Re-establishing alliances: “Old Friends” confronting obesity, inflammation, and stress-related psychiatric disorders

The prevalence of obesity is increasing in modern urban societies, resulting in a significant burden on public health systems globally. The current review explores research supporting the premise that chronic consumption of a Western diet alters the diversity and community composition of the gut microbiome, promotes “leaky gut”, systemic low-grade inflammation, and neuroinflammation, enhancing risk for obesity and stress-related psychiatric disorders. Specifically, consumption of a Western diet promotes metabolic endotoxemia by altering the gut microbiome, disrupting the mucus layer, and increasing permeability of the mucosal barrier. Specifically, increased permeability of the mucosal barrier leads to translocation of gut contents, including bacteria and bacterial metabolites, across the mucosal barrier. Translocation of gram-negative bacteria or lipopolysaccharide (LPS) can promote metabolic endotoxemia, heightened inflammation, and disruption of physiological function, leading to metabolic diseases. The review explores a novel approach to counteracting the metabolic effects of the Western diet by utilizing “Old Friends”, i.e., anti-inflammatory, immunoregulatory microbes that humans co-evolved with, but are reduced or absent in modern urban societies. Particularly, Mycobacterium vaccae ATCC 15483, one of these “Old Friends”, has showcased promising results by protecting against Western diet-induced systemic inflammation, obesity, and anxiety-like defensive behavioral responses associated with stress-related psychiatric disorders. Furthermore, M. vaccae ATCC 15483 decreases biomarkers of hippocampal microglial priming, suggesting a potential mechanism underlying stress resilience effects. While more research is warranted, harnessing the therapeutic potential of “Old Friends” like Mycobacterium vaccae ATCC 15483 may offer a novel strategy to combat modern diseases associated with consumption of a Western diet. • Chronic consumption of a Western diet promotes a leaky gut • Excessive development of visceral adipose tissue increases peripheral inflammation • Chronic consumption of a Western diet enhances neuroinflammation • Western diet-associated inflammation increases risk for psychiatric disorders • “Old Friends” counteract the effects of chronic consumption of a Western diet