The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Abstract

The gut microflora is a community of trillions of bacterial cells synergistically inhabiting the human gastrointestinal tract. These microbes contact everything that is consumed and release regulatory factors that affect host energy homeostasis, lipid and carbohydrate metabolism, activation of immune cells, oxidative state, epithelial cell wall integrity and even neurological signals. The gut microflora is essentially an independent organ supporting human health where imbalances in the gut community populations (dysbiosis) manifest in disease. Diabetes and neurodegenerative disorders such as Alzheimer's and Parkinson's disease share a similar molecular pathology rooted in gut microflora activity. Both of these conditions are associated with a dysbiosis characterized by low species diversity, a higher proportion of pathobionts at the expense of symbionts, an abundance of proinflammatory microbes and fewer butyrate-producing strains. Many of these factors can be ameliorated with Lactobacillus spp. and Bifidobacterium spp. probiotic treatment aimed to reestablish healthy gut microflora diversity. Indeed, certain commensal and pathogenic strains promote chronic low-grade inflammation that stresses cellular infrastructure eventually leading to apoptosis in both the pancreas and the brain. Also, lack of some beneficial fermentation products such as butyrate and ferulic acid initiates a cascade of events disrupting metabolic homeostasis. Finally, signaling initiated by the microflora and its metabolites has been shown to disrupt the delicate intracellular balance of PI3K/Akt/mTOR signaling, which fundamentally regulates events leading up to diabetes and neurodegenerative disease pathogenesis. The following review investigates the relationship between the manifestation and molecular signaling of diabetes and neurodegenerative disorders and how the balance of gut microflora populations is critical to both prevent and possibly treat these diseases.

Streptozotocin-induced hyperglycemia alters the cecal metabolome and exacerbates antibiotic-induced dysbiosis

“…For example, the host controls colonic sugar concentrations via a combination of SI transporter expression, gastric emptying rate, and enteroendocrine function ( Chen et al, 2016 ; Holst et al, 2016 ; Koepsell, 2020 ; Ussar et al, 2017 ). Disruptions of host metabolism, like digestive and metabolic disorders, are correlated with microbial dysbiosis, highlighting the connection between host and microbial systems in the GI ( Brestoff and Artis, 2013 ; Westfall et al, 2015 ; Qin et al, 2012 ; Sabatino et al, 2017 ). For example, dysglycemic patients demonstrate bacterial infiltration of the intestinal epithelial mucosa, suggesting that dysglycemia triggers an inflammatory intestinal phenotype by prompting microbial breakdown of mucus glycoproteins ( Chassaing et al, 2017 ).…”