In this Issue
October 2016; volume 311, issue 4
Neurogastroenterology and Motility
- Upregulation of L-type calcium channels in colonic inhibitory motoneurons of P/Q-type calcium channel-deficient mice
P/Q-type Ca2+ channels contribute to neurotransmission in the gut. Tottering mice (tg/tg) have a loss of function mutation in the gene encoding P/Q-type Ca2+ channels. Colonic motility and inhibitory neuromuscular neurotransmission are similar in wild-type and tg/tg mice. This is associated with upregulation of L-type Ca2+ channel function in colonic myenteric neurons in tg/tg mice. These data demonstrate that the enteric nervous system adapts to ion channel gene mutations to maintain normal gut function.
Stem Cells, Tissue Engineering, Development, and Cancer
Liver and Biliary Tract Physiology/Pathophysiology
- The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice
The kielin/chordin-like protein (KCP) attenuates transforming growth factor-β (TGF-β) signaling in development and disease. Loss of KCP promotes liver pathology in aging mice, similar to hepatosteatosis, whereas overexpression of KCP in transgenic mice protects livers from the effects of a high-fat diet. Thus manipulating the TGF-β superfamily signaling pathways by an extracellular, secreted protein can dramatically alter liver pathology under normal aging or high-fat conditions in mice, suggesting novel avenues of intervention for fatty liver disease.
- Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice
This study demonstrates that hepatocellular-specific knockout of autophagy in mice strongly affects the unfolded protein response, another essential cellular homeostatic mechanism. Surprisingly, these alterations were in a specific pattern, leaving the inositol-requiring enzyme-1α pathway unaltered, whereas the protein kinase RNA-like ER kinase and activating transcription factor 6 (ATF6) pathway were respectively induced and reduced. The loss of fasting-induced steatosis in autophagy-deficient mice might in part be explained by the alterations of the ATF6 pathway.
Inflammation, Immunity, Fibrosis, and Infection
- Probiotic Saccharomyces boulardii CNCM I-745 prevents outbreak-associated Clostridium difficile-associated cecal inflammation in hamsters
By utilizing a well-established hamster model of CDI we show that oral gavage of Saccharomyces boulardii CNCM I-745 (S.b) effectively prevented cecal tissue damage, NF-κB phosphorylation, and TNFα expression in hamsters infected with hypervirulent C. difficile strains. S.b culture supernatants also prevented toxin-mediated cellular actin disruption induced by conditioned medium from cultures of hypervirulent C. difficile strains. Thus S.b may reduce the risk of infection of several outbreak-associated C. difficile strains.
- Dual effects of a high-protein diet on DSS-treated mice during colitis resolution phase
A high-protein diet exerts a biphasic effect on dextran sulfate sodium (DSS)-induced colitis by worsening inflammation during the induction-resolution phase, but also by helping colonic crypt repair after acute inflammation likely through modulation of colonic epithelial proliferation, differentiation, and expression of intestinal barrier proteins. This study points out the potential impact of the dietary protein amount during the colitis course and raises the possibility of a causal link between colonic epithelial repair and survival in our irritable bowel diseases (IBD) model.
- Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease
This study shows that anti-TNFα therapy decreased tissue inflammation and both proinflammatory and profibrotic cytokine gene expression when given early but not late in the course of peptidoglycan-polysaccharide (PG-PS)-induced enterocolitis. Hence this study provides a translational model that supports the clinical idea that anti-TNF therapy is most effective when begun early in the course of Crohn's disease.
- Deficiency of stearoyl-CoA desaturase-1 aggravates colitogenic potential of adoptively transferred effector T cells
Alterations in de novo lipogenesis in T cells can modulate their procolitogenic potential. In this study, we show that stearoyl-CoA desaturase-1 (SCD1)-deficient T cells exhibit an altered cytokine expression profile and membrane fatty acid composition. Using the murine T-cell adoptive transfer model of chronic colitis, we demonstrate that Scd1KO CD4+CD25− T cells induce aggravated and accelerated colitis in the recipients, compared with mice receiving wild-type (WT) CD4+CD25− T cells.
- Statins improve NASH via inhibition of RhoA and Ras
Statins are established cholesterol-lowering drugs and have additional pleiotropic properties. This work demonstrates that treatment with activated simvastatin decreased hepatic inflammation and fibrosis in mice with nonalcoholic fatty liver disease, without changing hepatic steatosis. These effects are mediated through the inhibition of RhoA and Ras signaling.
Microbiome and Host Interactions
- Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress
Inflammatory bowel disease treatment has focused on interventions that block inflammatory mediators. However, mechanisms that allow epithelial cells to resist damage are largely unknown. Bifidobacteria and other Gram-positive bacteria secrete small molecules that target and inhibit proteasomes. In the present study, we demonstrate that proteasomal inhibition induces expression of a number of autophagy proteins. Autophagy induction decreases oxidant-induced apoptotic activity and mitigates intestinal damage during inflammation.
- Bacterial nutrient foraging in a mouse model of enteral nutrient deprivation: insight into the gut origin of sepsis
Using a mouse model of total parenteral nutrition (TPN), this study shows that enteral nutrient deprivation leads to the permeation of TPN-derived nutrients into the gut lumen, where they are preferentially utilized by Enterobacteriaceae. This provides insight into the mechanisms behind the loss of epithelial barrier function and subsequent complications seen in the TPN-dependent state. Dysbiosis related to TPN may be exacerbated by an altered intestinal metabolome.
- Anti-inflammatory effects of Bifidobacterium longum subsp infantis secretions on fetal human enterocytes are mediated by TLR-4 receptors
The pathogenesis of necrotizing enterocolitis (NEC) involves the use of the Toll-like receptor-4 (TLR-4). Probiotics or their secretions protect premature infants against NEC through anti-inflammatory mechanisms. Using secretions from Bifidobacterium longum supp infantis, we show that fetal enterocyte reduction of IL-6 activation after IL-1β stimulation is mediated through TLR-4 and specifically affects IL-1 receptor-associated kinase 2 (IRAK-2) mRNA and c-Jun and c-Fos phosphorylation of the activator-protein 1 (AP-1) transcription factor. These observations may help in future prevention of NEC.