The introduction of anti-TNF antibody therapy has changed the course of treatment for Crohn's disease. However, the fundamental mechanism for the onset of Crohn's disease is still unknown, and the ...treatment strategy for this disease remains suboptimal. The assessment of the disease phenotype based on key environmental factors and genetic background may indicate options for the personalized treatment of Crohn's disease. In this issue of the JCI, Liu et al. show that consumption of tobacco and the mutation of ATG16L1T300A, a prevalent Crohn's disease susceptibility allele, drive defects in cells at the bottom of the intestinal crypt, the Paneth cells. These factors may provide novel targets for personalized medicine.
Background:The cardiopulmonary exercise test (CPX) is a tool for evaluating disease severity and limitations in activities of daily living in patients with cardiac disorders. However, few studies ...have evaluated the association between exercise oscillatory ventilation (EOV) severity and prognosis in heart failure (HF) patients with EOV. EOV severity can be evaluated by detecting endtidal CO2pressure (PETCO2, an indicator of the arterial partial pressure of CO2(PaCO2)) and minute ventilation, which is a reflection of the respiratory response to elevated CO2. We hypothesized that the magnitude of EOV severity can predict the severity and prognosis of cardiac disorders and aimed to validate this hypothesis.Methods and Results:In total, 2,043 patients who underwent symptom-limited maximal CPX between 2010 and 2016 were evaluated. We enrolled 70 patients who had HF with reduced ejection fraction (HFrEF) and EOV. The endpoint was cardiovascular death. During a median follow-up of 4.3 years, 34 participants died (48%). Those who died showed significantly larger EOV loop size and lower hemoglobin (Hb) levels than those who survived (17.3±7.0 cm2vs. 12.8±6.1 cm2, P<0.001; 12.2±1.2 g/dL vs. 13.2±2.9 g/dL, P=0.004). Cox regression analyses revealed Hb levels and EOV loop size as independent predictors of cardiovascular death in HFrEF patients with EOV.Conclusions:EOV loop size was associated with cardiovascular death of HFrEF patients with EOV.
In Japan and other Asian countries, increased fat uptake induced by a westernized diet is thought to be associated with an increased incidence of inflammatory bowel disease, colorectal cancer and ...food allergies; however, the mechanism for this remains unclear. High-fat diet (HFD)-fed mice are common animal models used to examine the effect of fat intake in vivo. HFDs are reported to exacerbate DSS-induced colitis and intestinal tumorigenesis, but the effect of HFDs on the intestines before disease induction is often overlooked. We found that the intestinal and gut-associated lymphoid tissue (GALT) morphology of HFD-fed mice differed from that of standard diet (SD)-fed mice. To clarify the mechanism by which fat intake increases intestinal diseases, we analyzed the morphological and immunological aspects of the intestines of HFD-fed mice as well as the molecular mechanisms and physiology.
Feeding an HFD for 3 weeks induced atrophy of the small intestine, colon and GALT and reduced the number of small intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). Feeding an HFD for only one day reduced the number of small intestinal (SI)-IELs and SI-LPLs. The effect of feeding a 3-week HFD continued for 2 weeks after returning to the SD. The effect of the HFD on the intestinal immune system was independent of the gut microbes. We hypothesized that the cytotoxicity of the abundant HFD-derived free fatty acids in the intestinal lumen impairs the intestinal immune system. Both saturated and unsaturated free fatty acids were toxic to intestinal T-cells in vitro. Orally administering free fatty acids reduced the number of SI-IELs and LPLs. Using a lipase inhibitor to reduce the luminal free fatty acids attenuated the HFD-induced changes in the intestinal immune system, while using a statin to reduce the serum free fatty acids did not. Thus, HFD-induced free fatty acids damaged the intestines; this effect was termed “intestinal lipotoxicity”. Because sustained reduction of SI-LPLs after HFD feeding exacerbated indomethacin-induced small intestinal damage, lipotoxicity to the human intestines incurred by consuming a westernized diet in Japan may increase intestinal diseases such as IBD, colorectal cancer or food allergies.
•Feeding a high-fat diet (HFD) induced atrophy of the intestines.•Feeding an HFD reduced the number of small intestinal T-cells, too.•We defined these phenotypes as termed intestinal lipotoxicity.•Intestinal lipotoxicity was caused by cytotoxicity from HFD-derived free fatty acids.•Intestinal lipotoxicity exacerbated indomethacin-induced small intestinal damage.
Background
l
-amino acids are the predominant forms of organic molecules on the planet, but recent studies have revealed that various foods contain
d
-amino acids, the enantiomers of
l
-amino acids. ...Though diet plays important roles in both the development and progression of inflammatory bowel disease (IBD), to our best knowledge, there has been no report on any potential interactions between
d
-amino acids and IBD. In this report, we aim to assess the effects of
d
-serine in a murine model of IBD.
Materials and methods
To induce chronic colitis, naïve CD4 T cells (CD4
+
CD62
+
CD44
low
) from wild-type mice were adoptively transferred into
Rag2
−/−
mice, after or before the mice were orally administered with
d
-serine. In vitro proliferation assays were performed to assess naïve CD4 T cell activation under the Th-skewing conditions in the presence of
d
-serine.
Results
Mice treated with
d
-serine prior to the induction of colitis exhibited a reduction in T-cell infiltration into the lamina propria and colonic inflammation that were not seen in mice fed with water alone or
l
-serine. Moreover,
d
-serine suppressed the progression of chronic colitis when administered after the disease induction. Under in vitro conditions,
d
-serine suppressed the proliferation of activated CD4 T cells and limited their ability to differentiate to Th1 and Th17 cells.
Conclusion
Our results suggest that
d
-serine not only can prevent, but also has efficacious effects as a treatment for IBD.
A20 is an anti-inflammatory protein linked to multiple human diseases; however, the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We found that A20-deficient T cells ...and fibroblasts were susceptible to caspase-independent and kinase RIPK3-dependent necroptosis. Global deficiency in RIPK3 significantly restored the survival of A20-deficient mice. A20-deficient cells exhibited exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 underwent physiological ubiquitination at Lys5 (K5), and this ubiquitination event supported the formation of RIPK1-RIPK3 complexes. Both the ubiquitination of RIPK3 and formation of the RIPK1-RIPK3 complex required the catalytic cysteine of A20's deubiquitinating motif. Our studies link A20 and the ubiquitination of RIPK3 to necroptotic cell death and suggest additional mechanisms by which A20 might prevent inflammatory disease.
Crohn's disease is an inflammatory disease of the gut caused by a complex interplay among genetic, microbial, and environmental factors. The intestinal tract is constantly exposed to metals and other ...trace elements ingested as food. Synchrotron radiation-induced X-ray fluorescence spectroscopy and X-ray absorption fine structure analysis revealed the deposition of nickel particles within Crohn's disease tissue specimens. After nickel particle stimulation, THP-1 cells showed filopodia formation and autophagic vacuoles containing lipid bodies. Nickel particles precipitated colitis in mice bearing mutations of the IBD susceptibility protein A20/TNFAIP3. Nickel particles also exacerbated dextran sulfate sodium-induced colitis in mice harboring myeloid cell-specific Atg5 deficiency. These findings illustrate that nickel particle ingestion may worsen Crohn's disease by perturbing autophagic processes in the intestine, providing new insights into environmental factors in Crohn's disease pathogenesis.
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•Nickel particles are present in Crohn's disease tissue.•Nickel particles trigger autophagy in macrophages.•Nickel particles exacerbate DSS colitis in macrophage-specific Atg5-deficient mice.•Nickel particles exacerbate intestinal inflammation in A20/TNFAIP3-mutated mice.
The influences of antiplatelet therapy discontinuation on the risk of stent thrombosis and long-term clinical outcomes after drug-eluting stent implantation have not yet been addressed adequately.
In ...an observational study in Japan, 2-year outcomes were assessed in 10 778 patients undergoing sirolimus-eluting stent implantation. Data on status of antiplatelet therapy during follow-up were collected prospectively. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, P<0.001; 0.72% versus 0.07%, P=0.02; and 2.1% versus 0.14%, P=0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Adjusted rates of death or myocardial infarction at 24 months were 4.1% for patients taking thienopyridine and 4.1% for patients not taking thienopyridine (P=0.99) in the 6-month landmark analysis.
Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.
Recent advances in research suggest that aging has a controllable chronic inflammatory disease aspect. Aging systemic T cells, which secrete pro-inflammatory factors, affect surrounding somatic ...cells, and accelerate the aging process through chronic inflammation, have attracted attention as potential therapeutic targets in aging. On the other hand, there are few reports on the aging of the intestinal immune system, which differs from the systemic immune system in many ways. In the current study, we investigated the age-related changes in the intestinal immune system, particularly in T cells. The most significant changes were observed in the CD4
T cells in the small intestinal IEL, with a marked increase in this fraction in old mice and reduced expression of CD27 and CD28, which are characteristic of aging systemic T cells. The proliferative capacity of aging IEL CD4
T cells was significantly more reduced than that of aging systemic T cells. Transcriptome analysis showed that the expression of inflammatory cytokines was not upregulated, whereas
, NK receptors, and Granzymes were upregulated in aging IEL CD4
T cells. Functional analysis showed that aging IEL T cells had a higher cytotoxic function against intestinal tumor organoids
than young IEL T cells. scRNAseq revealed that splenic T cells show a transition from naïve to memory T cells, whereas intestinal T cells show the emergence of a CD8αα
CD4
T cell fraction in aged mice, which is rarely seen in young cells. Further analysis of the aging IEL CD4
T cells showed that two unique subsets are increased that are distinct from the systemic CD4
T cells. Subset 1 has a pro-inflammatory component, with expression of
and upregulation of NFkB signaling pathways. Subset 2 does not express
, but upregulates inhibitory molecules and nIEL markers. Expression of
and
was common to both. These fractions were in opposite positions in the clustering by UMAP and had different TCR repertoires. They may be involved in the suppression of intestinal aging and longevity through anti-tumor immunity, elimination of senescent cells and stressed cells in the aging environment. This finding could be a breakthrough in aging research.
Expression of mucin MUC2, a component of the colonic mucus layer, plays a crucial role in intestinal homeostasis. Here, we describe a new regulator of MUC2 expression, the deubiquitinase ZRANB1 ...(Trabid). A ZRANB1 mutation changing cysteine to serine in amino acid position 443, affects ubiquitination. To analyze ZRANB1 function in the intestine, we generated Zranb1 C443S mutant knock-in (Zranb1C443S/C443S) mice using the CRISPR/Cas9 system. Zranb1C443S/C443S mice exhibited decreased mRNA expression and MUC2 production. Colonic organoids from Zranb1C443S/C443S mice displayed decreased Muc2 mRNA expression following differentiation into goblet cells. Finally, we analyzed dextran sulfate sodium-induced colitis to understand ZRANB1's role in intestinal inflammation. Zranb1C443S/C443S mice with colitis exhibited significant weight loss, reduced colon length, and worsening clinical and pathological scores, indicating that ZRANB1 contributes to intestinal homeostasis. Together, these results suggest that ZRANB1 regulates MUC2 expression and intestinal inflammation, which may help elucidating the pathogenesis of inflammatory bowel disease and developing new therapeutics targeting ZRANB1.
•ZRANB1 regulates MUC2 expression and intestinal inflammation.•In the intestine, a single point mutation to ZRANB1 altered MUC2 expression.•ZRANB1 contributes to intestinal homeostasis.
A 19-year-old man was referred due to sudden onset of right foot pain and chest discomfort. Contrast-enhanced computed tomography revealed massive thrombi in the right pulmonary artery and femoral ...vein. The patient's father had experienced multiple recurrences of venous thromboembolism (VTE) and was diagnosed with inherited antithrombin deficiency by a genetic examination. The patient was administered the oral factor Xa inhibitor rivaroxaban (30 mg). After seven days, the thrombus disappeared. Rivaroxaban (15 mg) was continued for 6 months with no recurrence, indicating the efficacy of this factor Xa inhibitor for the treatment and prevention of VTE in patients with antithrombin deficiency.