Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity

Abstract

SummaryIntestinal barrier dysfunction is an evolutionarily conserved hallmark of aging, which has been linked to microbial dysbiosis, altered expression of occluding junction proteins, and impending mortality. However, the interplay between intestinal junction proteins, age-onset dysbiosis, and lifespan determination remains unclear. Here, we show that altered expression of Snakeskin (Ssk), a septate junction-specific protein, can modulate intestinal homeostasis, microbial dynamics, immune activity, and lifespan in Drosophila. Loss of Ssk leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation following oral infection with pathogenic bacteria. Furthermore, intestinal up-regulation of Ssk improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. Our findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals.

JNK-dependent intestinal barrier failure disrupts host-microbe homeostasis during tumorigenesis

“…Our experiments show that tumor growth impairs the intestinal renewal capacity and barrier function by inducing gut integrity loss, immune activation, reduced Duox expression and in turn causes intestinal dysbiosis. This is consistent with previous results showing that intestinal barrier failure after loss of a septate junction protein Snakeskin results in altered gut morphology, dysbiosis and reduced Duox level (Salazar et al, 2018). Duox act as an important defence mechanism in ECs against enteric infection and its expression is increased in the intestine during infection and ageing (Lee et al, 2018;Guo et al, 2014), suggesting that Duox expression is induced during normal intestinal regeneration under infection or ageing, while its expression is dampened in the tumor bearing intestine with massive loss of ECs and impaired EC renewal capacity.…”

“…2C). Since the comparative analysis did not provide information about the extent changes in taxa abundance and changes in the overall microbiome (Vandeputte et al, 2017), we examined the load of various bacteria by CFU assays on selective mediums for Acetobacteriaceae and other bacteria (NR) (Ryu et al, 2008;Guo et al, 2014) as well as by taxa-specific 16S qPCR (Clark et al, 2015;Salazar et al, 2018). In these experiments, we observed intestinal dysbiosis in Dpp/BMP knock-down conditions (Mad/Med, Shn RNAi), as shown in Fig.…”

“…The complex rearrangements of cell-cell adhesion are required for shaping the intestine and for maintaining tissue integrity during development (Bryant & Mostov, 2008;Oh et al, 2012). The maintenance of the intestinal barrier is essential for preserving homeostasis and organismal health (Clark et al, 2015;Salazar et al, 2018). To test whether loss-of BMP-induced intestinal tumors disrupts barrier function by altering cell adhesion molecules, we monitored the expression of septate junction proteins Disc large (Dlg) and Fascillin III (Fas III) using immunostaining.…”

Septate junctions regulate gut homeostasis through regulation of stem cell proliferation and enterocyte behavior inDrosophila

“…During the preparation of our manuscript, two groups published interesting phenotypes of the sSJ-protein-deficient adult midgut in Drosophila that are highly related to the present study. Salazar et al (2018) reported that reduced expression of ssk in ECs leads to gut barrier dysfunction, altered gut morphology, increased stem cell proliferation, dysbiosis, and reduced lifespan. They also showed that up-regulation of Ssk in the midgut protects flies against microbial translocation, limits dysbiosis, and prolongs lifespan.…”

Glucose extends lifespan through enhanced intestinal barrier integrity inDrosophila

“…Similar to vertebrates, disruption of septate junctions affects both health and longevity. For example, loss of Ssk affects composition of the gut bacterial community, and upregulation of Ssk extends lifespan (Salazar et al 2018).…”