The enteric nervous system relays psychological stress to intestinal inflammation.

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

Small molecules, big effects: microbial metabolites in intestinal immunity.

The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this minireview, we survey these recent findings, which taken together reveal nuanced interactions that we are just beginning to understand.

Enteropathogenic E. coli effectors EspG1/G2 disrupt microtubules, contribute to tight junction perturbation and inhibit restoration.

Enteropathogenic Escherichia coli (EPEC) uses a type 3 secretion system to transfer effector proteins into the host intestinal epithelial cell. Several effector molecules contribute to tight junction disruption including EspG1 and its homologue EspG2 via a mechanism thought to involve microtubule destruction. The aim of this study was to investigate the contribution of EspG-mediated microtubule disruption to TJ perturbation. We demonstrate that wild type EPEC infection disassembles microtubules and induces the progressive movement of occludin away from the membrane and into the cytosol. Deletion of espG1/G2 attenuates both of these phenotypes. In addition, EPEC infection impedes barrier recovery from calcium switch, suggesting that inhibition of TJ restoration, not merely disruption, prolongs barrier loss. TJs recover more rapidly following infection with ΔespG1/G2 than with wild type EPEC, demonstrating that EspG1/G2 perpetuate barrier loss. Although EspG regulates ADP-ribosylation factor (ARF) and p21-activated kinase (PAK), these activities are not necessary for microtubule destruction or perturbation of TJ structure and function. These data strongly support a role for EspG1/G2 and its associated effects on microtubules in delaying the recovery of damaged tight junctions caused by EPEC infection.

Microtubules are required for efficient epithelial tight junction homeostasis and restoration.

Epithelial tight junctions are critical for creating a barrier yet allowing paracellular transport. Although it is well established that the actin cytoskeleton is critical for preserving the dynamic organization of the tight junction and maintaining normal tight junction protein recycling, contributions of microtubules to tight junction organization and function remain undefined. The aim of this study is to determine the role of microtubules in tight junction homeostasis and restoration. Our data demonstrate that occludin traffics on microtubules and that microtubule disruption perturbs tight junction structure and function. Microtubules are also shown to be required for restoring barrier function following Ca(2+) chelation and repletion. These processes are mediated by proteins participating in microtubule minus-end-directed trafficking but not plus-end-directed trafficking. These studies show that microtubules participate in the preservation of epithelial tight junction structure and function and play a vital role in tight junction restoration, thus expanding our understanding of the regulation of tight junction physiology.

The Microbiome as a Circadian Coordinator of Metabolism.

The microbiome is critically involved in the regulation of systemic metabolism. An important but poorly understood facet of this regulation is the diurnal activity of the microbiome. Herein, we summarize recent developments in our understanding of the diurnal properties of the microbiome and their integration into the circadian regulation of organismal metabolism. The microbiome may be involved in the detrimental consequences of circadian disruption for host metabolism and the development of metabolic disease. At the same time, the mechanisms by which microbiome diurnal activity is integrated into host physiology reveal several translational opportunities by which the time of day can be harnessed to optimize microbiome-based therapies. The study of circadian microbiome properties may thus provide a new avenue for treating disorders associated with circadian disruption from the gut.

Enteropathogenic E. coli effectors EspG1/G2 disrupt tight junctions: new roles and mechanisms.

Enteropathogenic E. coli (EPEC) infection is a major cause of infantile diarrhea in the developing world. Using a type-three secretion system, bacterial effector proteins are transferred to the host cell cytosol where they affect multiple physiological functions, ultimately leading to diarrheal disease. Disruption of intestinal epithelial cell tight junctions is a major consequence of EPEC infection and is mediated by multiple effector proteins, among them EspG1 and its homologue EspG2. EspG1/G2 contribute to loss of barrier function via an undefined mechanism that may be linked to their disruption of microtubule networks. Recently new investigations have identified additional roles for EspG. Sequestration of active ADP-ribosylating factor (ARF) proteins and promotion of p21-activated kinase (PAK) activity as well as inhibition of Golgi-mediated protein secretion have all been linked to EspG. In this review, we examine the functions of EspG1/G2 and discuss potential mechanisms of EspG-mediated tight junction disruption.