Clostridia Bacteria, Dopamine Beta-Hydroxylase and Fatty Acid Beta-Oxidation Inhibition, and Their Links to Autism (part 1)
Review of hypothesis article from Integrative Medicine 2023 by Shaw
Autism is a complex neurodevelopmental disorder characterized by behavioral, cognitive, language, and socialization challenges. There are many factors that cause and contribute to the severity of an person’s autism condition, including environmental exposures, genetics, epigenetic influences, and biochemical imbalances.
A major area of focus over many years in autism intervention, primarily from a functional and integrative medicine perspective, is the contribution to autism severity induced by opportunistic and pathogenic digestive system organisms. Fungal colonization within the gut by various mold species such as aspergillus is known to exist, as well as overgrowth of commensal candida. However, it is the existence of certain clostridia bacteria that often takes center stage with regards to concerning negative influences on neurochemistry, along with compromised brain function. Most medical research from around the world has focused on Clostridium difficile as an inducer of digestive system disease. However, the story of clostridia, particularly as it relates to autism, goes well beyond the gut.
Image 1 - clostridia are anaerobic spore-forming bacteria. The spores allow for survival through the small intestine to unleash their toxic chemicals within the large intestine. It is within the colon where clostridia is most pathogenic.
Clostridia bacteria, which includes Clostridium difficile, aka C. diff., are common pathogens (not all of them) within the digestive system of autistic individuals. Apart from the well-known virulent toxins A and B of C. diff. causing diarrhea or the severe pseudomembraenous colitis, there are other chemicals such as 4-cresol and HPHPA which can alter neurochemistry as a potential cause of autism or more commonly an exacerbating factor in autism severity.
Image 2 - the virulence toxins A and B of Clostridium difficile are the main factors involved in inflammatory bowel disease secondary to a C. diff. infection.
This series of Substack articles will highlight key concepts from a 2023 article from William Shaw, PhD discussing the complex aspects of specific clostridium bacteria produced compounds and their relationship to autism. I begin this article series with a brief overview of key points. In subsequent articles, I will discuss this information in more detail.
Key Points From Shaw’s Article
Individuals with autism frequently have elevated levels of the neurotransmitter dopamine and its metabolites in urine and cerebrospinal fluid samples.
These same autistic individuals often have compounds measurable in urine samples known to be produced by various clostridia bacteria which includes 3-hydroxy-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA).
HPHPA, as well as 4-cresol (another clostridia produced compound), are known inhibitors of dopamine beta-hydroxylase (DBH), the nervous system enzyme which converts dopamine to norepinephrine. Inhibition of DBH activity by these clostridia compounds leads to elevated dopamine and its metabolites seen in autism.
Image 3 - HPHPA and 4-cresol from clostridia bacteria are known inhibitors of dopamine beta-hydroxylase (DBH). DBH converts dopamine to norepinephrine. High levels of dopamine within a nerve cell can lead to oxidative stress and neurological damage.
High levels of cellular dopamine (in the cytosol) convert to unstable quinones. These quinones can trigger superoxide oxygen radicals which damage cellular structures, including mitochondria.
In addition to DBH inhibition and the subsequent problems of quinone toxicity, HPHPA can lead to depletion of free coenzyme A (CoASH) which is needed for metabolic energy pathways, as well as the production of cholesterol and palmitic acid in the form of palmitate-CoA.
Low cholesterol is common in autism. Cholesterol is one chemical component in the activation of a critical protein involved in neurodevelopment called sonic hedgehog. The other compound is palmitic acid.
Palmitic acid, a 16-carbon saturated fatty acid, is metabolized through beta-oxidation, via the presence of CoASH. The palmitate-CoA derivative, along with cholesterol, is need to make activated sonic hedgehog.
Inactivated sonic hedgehog can impair normal neurodevelopment, as well as limb and digit formation. Highly relevant to autism is its influence on brain structure and functional influences. For example, sonic hedgehog is produced by Purkinje cells in the cerebellum. The cerebellum is often compromised in autism leading to poor motor skills, along with poor attention and focusing abilities.
HPHPA may interfere with fatty acid metabolism by sequestering free CoASH. This can affect overall fatty acid metabolism needed for energy production, including biochemical pathways such as glycolysis and pyruvate production, Krebs cycle activity, and the action of branched chain ketoacid dehydrogenase activities necessary for leucine, isoleucine, and valine metabolism.
Image 4 - diagram from Shaw article highlighting the adverse influences of HPHPA on cellular metabolism.
Researchers from around the world, including those in Italy (Mussap, et al, 2020) and China (Xiong, et al, 2016), have reported consistently high values of HPHPA in urine samples of autistic individuals.
Mussap, et al, in evaluating 154 markers in urine samples of autistics found that palmitic acid, adipic acid, and HPHPA were highly diagnostic of autism. Palmitic acid had the highest correlation with autism severity.
Xiong, et al, determined that HPHPA in 62 urine samples from an autism group was significantly higher than those in a control group. The elevated HPHPA was linked to a 96% accuracy in autism diagnosis.
Conclusion
There are other compounds discoverable through urine, primarily via organic acid testing, that are relevant in this discussion regarding autism diagnosis and severity. For example, Xiong, et al, also found high levels of 3-hydroxyhippuric and 3-hydroxyphenylacetic to be strongly associated with an autism diagnosis when combined with HPHPA.
Adipic acid, commonly found elevated on the organic acids test (OAT), is a six-carbon acid which is a reflection of the omega-oxidation often seen as a back-up pathway for compromised beta-oxidation of fatty acids. Beta-oxidation imbalances can occur from genetic mutations, cofactor deficiencies, prolonged high-fat diets, depletion of CoASH, the inability to make CoASH adequately from pantothenic acid conversion, and L-carnitine deficiency.
This brief introduction to the interactions of HPHPA on fatty acid metabolism, and the potential reduction of sonic hedgehog activation will be discussed in more detail through subsequent articles. In part 2 of this article series I will detail more specifics about the relationship between clostridia, its production of HPHPA, and related issues on cellular metabolism.