Gastroenterology
Abstract
Colorectal cancer (CRC) very severely threatens human health and lifespan. Effective therapeutic strategy has not been established because of without clearly knowing its pathogenesis. Here we report that ceramide and SOAT1 have the roles on both spontaneous and chemical-induced intestine cancers. It was first found by us that miR-148a deficiency dramatically increased mouse gut dysbiosis through upregulating Cers5 expression, which promoted ceramide synthesis afterward. The newly generated ceramide further promoted both AOM/DSS-induced and ApcMin/+ spontaneous intestine tumorigenesis via increasing mouse gut dysbiosis. Meanwhile, increased level of ceramide correlated with the significant enhancements on both β-catenin activity and colorectal tumorigenesis in a fashion of TLR4-dependent. Next, it was found that a direct binding of β-catenin to SOAT1 promoter to activate transcriptional expression of SOAT1, which further induced cholesterol esterification and colorectal tumorigenesis. In human patients of CRC, the same CERS5-TLR4-β-catenin-SOAT1 axis was also found with dysregulation. Finally, the SOAT1 inhibitor (Avasimibe) showed the significant levels of therapeutic effects on both AOM/DSS-induced and ApcMin/+ spontaneous intestine cancer. Our study clarified that ceramide promoted CRC development through increasing gut dysbiosis, further resulting in the increase of cholesterol esterification in a special way of SOAT1-dependent. The treatment through Avasimibe to specifically decrease cholesterol esterification could be considered as a clinical strategy for effective CRC therapy in future study.
Authors
Yahui Zhu, Li Gu, Xi Lin, Jinmiao Zhang, Yi Tang, Xinyi Zhou, Bingjun Lu, Xingrong Lin, Cheng Liu, Edward V. Prochownik, Youjun Li
Abstract
Despite decades of research there is no specific therapy for Acute Pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an anti-inflammatory and anti-fibrotic agent which is FDA-approved for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (i.e. after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In-vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10 Knock Out mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously. Key Words: Acute Pancreatitis, Pirfenidone, Interleukin-10, L-arginine pancreatitis, Systemic inflammation, lung injury
Authors
Ejas Palathingal Bava, John George, Mohammad Tarique, Srikanth Iyer, Preeti Sahay, Beatriz Gomez Aguilar, Dujon B. Edwards, Bhuwan Giri, Vrishketan Sethi, Tejeshwar Jain, Prateek Sharma, Utpreksha Vaish, Harrys K. C. Jacob, Anthony Ferrantella, Craig L. Maynard, Ashok K. Saluja, Rajinder K. Dawra, Vikas Dudeja
Abstract
Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells, from three left-sided and three right-sided CRC patients were profiled by scRNA-seq. Right-sided CRC harbors a significant proportion of exhausted CD8 T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of “pre-exhausted” to exhausted T cells were favorable prognostic markers. Notably, we identified a novel RBP4+ NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.
Authors
Wei Guo, Cuiyu Zhang, Xia Wang, Dandan Dou, Dawei Chen, Jingxin Li
Abstract
Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial glucocorticoid receptor (GR), but not whole intestinal tissue GR, promotes chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In colorectal cancer patients, GR is enriched in intestinal epithelial cells and high epithelial GR is associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increases macrophage infiltration, improves tissue recovery, and enhances anti-tumor response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice develop fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early-phase of tissue injury delays recovery and accelerates the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling represses acute colitis but promotes chronic inflammation-associated colorectal cancer, and suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that although synthetic glucocorticoid treatment for IBD should be used with caution, there is a therapeutic window for glucocorticoid therapy during colorectal cancer development in immunocompetent patients.
Authors
Shuang Tang, Zhan Zhang, Robert H. Oakley, Wenling Li, Weijing He, Xiaojiang Xu, Ming Ji, Qing Xu, Liang Chen, Alicia S. Wellman, Qingguo Li, Leping Li, Jian-Liang Li, Xinxiang Li, John A. Cidlowski, Xiaoling Li
Abstract
Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT in xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using autochthonous mouse models of intestinal cancer and tumor organoid cultures to assess the effectiveness and consequences of oral treatment with aromatase A-deficient STm (STm∆aroA). STm∆aroA delivered by oral gavage significantly reduced tumor burden and tumor load in both a colitis-associated colon cancer model (CAC) and in a spontaneous Apcmin/+ intestinal cancer model. STm∆aroA colonization of tumors caused alterations in transcription of mRNAs associated with tumor stemness, epithelial–mesenchymal transition and cell cycle. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STm∆aroA-treated tumors, suggesting STm∆aroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro recapitulated effects seen on tumor stemness, mesenchymal markers and altered metabolome. Furthermore, live STm∆aroA was required, demonstrating active mechanisms including metabolite usage. We demonstrate that BCT is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium affecting tumor stem cells.
Authors
Gillian M. Mackie, Alastair Copland, Masumi Takahashi, Yumiko Nakanishi, Isabel Everard, Tamotsu Kato, Hirotsugu Oda, Takashi Kanaya, Hiroshi Ohno, Kendle M. Maslowski
Abstract
Oral conditions are relatively common in patients with inflammatory bowel disease (IBD). However, the contribution of oral maladies to gut inflammation remains unexplored. Here, we investigated the impact of periodontitis on disease phenotypes of IBD patients. In all, 60 IBD patients (42 with ulcerative colitis [UC] and 18 with Crohn’s disease [CD]) and 45 non-IBD healthy controls (HCs) were recruited for this clinical investigation. The effects of incipient periodontitis on the oral and gut microbiome, IBD characteristics were examined. In addition, patients were prospectively monitored up to 12 months after enrollment. We found that in both UC and CD patients, the gut microbiome was significantly more similar to the oral microbiome than in HCs, suggesting that ectopic gut colonization by oral bacteria is increased in IBD patients. Incipient periodontitis did not further enhance gut colonization by oral bacteria. The presence of incipient periodontitis did not significantly affect the clinical outcomes of UC and CD patients. However, the short Crohn’s disease activity index increased in CD patients with incipient periodontitis but declined or unchanged during the study period in patients without periodontitis. Thus, early periodontitis may associate with worse clinically symptoms in some patients with CD.
Authors
Jin Imai, Hitoshi Ichikawa, Sho Kitamoto, Jonathan L. Golob, Motoki Kaneko, Junko Nagata, Miho Takahashi, Merritt G. Gillilland, Rika Tanaka, Hiroko Nagao-Kitamoto, Atsushi Hayashi, Kohei Sugihara, Shrinivas Bishu, Shingo Tsuda, Hiroyuki Ito, Seiichiro Kojima, Kazunari Karakida, Masashi Matsushima, Takayoshi Suzuki, Katsuto Hozumi, Norihito Watanabe, William V. Giannobile, Takayuki Shirai, Hidekazu Suzuki, Nobuhiko Kamada
Abstract
In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion towards a quiescent-like state, a process denominated deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the de/activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cells quiescence. In this work, we show that lack of GATA4 in adult mice causes hepatic stellate cell activation and consequently, liver fibrosis. During regression of liver fibrosis, Gata4 is reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promotes liver fibrosis regression in CCl4-treated mice. GATA4 induces changes in the expression of fibrogenic and antifibrogenic genes promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly represses EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.
Authors
Noelia Arroyo, Laura Villamayor, Irene Díaz, Rita Carmona, Mireia Ramos-Rodríguez, Ramon Muñoz-Chapuli, Lorenzo Pasquali, Miguel G. Toscano, Franz Martin, David A. Cano, Anabel Rojas
Abstract
A diet high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) (HFM) induces gastrointestinal symptoms in patients with irritable bowel syndrome (IBS) and a diet low in FODMAPs (LFM) improves symptoms in up to 60% of IBS patients. However, the mechanism by which FODMAPs affect IBS symptoms is unclear. We showed that mice fed on an HFM diet have mast cell activation and colonic barrier loss. Using mast cell-deficient mice with/without mast cell reconstitution, we showed that HFM-mediated colonic barrier loss is dependent on TLR4-dependent mast cell activation. In in vitro studies, we demonstrated IBS fecal supernatant stimulates mast cell significantly more compared to fecal supernatant from healthy controls. This effect of IBS fecal supernatant on mast cell stimulation is ameliorated in absence of TLR4 receptor and after an LFM diet. Translating these findings into IBS patients, we found an LFM diet improves colonic barrier function and reduces mast cell activation while decreasing fecal LPS levels. Our findings indicate that a HFM diet causes mast cell activation via LPS which in turn leads to colonic barrier loss and an LFM diet reverses these pathophysiologic mucosal changes.
Authors
Prashant Singh, Gintautas Grabauskas, Shi-Yi Zhou, Jun Gao, Yawen Zhang, Chung Owyang
Abstract
HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4 T-cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on ART or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal ARV drugs revealed no differences in drug peneration between the duodemum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T-cell activation was inversely correlated with loss of gut CD4 T-cells in PLWH alone. T-cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4 T-cells is a key event in the HIV pathogensis of PLWH in South Africa, yet the underlying mechanisms remain unknown.
Authors
Osaretin E. Asowata, Alveera Singh, Abigail Ngoepe, Nicholas Herbert, Rabiah Fardoos, Kavidha Reddy, Yenzekile Zungu, Faith Nene, Ntombifuthi Mthabela, Dirhona Ramjit, Farina Karim, Katya Govender, Thumbi Ndung’u, J. Zachary Porterfield, John H. Adamson, Fusi G. Madela, Vukani T. Manzini, Frank Anderson, Alasdair Leslie, Henrik N. Kløverpris
Abstract
Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.
Authors
Pingping Xu, Danfeng Sun, Yaqi Gao, Yi Jiang, Ming Zhong, Gang Zhao, Jinxian Chen, Zheng Wang, Qiang Liu, Jie Hong, Haoyan Chen, Ying-Xuan Chen, Jing-Yuan Fang
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