Systemic and stem cell niche-emanating cytokines and growth factors can promote regeneration, through mitosis. High mitosis, however, predisposes for all types of cancer and, thus, a trade-off exists between regeneration capacity and tissue homeostasis. Here, we study the role of tissue-intrinsic regenerative signaling in stem cell mitosis of adult Drosophila midgut of different genetic backgrounds. We provide evidence of two naturally occurring types of balance between mitosis and enterocyte nucleus growth: one based mostly on stem cell mitosis producing new cells and the other based mostly on the degree of young enterocyte nucleus size increase. Mitosis promotes intestinal host defense to infection, but predisposes for dysplasia in the form of stem cell-like clusters. Enterocyte nucleus growth also promotes host defense, without the drawback of promoting dysplasia. Through quantitative genetics, we identified eiger as an autocrine and paracrine inducer of stem cell mitosis. eiger expression in immature epithelial cells tilts the balance towards mitosis and dysplasia via a positive-feedback loop of highly mitotic stem cells sustaining more small nucleus enterocytes, which in turn supply more Eiger.

Colorectal cancer (CRC) is one of the most prevalent cancers affecting humans, with a complex genetic and environmental aetiology. Unlike cancers with known environmental, heritable, or sex-linked causes, sporadic CRC is hard to foresee and has no molecular biomarkers of risk in clinical use. One in twenty CRC cases presents with an established heritable component. The remaining cases are sporadic and associated with partially obscure genetic, epigenetic, regenerative, microbiological, dietary, and lifestyle factors. To tackle this complexity, we should improve the practice of colonoscopy, which is recommended uniformly beyond a certain age, to include an assessment of biomarkers indicative of individual CRC risk. Ideally, such biomarkers will be causal to the disease and potentially modifiable upon dietary or therapeutic interventions. Multi-omics analysis, including transcriptional, epigenetic as well as metagenomic, and metabolomic profiles, are urgently required to provide data for risk analyses. The aim of this article is to provide a perspective on the multifactorial derailment of homeostasis leading to the initiation of CRC, which may be explored via multi-omics and Gut-on-Chip analysis to identify much-needed predictive biomarkers.

A trade-off hypothesis pertains to the biased allocation of limited resources between two of the most important fitness traits, reproduction and survival to infection. This quid pro quo manifests itself within animals prioritizing their energetic needs according to genetic circuits balancing metabolism, germline activity and immune response. Key evidence supporting this hypothesis includes dipteran fecundity being compromised by systemic immunity, and female systemic immunity being compromised by mating. Here, we reveal a local trade-off taking place in the female Drosophila midgut upon immune challenge. Genetic manipulation of intestinal motility, permeability, regeneration and three key midgut immune pathways provides evidence of an antagonism between specific aspects of intestinal defense and fecundity. That is, juvenile hormone (JH)-controlled egg laying, lipid droplet utilization and insulin receptor expression are specifically compromised by the immune deficiency (Imd) and the dual oxidase (Duox) signaling in the midgut epithelium. Moreover, antimicrobial peptide (AMP) expression under the control of the Imd pathway is inhibited upon mating and JH signaling in the midgut. Local JH signaling is further implicated in midgut dysplasia, inducing stem cell-like clusters and gut permeability. Thus, midgut JH signaling compromises host defense to infection by reducing Imd-controlled AMP expression and by inducing dysplasia, while midgut signaling through the Imd and Duox pathways compromises JH-guided metabolism and fecundity.

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