Summary Inflammatory diseases of the gastrointestinal tract are frequently associated with changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria), a common signature of dysbiosis (1–8). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum cofactor-dependent microbial respiratory pathways that are only operational during episodes of inflammation. In contrast, tungstate treatment caused no overt changes in the microbiota composition under homeostatic conditions. Importantly, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in murine models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the setting of gut inflammation.

Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules. Among them, the COMMD/CCDC22/CCDC93 (CCC) complex plays a critical role in recycling events. While CCC is closely associated with retriever, a cargo recognition complex, its mechanism of action remains unexplained. Herein we show that CCC and retriever are closely linked through sharing a common subunit (VPS35L), yet the integrity of CCC, but not retriever, is required to maintain normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P). CCC complex depletion leads to elevated PI(3)P levels, enhanced recruitment and activation of WASH (an actin nucleation promoting factor), excess endosomal F-actin and trapping of internalized receptors. Mechanistically, we find that CCC regulates the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. Taken together, we show that the regulation of PI(3)P levels by the CCC complex is critical to protein recycling in the endosomal compartment.

SUMMARY Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis.

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Epigenetics describes modiications that afect gene expression that are not encoded within the DNA sequence. DNA methylation is the longest appreciated epigenetic modiication and has been accepted to play a critical role in maintaining euchromatin and silencing genes. Recently, a separate and distinct covalent modiication has been recognized; hydroxymethylation, which has been associated with increased gene expression as opposed to gene silencing. However, traditional methods to study DNA methylation also recognized hydroxymethylation and did not distinguish between these two distinct DNA covalent modiications. Furthermore, TET enzymes have been identiied to play a critical role in active hydroxymethylation of previously methylated cytosine residues and may further result in conversion to cytosine. TET1 plays a critical role in intestinal epithelial diferentiation and development, and this is also correlated with increased hydroxymethylation in terminally diferentiated epithelial cells. Colon cancer, which arises from the colonic epithelium, exhibits decreased hydroxymethylation and altered gene expression.

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