Exploring human gut microbiome variations across life: from eubiosis to dysbiosis in Western populations

The human gut microbiome (GM) is an extremely dynamic ecosystem, able to establish peculiar configurations in response to endogenous and exogenous stimuli – ageing, diet, lifestyle, disease. To explore microbiome-host relationship and unravel GM variations throughout the human lifespan, we studied specific functional aspects related to eubiosis and dysbiosis in Western populations using next-generation sequencing approaches, and developed a versatile murine model of intestinal inflammation to better explore the transition towards dysbiotic layouts. As for the aspects related to eubiotic microbiota configurations, we characterized age-related GM functional changes across life up to extreme longevity (22-109 years), highlighting life-long adaptive responses potentially supporting a new homeostasis. When compared to traditional populations – whose lifestyle resembles that of our ancestors – the Western GM is characterized by reduced biodiversity and supposed to contribute to the rising incidence of non-communicable diseases (NCDs). Consequently, we assessed the possibility to modulate the Western GM towards a more ‘ancestral’ configuration through a dietary intervention with a modern Paleolithic diet. Focusing on dysbiotic variations, we investigated links between diet, GM and obesity. Through a 4-year prospective study, we identified early markers and individual microbiome-host-diet configurations as a potential predictor related to the onset of the disease during childhood. Metagenomic and metatranscriptomic approaches were merged to unravel specific obese-related GM layouts and metabolic activities possibly associated with food addiction in obese women. The shift towards a dysbiotic microbiome structure and its association with several diseases have made the GM a strategic therapeutic target, paving the way for the development of a wide range of microbiome-tailored intervention strategies aimed at the restoration of eubiotic, health-promoting layouts. In this perspective, we developed a murine model of intestinal inflammation and provided researchers with a versatile tool for testing anti-inflammatory agents and/or new microbiome modulators such as classic or next-generation probiotics.