- and bi-strain products brings reports of reductions in the clinical effects seen over time. For instance, in the case of autism, a child for whom pretreatment causes diarrhea or some other gastrointestinal distress will improve dramatically when first supplemented with these products. He or she will start producing well-formed stools on a regular basis. However, in some cases, the child will go back to the previous distressed state. Two approaches seem to have answers for this troubling phenomenon.
First is the “pulse” step of the Brudnak method of pulsing and rotating probiotics, mentioned earlier. Here, when the clinical effect begins to change, the physician can stop the probiotic supplementation for a period of time and then later repeat the application. The body appears to reset itself after the therapy has been stopped. During this period, changes occur in the GI tract that may make the local environment more hospitable to the probiotics. Additionally, there are certainly changes in the immune functioning of the gut.
It’s well established that the intestines are a major source of immune competence. It’s also well established that certain genetic elements respond to heavy metals—in particular, to mercury. Perhaps upon first being exposed to the probiotics, the gut-associated immune system is mobilized and attacks the probiotics. Then, after withdrawal of the probiotics, the immune reaction tapers off until another exposure occurs. This cycle is not a bad thing; in fact, it can be used to great advantage by pulsing with probiotics.
A variation on that theme also can be employed. It seems logical that instead of withdrawing all of the probiotics for any period of time, another product, containing different organisms, could be substituted. For instance, if a product that contains just L. rhamnosus is being used and the above condition presents, a product that contains just Bifidobacterium could be substituted in a subsequent treatment. If a single strain of Bifidobacterium is used and, again, the same situation occurs, then a third product containing several strains could be substituted. What strain is used in what instance would certainly have to be determined on a case-by-case basis, according to the physician’s observations. In the foreseeable future, products will be designed specifically to address the issue in this way. This probiotic rotation will be applicable in a variety of situations.
Dr. Hoener also passed along a clinical observation regarding how the body becomes accustomed to one organism, such that it has less and less of a positive effect: In children with autism, it is extremely common to see that they do very well on a probiotic supplement for a period of time and then it appears to lose its efficacy. For example, after starting a probiotic, they may have a resolution of their diarrhea, more well-formed stools, less gassiness and abdominal bloating, and less abdominal discomfort. If these benefits appear to lessen after a period of several weeks, we can switch them to a different strain of probiotic and the positive improvements will generally return. I’ve spoken with dozens of parents who have tried this pulsing-and-rotating approach with their autistic child and obtained very favorable results.
Clearly, the area of probiotics is still in its infancy. This neonate will soon grow up, however, as major pharmaceutical companies enter this exciting and efficacious area of health care. As clinical data from the application of probiotics to conditions such as autism come to light, consumers’ and patients’ awareness of the importance of these organisms and the demand for treatment using them will likewise increase. With that, we can expect that better products, tailored to specific conditions, will also be developed.
Currently, there is a demand in the autism community for foods and supplements that are both casein and gluten free (or GFCF). There is also an increasing demand for probiotic organisms. Some question has arisen about the ability to produce probiotic organisms that can qualify as GFCF. The GFCF issue presents several technical issues, which have not yet been addressed.
Today, the overwhelming majority of probiotics are produced in growth media that, at some point, contain at least one dairy product. However, it’s generally agreed that by paying proper attention to growth conditions, as well as processing methods, the final products can be considered casein (or milk) free. This is because during normal growth and processing, the bacteria consume the dairy elements of the growth media and the residuals are separated during the concentration/ purification of the probiotics. However, there are often problems demonstrating this result due to the inherent problems of current assay methods (that is, the methods used to take apart the substance and examine its individual elements).
Several types of assay methods are currently used to detect casein in probiotics. The first is precipitation and quantification by total protein methods, such as the Kjeldahl procedure. The second is by an enzyme linked immune sorbent assay (ELISA), which utilizes antibodies to detect the casein as a target antigen with subsequent reporter systems (for example, colorometric). Let’s look at both in some detail.
The total protein method evolved out of the food-processing industry as a way to test milk products for casein. It relies on the fact that the vast majority of protein present in milk is casein, and for this industry, this method has proven useful. Additionally, the probiotics are living organisms that produce a wide variety of proteins. These, too, can contribute to a false-positive signal from the reporter system due to a similarity to casein in sequence. The chance of this happening when using a monoclonal antibody (mAb) is much less than when using a polyclonal antibody. (pAb). However, the standard kit used to detect casein contains pAbs, not mAbs.
The technicalities of the antibodies and their differences are not important. What is important is that they give different results. In particular, different bacteria produce different levels of various proteins, so there can be seemingly inconsistent results from species to species and even strain to strain. Because probiotic organisms contain thousands of different proteins at any given time, the total protein method is not appropriate for determining casein in any given culture.
The second assay method the ELISA method also has several drawbacks. First, it’s most desirable in this method to use a monoclonal antibody (mAb), not a polyclonal antibody (pAb), for reasons of specificity. With a mAb, the chance of getting a false-positive is much less because the mAb is considerably more specific for the desired target (in this case, casein) than is the pAb. The pAb is, by definition, specific for several, if not many, different targets. Why? A pAb is not one single antibody but consists of many different Abs hence, the prefix poly-. For many purposes, a pAb is sufficient. The reasons for using a pAb over a mAb range from time to cost. In sum, a pAb can be produced much faster than a mAb and at much less cost.
The ELISA assay is a very good assay technique, but it’s less than desirable for assaying casein in probiotics. The reason for this (in addition to those just mentioned) has to do with how the reporter portion of the ELISA functions. While there are different ways to perform the ELISA assay, they all can be generalized as follows: During ELISA, when a target molecule binds to the Ab, a subsequent enzymatic reaction (typically, the enzyme is linked to the antibody) is used to report that the binding occurred. This enzymatic reaction, more often than not, involves a peroxidase or phosphatase. Herein lies the problem, because probiotics produce peroxidases and phosphatases.
The problem is further confounded because different bacteria produce different levels of these enzymes. For instance, Lactobacillus acidophilus (LA) produces peroxidase. Not surprisingly, LA shows up as a positive using the ELISA method, even when produced using the very same procedure for other strains that show up as negatives. Furthermore, other enzymes are probably produced by the bacteria, which can similarly trigger the reporter system and result in a false positive.
A third, although much less common, method for detecting casein utilizes gel (typically, SDS-polyacrylamide) chromatography. In this method, cellular extracts are placed in an electric field at one end of a gel matrix. The matrix allows the smaller proteins to move through first and the larger proteins to migrate more slowly thus, lagging relative to the smaller proteins. This differential mobility in the gel affords a separation of proteins and protein fragments. The main problem with this method is that it is not only possible but probable that two very different proteins (based on sequence) can have the same mobility in the gel. This limitation can be overcome, to some degree, using isoelectric-focusing gels. This process also has similar problems associated with it.
Keep in mind that the fundamental reason for concern over casein is the fear of producing exorphins from it. This is important because the probiotic organisms that are being subjected to the casein analysis themselves contain enzymes that are capable of breaking down such exorphins. As noted earlier, research has recently shown that probiotic organisms currently utilized as health supplements contain analogues of the DPPIV enzyme (for example, PepX), which is known to be able to digest exorphins. Noteworthy is the fact that the higher the concentration of probiotics a supplement might contain, the higher the chance it will test as a false-positive for casein while concurrently producing unusually large amounts of the DPPIV analogues.
Taken as a whole, this information clarifies several standing issues regarding both probiotic supplementation in treating autism and reported test discrepancies. In light of recent advances in understanding about the underlying enzymology of probiotic organisms, it makes sense to view casein testing in light of the actual biological significance that any detected presence might have.
Further, the current state-of-the-art of casein testing should be given proper consideration. I buy my products from a manufacturer who has been selling probiotics specifically for many years, not just a few. Anyone who decides to go with a start-up company should make sure it’s associated with a reputable manufacturer. It’s important to look for quality trademarks, such as MAKTech and HOWARU.
When I look for products for the autism community in my consulting work, I usually look for those from certain manufacturers. (Again, see the list of suppliers in the Resources section.) In addition to having good probiotic products and plans for future products that fit the Brudnak method of pulsing and rotating probiotics, they also carry food items that are casein and gluten free. Several of the companies I know are very helpful, and several seem especially interested in the autism community and its kids.