Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias

A stem cell marker-expressing subset of enteroendocrine cells resides at the crypt base in the small intestine

The spatial orientation of the enteroendocrine cells along the crypt-villus axis is closely associated with their differentiation in the intestine. Here we studied this relationship using primary duodenal crypts and an ex vivo organoid system established from cholecystokinin-green fluorescent protein (CCK-GFP) transgenic mice. In the primary duodenal crypts, GFP+ cells were found not only in the upper crypt but also at the crypt base, where the stem cells reside. Many GFP+ cells below +4 position were positive for the putative intestinal stem cell markers, leucine-rich repeat-containing G protein-coupled receptor 5, CD133, and doublecortin and CaM kinase-like-1, and also for the neuroendocrine transcription factor neurogenin 3. However, these cells were neither stem nor transient amplifying precursor cells because they were negative for both Ki-67 and phospho-Histone H3 and positive for the mature endocrine marker chromogranin A. Furthermore, these cells expressed multiple endocrine hormones. Tracking of GFP+ cells in the organoids from CCK-GFP mice indicated that GFP+ cells were first observed around the +4 position, some of which localized to the crypt base later in the culture period. These results suggest that a subset of enteroendocrine cells migrates down to the crypt base or stays localized at the crypt base, where they express stem and postmitotic endocrine markers. Further investigation of the function of this subset may provide novel insights into the genesis and development of enteroendocrine cells as well as enteroendocrine tumorigenesis