The Gut / Brain Connection
|Art Credit: Debra Solomon |
|Trillions of microorganisms, collectively known as the human microbiota, colonize our gut, skin, and other tissues. This arrangement has proven largely beneficial, as these organisms can aid digestion and nutrient absorption, protect against pathogens, and even shape the development of our nascent immune system (1). However, mounting evidence suggests alterations in the microbiota play a role in the etiopathology of disease. In a follow up to our recent blog post, today we explore the emerging role of the human microbiota in the development and progression of neurological disorders.|
The Bugs in Your Gut
|The gut microbiota is generally thought to originate at birth. The composition of a newborn’s fecal flora is similar to that of the mother (depending on method of delivery), but is largely composed of bacteria from Actinobacteria and Proteobacteria phyla. The microbiota develops until about 2.5 years of age, at which time the function, diversity, and composition resembles that of an adult (1,2). Strains from Bacteroidetes and Firmicutes are most common, followed by Actinobacteria, Fusobacteria, Spriochaetes, Verrucomicrobia, and Lentisphaerae (4). Once a person reaches adulthood, their individual microbiota is somewhat stable, but can be altered by factors such as diet, antibiotics, and advancing age (1-3). |
Importantly, the gut microbiota can vary significantly between individuals (4). So with all this talk of composition, diversity, and stability, what constitutes a “healthy” versus an “unhealthy” flora? The answer, disappointingly, is that the scientific community does not yet know. Despite this, mounting evidence suggests that deviation from the microbial “norm” (bacterial dysbiosis) is associated with the pathogenesis of certain neurological diseases.
Bacteria and Neurodegeneration
|As we touched on in a previous blog post, the autoimmune disease multiple sclerosis (MS) is associated with intestinal dysbiosis. Intriguing evidence for the connection of gut commensals with MS comes from experiments conducted in experimental autoimmune encephalomyelitis (EAE) mouse models of MS. Germ-free mice were found to be resistant to EAE, unless they received a fecal transplant from mice with a normal gut flora (5). Multiple studies to date in humans have noted differences in the abundance of several bacterial genera when comparing MS patients with healthy controls, such as reductions in Lactobacillus, Clostridium, Bacteroides, and Haemophilus (6). Protein misfolding and aggregation is a hallmark of many neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These proteins aggregates can induce neuroinflammation and spread cell-to-cell, similar to infectious spread of prion protein characteristic of prion disease (5). The presence of amyloid-β (Aβ) aggregates and hyperphosphorylated tau are hallmarks of AD, while α-synuclein deposits known as Lewy bodies are found in PD. Coinciding with data from EAE models, germ-free α-synuclein overexpressing mice demonstrated significantly reduced motor dysfunction and neuroinflammation (5). Neuroinflammation and Aβ plaque deposition was similarly lowered in transgenic mouse AD models undergoing long-term antibiotic treatment (10).|
|So how does the microbiota influence the development of these diseases? It is now known that microorganisms can produce substances that cause distal neurophysiological changes via circulation. In the case of MS, Clostridium and Bacteroides are known producers of short chain fatty acids (SCFA) and capsular polysaccharide A (PSA). SCFA fermentation products and PSA in turn promote the accumulation of Foxp3+ regulatory T cells, which have been shown to suppress neuro-inflammation in the EAE model (6,7). Increased abundance in MS patient stool samples of Methanobrevibacter and Akkermansia, the latter of which produces SCFA through the degradation of mucins, was positively correlated with upregulation of proinflammatory genes in circulating T cells and monocytes (6,8). Most recently, researchers showed metabolites of dietary tryptophan could hamper the pathogenic activities of microglia and astrocytes in murine EAE (9). |
Art Credit: Public Domain
Evidence suggests that the microbiota may also promote neurodegeneration by promoting the formation of protein aggregates or by enhancing the inflammatory response to them. Multiple genera present in the microbiota produce fibers that share structural similarities with misfolded proteins. A theory holds that curli or other bacterial fibers may “cross seed” or enhance the nucleation of Aβ or α-synuclein (11). Rats exposed to bacteria that produced curli demonstrated increased production of α-synuclein in the brain and gut (12). Fibers produced by gut bacteria may also prime the immune system to mount an enhanced inflammatory response to neuronal plaques, aggravating cognitive dysfunction associated with disease. In support of this, heightened levels of neural inflammation characterized by microgliosis, astrogliosis, and increased expression of TNF, TLR2, and IL-6 was found in rats exposed to curli-expressing bacteria (12).
With the prevalence of neurodegenerative disorders increasing due in part to lengthened lifespans, new therapies are desperately needed. Much of the evidence linking gut commensals with neurological disease remains correlative. The possibility exists that one day the microbiome may be utilized for its prognostic value, or even targeted as a treatment modality.
|Contributed by Christopher Dougher, PhD.|