ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt.

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.

A single cell survey of the microbial impacts on the mouse small intestinal epithelium.

The small intestinal epithelial barrier inputs signals from the gut microbiota in order to balance physiological inflammation and tolerance, and to promote homeostasis. Understanding the dynamic relationship between microbes and intestinal epithelial cells has been a challenge given the cellular heterogeneity associated with the epithelium and the inherent difficulty of isolating and identifying individual cell types. Here, we used single-cell RNA sequencing of small intestinal epithelial cells from germ-free and specific pathogen-free mice to study microbe-epithelium crosstalk at the single-cell resolution. The presence of microbiota did not impact overall cellular composition of the epithelium, except for an increase in Paneth cell numbers. Contrary to expectations, pattern recognition receptors and their adaptors were not induced by the microbiota but showed concentrated expression in a small proportion of epithelial cell subsets. The presence of the microbiota induced the expression of host defense- and glycosylation-associated genes in distinct epithelial cell compartments. Moreover, the microbiota altered the metabolic gene expression profile of epithelial cells, consequently inducing mTOR signaling thereby suggesting microbe-derived metabolites directly activate and regulate mTOR signaling. Altogether, these findings present a resource of the homeostatic transcriptional and cellular impact of the microbiota on the small intestinal epithelium.

Sending signals - The microbiota's contribution to intestinal epithelial homeostasis.

The intestine is inhabited by a diverse range of microorganisms, which requires the host to employ numerous barrier measures to prevent bacterial invasion. However, the intestinal microbiota additionally acts symbiotically with host cells to maintain epithelial barrier function, and perturbation to this interaction plays a pivotal role in intestinal pathogenesis. In this review, we highlight current findings of how the intestinal microbiota influences host intestinal epithelial cells. In particular, we review the roles of numerous microbial-derived products as well as mechanisms by which these microbial products influence the regulation of intestinal epithelial population dynamics and barrier function.

Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells.

Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains intra-tumoral arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive activity of myeloid cells and fuel tumor progression in CRC.

High temperature in-situ synchrotron-based XRD study on the crystal structure evolution of C/C composite impregnated by FLiNaK molten salt.

An in-situ real-time synchrotron-based grazing incidence X-ray diffraction was systematically used to investigate the crystal structural evolution of carbon fiber reinforced carbon matrix (C/C) composite impregnated with FLiNaK molten salt during the heat-treatment process. It was found that the crystallographic thermal expansion and contraction rate of interlayer spacing d 002 in C/C composite with FLiNaK salt impregnation is smaller than that in the virgin sample, indicating the suppression on interlayer spacing from FLiNaK salt impregnated. Meanwhile the crystallite size L C002 of C/C composite with FLiNaK salt impregnation is larger than the virgin one after whole heat treatment process, indicating that FLiNaK salt impregnation could facilitate the crystallization of C/C composite after heat treatment process. This improved crystallization in C/C composite with FLiNaK salt impregnation suggests the synthetic action of the salt squeeze effect on crooked carbon layer and the release of internal residual stress after heating-cooling process. Thus, the present study not only contribute to reveal the interaction mechanism between C/C composite and FLiNaK salt in high temperature environment, but also promote the design of safer and more reliable C/C composite materials for the next generation molten salt reactor.