The organism constantly has to integrate information about the internal state with external environmental cues to adapt behavioral and autonomic responses to ensure the correct, optimal physiological homeostasis. Therefore, the integrated coordination of the internal state signals of the organism with external environmental cues critically determines lifespan and the onset and development of age-associated diseases. Key neuronal networks in the hypothalamus provide an ideal integration point where neurons are specialized to sense fuel-state-communicating hormones and nutrients as well as to respond to external environmental cues such as sensory food perception, smell, and temperature. In turn, these neurons coordinate a broad spectrum of physiological responses, such as control of feeding, drinking, and circadian rhythm, as well as the regulation of the systemic glucose homeostasis. Impairments of these responses and processes can lead to a variety of major health problems, especially during aging. Interestingly, recent studies have linked the diversity of the gut microbiota with host immune, metabolic, as well as neurological conditions. The production of microbial metabolites as well as the sensing of microbes by the immune system has been proposed as key functions in host-microbiota crosstalk regulating host physiology. The key objectives of RA-3 are to investigate:
Figure 1: (Above) Age-dependent changes in gut microbiota composition are characterised by decreased overall taxonomic diversity and overproliferation of potentially pathogenic Gammaproteobacteria and Betaproteobacteria. Changes in bacterial composition in older individuals are associated with gut dysfunction, consisting in increased fibrosis and inflammation.
(Below) Eterochronic microbiota transfer from young to middle-age killifish leads to life span extension, higher taxonomic diversity of the microbiota of older individuals, and remodelling of gut extracellular matrix.
Figure 2: (Above) Laboratory killifish have higher gut bacterial taxonomic richness (alpha diversity) compared to laboratory C. elegans and flies, of the same order of magnitude of mice and humans.
(Below) Being very short-lived vertebrates, killifish are an optimal vertebrate system to study the impact of a complex microbiota on host ageing and lifespan.
Figure 3: Evolutionary and ecological community changes during host ageing may play fundamental roles in shaping age-specific microbial communities. (Above) De novo mutations (asterisk) or horizontal gene transfer in young-associated commensal bacterial species may lead to the evolution of highly fit bacterial strains that become more abundant in aged individuals, eventually leading to age-related pathogenicity. (Middle) Species-species bacterial ecological interactions could affect community dynamics that shape microbiota composition throughout host life span, ultimately affecting host physiology during ageing. (Bottom) An age-dependent decline in immune function may cause decreased surveillance over microbial communities over time, leading to age-dependent dysbiosis. On the other hand, a healthy microbiota itself could be necessary to preserve a healthy immune function during aging.
Figure 4: Eterochronic microbiota transfer from young to middle-age killifish extends life span and delays behavioural ageing (inset: swimming velocity) in killifish. Fish Experimental group legend, Abx: fish receiving only antibiotic treatment at 9.5 weeks without direct recolonization. Omt: fish receiving same-age GM transfer after antibiotic treatment at 9.5 weeks. Wt: wild-type, untreated fish. Ymt: fish receiving 6-week-old fish GM transfer after antibiotic treatment at 9.5 weeks. VMNA: antibiotic cocktail of vancomycin, metronidazole, neomycin and ampicillin.