A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

Abstract

18Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although 19 the intestine is the organ that comes into direct contact with all diet components, the 20 impact of HFD has mostly been studied in organs that are linked to obesity and obesity 21 related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD 22 activation. Surprisingly, we found that a HFD triggered induced stem cell activation 48 critically depends on the indigenous microbiota, as in germ free flies this reaction was 49 completely abolished. Moreover, HFD changed both, composition and abundance of the 50 microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we 51 assume that the increased bacterial load is the major cause for the HFD triggered stem cell 52 activation in the intestine. 53 54 55 High-fat diets induce stem cell activation

Intestinal miRNAs regulated in response to dietary lipids

“…Another pathway pointed out is JAK-STAT signalling pathway, which regulates the transcription of numerous genes and has been implicated in the pathogenesis of several diseases, including inflammatory bowel disease 42 . In addition, it has also been linked to the response of intestinal enterocytes to a high-fat diet, which triggers a transient activation of intestinal stem cells 43 . Historically, in vivo experiments have largely been performed on males to avoid complications related to feminine hormonal cycles, estrous cycle stages, etc., which has led to a sex-biased imbalance in research 44 .…”

Impact of high-fat diet on lifespan, metabolism, fecundity and behavioral senescence inDrosophila

“…This suggests that HFD causes a deregulation of the insulin-TOR pathway, at least in the short-term. At the gut level, HFD alters the microbiota, increases intestinal stem cell activity, and increases the number of enteroendocrine cells in the midgut (von Frieling et al, 2020). In this study, it was shown that the HFD directly activates JNK signaling in enterocytes that in turn signal with the cytokine unpaired 3 (upd3) to activate JAK/STAT signaling in the stem cells.…”

“…What are the mechanisms behind the shortened lifespan and behavioral senescence in flies kept on HFD? An excess of dietary lipids affects several tissues such as the intestine, the fat body, the central nervous system, and the heart, but also results in global effects on metabolism and the expression of a multitude of genes (Birse et al, 2010;Huang et al, 2020;Jung et al, 2018;Musselman and Kühnlein, 2018;Rivera et al, 2019;von Frieling et al, 2020;Woodcock et al, 2015). Some effects of HFD seem to be tissue specific, others are more global.…”

“…Drosophila has also been employed to model certain human diseases based on the fact that about 65% of human disease-related genes have functional orthologs in flies [see (Ugur et al, 2016;Yamamoto et al, 2014)]. Recently studies have emerged on the effect of HFD on health and physiology of Drosophila (Birse et al, 2010;Driver and Cosopodiotis, 1979;Heier and Kühnlein, 2018;Heinrichsen and Haddad, 2012;Huang et al, 2020;Jung et al, 2018;Musselman and Kühnlein, 2018;Rivera et al, 2019;Stobdan et al, 2019;Tatar et al, 2014;Toprak et al, 2020;Trinh and Boulianne, 2013;von Frieling et al, 2020;Woodcock et al, 2015). Most of these studies have investigated effects of relatively short exposure to HFD, ranging between one and three weeks, although some determined the effect of HFD on total lifespan (Heinrichsen and Haddad, 2012;Rivera et al, 2019;Woodcock et al, 2015).…”

“…It is clear that HFD significantly increases the mortality of both male and female flies and thereby shortens lifespan (Heinrichsen and Haddad, 2012;Rivera et al, 2019;Woodcock et al, 2015), and has detrimental effects on climbing behavior, short-term phototaxis memory, and behavioral responses to odor (Jung et al, 2018;Rivera et al, 2019). Even as short an exposure as one week to HFD had adverse effects on negative geotaxis, heart function, as well as insulin and glucose homeostasis (Birse et al, 2010) and gut physiology (von Frieling et al, 2020). Five days of exposure to HFD is sufficient to render flies more sensitive to starvation, seen as an enhancement of the starvation induced hyperactivity (Huang et al, 2020).…”