Plants, animals and humans, are colonized by microorganisms (microbiota) and transiently exposed to countless others. The microbiota affects the development and function of essentially all organ systems, and contributes to adaptation and evolution, while protecting against pathogenic microorganisms and toxins. Genetics and lifestyle factors, including diet, antibiotics and other drugs, and exposure to the natural environment, affect the composition of the microbiota, which influences host health through modulation of interrelated physiological systems. These include immune system development and regulation, metabolic and endocrine pathways, brain function and epigenetic modification of the genome. Importantly, parental microbiotas have transgenerational impacts on the health of progeny. Humans, animals and plants share similar relationships with microbes. Research paradigms from humans and other mammals, amphibians, insects, planktonic crustaceans and plants demonstrate the influence of environmental microbial ecosystems on the microbiota and health of organisms, and indicate links between environmental and internal microbial diversity and good health. Therefore, overlapping compositions, and interconnected roles of microbes in human, animal and plant health should be considered within the broader context of terrestrial and aquatic microbial ecosystems that are challenged by the human lifestyle and by agricultural and industrial activities. Here, we propose research priorities and organizational, educational and administrative measures that will help to identify safe microbe-associated health-promoting modalities and practices. In the spirit of an expanding version of “One health” that includes environmental health and its relation to human cultures and habits (EcoHealth), we urge that the lifestyle-microbiota-human health nexus be taken into account in societal decision making.