Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases

Abstract

The involvement of the gut microbiota and the metabolites of colon-residing bacteria in brain disease pathogenesis has been covered in a growing number of studies, but comparative literature is scarce. To fill this gap, we explored the contribution of the microbiota–gut–brain axis to the pathophysiology of seven brain-related diseases (attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, major depressive disorder, and bipolar disorder). In this article, we discussed changes in bacterial abundance and the metabolic implications of these changes on disease development and progression. Our central findings indicate that, mechanistically, all seven diseases are associated with a leaky gut, neuroinflammation, and over-activated microglial cells, to which gut-residing bacteria and their metabolites are important contributors. Patients show a pro-inflammatory shift in their colon microbiota, harbouring more Gram-negative bacteria containing immune-triggering lipopolysaccharides (LPS) in their cell walls. In addition, bacteria with pro-inflammatory properties (Alistipes, Eggerthella, Flavonifractor) are found in higher abundances, whereas lower abundances of anti-inflammatory bacteria (Bifidobacterium, Coprococcus, Eucbacterium, Eubacterium rectale, Faecalibacterium, Faecalibacterium prasunitzii, Lactobacillus, Prevotella, Roseburia) are reported, when compared to healthy controls. On the metabolite level, aberrant levels of short-chain fatty acids (SCFAs) are involved in disease pathogenesis and are mostly found in lower quantities. Moreover, bacterial metabolites such as neurotransmitters (acetylcholine, dopamine, noradrenaline, GABA, glutamate, serotonin) or amino acids (phenylalanine, tryptophan) also play an important role. In the future, defined aberrations in the abundance of bacteria strains and altered bacterial metabolite levels could likely be possible markers for disease diagnostics and follow-ups. Moreover, they could help to identify novel treatment options, underlining the necessity for a deeper understanding of the microbiota–gut–brain axis.

Gene Expression Changes Induced by Exposure of RAW 264.7 Macrophages to Particulate Matter of Air Pollution: The Role of Endotoxins

“…This leads to the induction of inflammatory processes in the digestive system and an increase in the penetration of LPS of intestinal bacteria into the circulation and further inflammatory signaling into the brain, which contributes to the pathomechanisms of many neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease or multiple sclerosis [ 91 ]. A similar mechanism has been described for major depression [ 92 ] and other neuropsychiatric disorders [ 93 ]. Thus, the LPS/endotoxins, though external factors and not produced by the human body, become signaling molecules that are importantly involved at the nexus of neuropsychiatric and neurodegenerative disorders.…”

Gut Microbiome and Mycobiome Alterations in an In Vivo Model of Alzheimer’s Disease

“…Interestingly, in our study, the Coprococcus genus, within the Firmicutes phylum, was significantly less abundant in the AD respect to the WT mice and this was one of the two bacterial features able to explain the difference between the two compared groups. Coprococcus is usually considered as an anti-inflammatory bacterium, and its abundance has been recently reported as reduced in seven different brain-related diseases, including AD (specifically, attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, major depressive disorder and bipolar disorder) [ 34 ]. In addition, the Coprococcus genus is involved in carbohydrate fermentation and short-chain fatty acid (SCFAs) production [ 35 ].…”

The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics

“…It must be recognized that a potential microbial etiology for neurodegenerative diseases has been postulated for some time, with the oral and gut microbiota particularly implicated, as reviewed extensively elsewhere [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. This has fostered the possibility of the development of suitable bacteria-targeted therapeutic strategies, some of which show promise in animal models [ 80 , 81 , 84 , 85 , 86 ].…”

“…It remains to be clarified if it is a general dysbiosis, specific bacteria and their virulence factors, or both that may be most important in the development of Parkinson’s disease, Alzheimer’s disease and other neuropathologies. In addition to direct mechanisms, etiological roles for bacterial-induced inflammation and an irregular microbial metabolome have also been posited [ 75 , 76 , 78 , 79 , 80 ]. Therefore, the unintended consequences of CB2-agonists with antimicrobial properties may be hard to predict.…”

“…However, with respect to the use of CB2 agonists as therapeutics for variant neuropathologies, the opposite approach would seem appropriate. This is highlighted by the growing evidence suggesting an association between the flux in the gut microbiome and neurological disorders such as Alzheimer’s and Parkinson’s diseases, with contemporary reviews available [ 79 , 104 , 105 ]. Osman et al have shown that photooxygenation of some cannabinoids resulted in multiple derivates, some with enhanced CB2 binding affinity, some with altered antimicrobial profiles [ 39 ].…”