Stem Cell Transcription Factor FoxO Controls Microbiome Resilience in Hydra

Abstract

The aging process is considered to be the result of accumulating cellular deterioration in an individual organism over time. It can be affected by the combined influence of genetic, epigenetic, and environmental factors including life-style-associated events. In the non-senescent freshwater polyp Hydra, one of the classical model systems for evolutionary developmental biology and regeneration, transcription factor FoxO modulates both stem cell proliferation and innate immunity. This provides strong support for the role of FoxO as a critical rate-of-aging regulator. However, how environmental factors interact with FoxO remains unknown. Here, we find that deficiency in FoxO signaling in Hydra leads to dysregulation of antimicrobial peptide expression and that FoxO loss-of-function polyps are impaired in selection for bacteria resembling the native microbiome and more susceptible to colonization of foreign bacteria. These findings reveal a key role of FoxO signaling in the communication between host and microbiota and embed the evolutionary conserved longevity factor FoxO into the holobiont concept.

Rethinking the Role of the Nervous System: Lessons From the Hydra Holobiont

“…[33] Similarly, the polyp's ability to select for bacterial communities resembling their native microbiota was impaired by both the targeted downregulation of arminin family AMPs and by disturbing the FoxO signaling in the epithelial cells. [29,34] However, a series of experiments elegantly combining host tissue and microbiota manipulations and biochemical assays together with modern imaging techniques, behavioral recordings and gene manipulation techniques, have recently revealed previously underappreciated roles of the nervous system in host-microbiome crosstalk in Hydra. [35][36][37][38] Thus, in addition to cells of the both epithelial lineages, also distinct differentiation products of the interstitial cell lineage, such as neurons, which have an elaborate secretion system, participate in the interactions with microbes.…”

“…[28] In a newly hatched polyp, Gram-positive bacteria dominate the microbial community, but disappear later in the adult polyp. [34] Therefore, microbiome and tissue homeostasis are deeply integrated at the molecular level. [72] A plausible explanation would be that certain microbes promote the neurogenesis in early Hydra development, in a way similar to the effects that the gut microbiota exerts on development of the nervous system in vertebrate models.…”

“…[73,74] Finally, our recent data suggest that the transcriptional factor FoxO serves as an intracellular hubprotein, and controls both bacterial colonization and stem cell activity in Hydra. [34] Therefore, microbiome and tissue homeostasis are deeply integrated at the molecular level. In order to obtain deep insights into the mechanisms mediating the microbiota effects on development, diverse morphogenetic processes (budding, regeneration, sexual induction) and tissue maintenance functions (cell proliferation, differentiation, and apoptosis) have to be compared between germ-free Hydra and polyps colonized with different microbial consortia.…”

The Microbiome Mediates Environmental Effects on Aging

“…Because the transcription factor forkhead box O3 (FoxO3)-which regulates genes involved in growth and www.advancedsciencenews.com www.bioessays-journal.com differentiation, has been consistently associated with human aging and longevity [21,22] and since in Hydra the single FoxO gene is strongly expressed in all stem cell lineages, [23] FoxO loss-offunction mutants can provide insights into the evolutionary conserved function of this gene. [24] FoxO loss-of-function polyps were more susceptible to colonization by foreign bacteria and impaired in selection for bacteria resembling the native microbiome. [24] FoxO loss-of-function polyps were more susceptible to colonization by foreign bacteria and impaired in selection for bacteria resembling the native microbiome.…”

“…Epithelial FoxO loss-of-function mutants revealed that a deficiency in FoxO signaling leads not only to malfunctions in the cell-cycle progression but also to dysregulation of multiple families of genes encoding antimicrobial peptides (AMPs). [24] FoxO loss-of-function polyps were more susceptible to colonization by foreign bacteria and impaired in selection for bacteria resembling the native microbiome. FoxO deficiency reduces the expression of AMPs, resulting in decreased selective pressure on colonizing microbial taxa and ultimately in reduced resilience of the microbiome.…”