Theorizing that Too Much Propionate Contributes to Alzheimer's Disease

Proprionate is generated by gut microbes, and is generally thought to be beneficial, acting to improve measures of health. Thus it has been lumped in with butyrate and a few other metabolites as beneficial outputs of the gut microbe that decline with age as the microbial populations shift. Researchers here instead discuss the possibility that excessive manufacture of proprionate by the aged gut microbiome can contribute to neurodegeneration. All compounds have a dose response curve, and too much can be just as bad as too little. This commentary on proprionate is an interesting viewpoint: one of the challenges in Alzheimer's research is to explain why only some people exhibit the condition. Perhaps the specific composition and metabolite production of the aged gut microbiome, highly varied between individuals, is an important factor.

The enzymes needed to digest most dietary fibers are lacking in the human body. Therefore, the microbiota in the intestine is tasked with fermenting dietary fibers. Fermentation results in the production of short-chain fatty acids (SCFAs), which serve several important functions. In the gut, they aid in microbial growth. They are also second messengers that can modulate gene expression and initiate the synthesis of gut peptides and hormones.

One of the major SCFAs is propionate. In addition to fermentation, two other sources of propionate are food and the oral microbiome. In 1984, the Food and Drug Administration (FDA) labeled propionate as generally recognized as safe (GRAS) and approved its use for food preservation. Therefore, most persons are exposed to dietary sources of propionate every day. As for the oral microbiome, oral microbiota can produce propionate. Increased propionate levels are associated with gingivitis and periodontal disease.

Propionate serves important roles in the human body. However, our review of the current literature suggests that under certain conditions, excess levels of propionate may play a role in Alzheimer's disease (AD). The cause of the excessive levels of propionate may be related to the Bacteroidetes phylum, which are the primary producers of propionate in the human gut. Studies have shown that the relative abundance of the Bacteroidetes phylum is significantly increased in older adults. Other studies have shown that levels of the Bacteroidetes phylum are increased in persons with AD.

There is evidence for such a wide array of different mechanisms that excess propionate likely leads to AD by way of a combination of multiple different mechanisms. Probably the most well-studied mechanism of propionate induced neurotoxicity is related to its ability to impair the urea cycle, the principal pathway for nitrogen metabolism. This condition, known as hyperammonemia, occurs in propionic acidemia (PA), an autosomal recessive genetic disease characterized by an abnormal accumulation of propionic acid. The clinical manifestations of chronic, slightly elevated blood ammonia levels have received relatively little research interest within the field of dementia research. However, considering the well-known neurotoxic nature of ammonia, it is reasonable to speculate that chronically elevated levels of ammonia might be associated with the development of AD.



In a study published Feb. 3 in Cell Host and Microbe, the investigators showed that patients with Crohn's disease have an overabundance of a type of gut bacteria called adherent-invasive Escherichia coli (AIEC), which promotes inflammation in the intestine. Their experiments revealed that a metabolite produced by the bacteria interacts with immune system cells in the lining of the intestine, triggering inflammation. Interfering with this process, by either reducing the bacteria's food supply or eliminating a key enzyme in the process relieved gut inflammation in a mouse model of Crohn's disease.

the AIEC bacteria uses to convert a byproduct of sugar fermentation in the gut to grow. Specifically, the AIEC uses 1,2-propanediol, a byproduct of the breakdown of a type of sugar called fucose that is found in the lining of the intestines. When the AIEC converts 1,2-propanediol, it produces propionate, which the study showed interacts with a type of immune system cell called mononuclear phagocytes that are also found in the lining of the gut. This sets off a cascade of inflammation.

Posted by: Robert Read at February 7th, 2021 8:11 AM

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