From bench to bedside: an interdisciplinary journey through the gut-lung axis with insights into lung cancer and immunotherapy.

This comprehensive review undertakes a multidisciplinary exploration of the gut-lung axis, from the foundational aspects of anatomy, embryology, and histology, through the functional dynamics of pathophysiology, to implications for clinical science. The gut-lung axis, a bidirectional communication pathway, is central to understanding the interconnectedness of the gastrointestinal- and respiratory systems, both of which share embryological origins and engage in a continuous immunological crosstalk to maintain homeostasis and defend against external noxa. An essential component of this axis is the mucosa-associated lymphoid tissue system (MALT), which orchestrates immune responses across these distant sites. The review delves into the role of the gut microbiome in modulating these interactions, highlighting how microbial dysbiosis and increased gut permeability ("leaky gut") can precipitate systemic inflammation and exacerbate respiratory conditions. Moreover, we thoroughly present the implication of the axis in oncological practice, particularly in lung cancer development and response to cancer immunotherapies. Our work seeks not only to synthesize current knowledge across the spectrum of science related to the gut-lung axis but also to inspire future interdisciplinary research that bridges gaps between basic science and clinical application. Our ultimate goal was to underscore the importance of a holistic understanding of the gut-lung axis, advocating for an integrated approach to unravel its complexities in human health and disease.

Depletion of muscularis macrophages ameliorates inflammation-driven dysmotility in murine colitis model.

Previously, the presence of a blood-myenteric plexus barrier and its disruption was reported in experimentally induced colitis via a macrophage-dependent process. The aim of this study is to reveal how myenteric barrier disruption and subsequent neuronal injury affects gut motility in vivo in a murine colitis model. We induced colitis with dextran sulfate sodium (DSS), with the co-administration of liposome-encapsulated clodronate (L-clodronate) to simultaneously deplete blood monocytes contributing to macrophage infiltration in the inflamed muscularis of experimental mice. DSS-treated animals receiving concurrent L-clodronate injection showed significantly decreased blood monocyte numbers and colon muscularis macrophage (MM) density compared to DSS-treated control (DSS-vehicle). DSS-clodronate-treated mice exhibited significantly slower whole gut transit time than DSS-vehicle-treated animals and comparable to that of controls. Experiments with oral gavage-fed Evans-blue dye showed similar whole gut transit times in DSS-clodronate-treated mice as in control animals. Furthermore, qPCR-analysis and immunofluorescence on colon muscularis samples revealed that factors associated with neuroinflammation and neurodegeneration, including Bax1, Hdac4, IL-18, Casp8 and Hif1a are overexpressed after DSS-treatment, but not in the case of concurrent L-clodronate administration. Our findings highlight that MM-infiltration in the muscularis layer is responsible for colitis-associated dysmotility and enteric neuronal dysfunction along with the release of mediators associated with neurodegeneration in a murine experimental model.

ABHD4-dependent developmental anoikis safeguards the embryonic brain.

A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic proliferation of misplaced progenitor cells are relatively rare. Here, we report that a process we term developmental anoikis distinguishes the pathological detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. We identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of pathologically detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.