Transplant of microbiota from Crohn's disease patients to germ-free mice results in colitis.

Although the role of the intestinal microbiota in the pathogenesis of inflammatory bowel disease (IBD) is beyond debate, attempts to verify the causative role of IBD-associated dysbiosis have been limited to reports of promoting the disease in genetically susceptible mice or in chemically induced colitis. We aimed to further test the host response to fecal microbiome transplantation (FMT) from Crohn's disease patients on mucosal homeostasis in ex-germ-free (xGF) mice. We characterized and transferred fecal microbiota from healthy patients and patients with defined Crohn's ileocolitis (CD_L3) to germ-free mice and analyzed the resulting microbial and mucosal homeostasis by 16S profiling, shotgun metagenomics, histology, immunofluorescence (IF) and RNAseq analysis. We observed a markedly reduced engraftment of CD_L3 microbiome compared to healthy control microbiota. FMT from CD_L3 patients did not lead to ileitis but resulted in colitis with features consistent with CD: a discontinued pattern of colitis, more proximal colonic localization, enlarged isolated lymphoid follicles and/or tertiary lymphoid organ neogenesis, and a transcriptomic pattern consistent with epithelial reprograming and promotion of the Paneth cell-like signature in the proximal colon and immune dysregulation characteristic of CD. The observed inflammatory response was associated with persistently increased abundance of Ruminococcus gnavus, Erysipelatoclostridium ramosum, Faecalimonas umbilicate, Blautia hominis, Clostridium butyricum, and C. paraputrificum and unexpected growth of toxigenic C. difficile, which was below the detection level in the community used for inoculation. Our study provides the first evidence that the transfer of a dysbiotic community from CD patients can lead to spontaneous inflammatory changes in the colon of xGF mice and identifies a signature microbial community capable of promoting colonization of pathogenic and conditionally pathogenic bacteria.

Effects of Anticoagulants and Corticosteroids therapy in patients affected by severe COVID-19 Pneumonia

BackgroundIn the absence of a standard of treatment for COVID-19, the combined use of anti-inflammatory (corticosteroids and Enoxaparin) and antiviral drugs may be more effective than using either modality alone in the treatment of COVID-19. MethodsPatients hospitalized between April 10th, 2020, through May 10th, 2020, who had confirmed COVID-19 infection with clinical or radiographic evidence of pneumonia, in which 65 patients have moderate COVID-19 pneumonia, and 63 patients have severe COVID-19 pneumonia. All patients received early combination therapy of anti-inflammatory (corticosteroids and Enoxaparin) and antiviral drugs. They assessed for type and duration of treatment, and days need to wean from oxygen therapy, length of stay, virus clearance time, and complication or adverse events. All patients had more than 28 days follow up after discharge from the hospital. ResultsModerate COVID-19 pneumonia group were 65 patients who received Enoxaparin, antiviral drugs, empirical antibiotics for pneumonia, and standard treatment for comorbidity. Male patients were 50 (76.9 %) and female patients were 15 (23.1 %). 34 (52.3 %) patients have comorbidity, 25 (38.5%) patients have Diabetes Mellitus and 2 (3.1 %) pregnant ladies. 19 (29.2 %) patients were on low flow oxygen therapy, 3L oxygen or less to maintain oxygen saturation more than 92%. All patients discharged home with no major or minor bleeding complications or significant complications. Severe COVID-19 pneumonia group were 63 patients who received methylprednisolone, enoxaparin, antiviral drugs, empirical antibiotics for pneumonia, and standard treatment for comorbidity. Male patients were 55 (87.3 %) and female patients were 8 (12.7 %). 37 (58.7 %) patients have comorbidity, and 24 (38.1%) patients have Diabetes Mellitus. 32 (50.8 %) patients were on low flow oxygen therapy, 4-9L oxygen, and 31 (49.2 %) patients were on low flow oxygen therapy, 10L oxygen or more, including 12 patients on a non-rebreathing mask. Patients received methylprednisolone were 37 (58.7 %) for 3 days, 16 (25.4 %) for 5 days and 10 (15.9 %) for more than 5 days. Sixty-two patients discharged home with one patient had a long stay, and the other two transferred to ICU. One long-stay patient transferred to ICU on low flow oxygen therapy. ConclusionEarly use of a combined anti-inflammatory (corticosteroids and Enoxaparin) and antiviral drugs treatment in patients with moderate to severe COVID-19 pneumonia prevent complications of the disease and improve clinical outcomes

NLRC3 Attenuates Colon Cancer by Down-Regulating PI3K-mTOR Signaling

The nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs) are intracellular sensors. Most of them positively affect inflammatory responses, particularly the inflammasome forming NLRs. On the other hand, several studies on gene-deficient mice have revealed that several NLRs negatively influence innate immune responses. Some recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively influence different pathways related to inflammation and carcinogenesis. Cytosolic pattern recognition receptor NRLC3 is a negative regulator of innate immune response. In this review we will discuss finding related with NLRC3 and its mechanism by which it alter cancer pathogenesis. Recently, it has been found that mice deficient in Nlrc3 are hyper-susceptible to colitis and colitis-associated colon carcinogenesis. Oncogenic inhibitory effect of NLRC3 is more dominant in epithelial compartment than hematopoietic compartment. It down regulates mTOR signaling and reduce cell proliferation. NLRC3 interact with PI3Ks and suppress activation of PI3K dependent kinase AKT. Understanding the role of NLRC3 in cancer may facilitate the recognition of new therapeutic strategies.

Chemicals from Cimicifuga dahurica and Their Inhibitory Effects on Pro-inflammatory Cytokine Production by LPS-stimulated Bone Marrow-derived Dendritic Cells

Inflammation is a biological response caused by overactivation of the immune system and is controlled by immune cells via a variety of cytokines. The overproduction of pro-inflammatory cytokines enhances abnormal host immunity, resulting in diseases such as rheumatoid arthritis, cardiovascular disease, Alzheimer's disease, and cancer. Inhibiting the production of pro-inflammatory cytokines such as interleukin (IL)-12p40, IL-6, and tumor necrosis factor (TNF)-α might be one way to treat these conditions. Here, we investigated the anti-inflammatory activity of compounds isolated from Cimicifuga dahurica (Turcz.) Maxim., which is traditionally used as an antipyretic and analgesic in Korea. In primary cell culture assays, 12 compounds were found to inhibit the production of pro-inflammatory cytokines (IL-12p40, IL-6, and TNF-α) in vitro in bone marrow-derived dendritic cells stimulated with LPS.

Suppression of Antimicrobial Defense and Stabilization of STAT3 by IRAK-M Expression in Tumor Cells Promotes Colorectal Carcinogenesis

Different environmental and genetic factors have been attributed to the etiology of colorectal cancer. Dysbiotic gut microbiota is associated with initiation and progression of colon carcinogenesis. Hyperactivation of STAT3 promotes carcinogenesis by upregulating cell proliferation, survival, tumor-induced immunosupression and angiogenesis. IRAK-M is a negative regulator of toll-like receptor signaling and inhibits innate immune response. The cancer cell may exploit this property of IRAK-M and evade host immune surveillance. Recently, it has been found that IRAK-M provide controlled feed back to bacteria involved in colorectal cancer by reducing antibacterial response in mice. Furthermore, IRAK-M increased the stability of STAT3 in tumor cells that support tumor promotion by upregulating cell proliferation and survival. Thus, it is suggested that IRAK-M promotes colitis associated colon cancer by enhancing bacterial colonization and stabilization of STAT3.

3-Hydroxy-4,7-megastigmadien-9-one, Isolated from Ulva pertusa Kjellman, Inhibits LPS-Induced Inflammatory Response by Down-Regulating Mitogen-Activated Protein Kinase and NF-κB Pathways

In the present study we evaluated the anti-inflammatory potential of 3-hydroxy-4,7-megastigmadien-9-one (Comp) isolated from Ulva pertusa Kjellman, in LPS-stimulated bone marrow-derived dendritic cells (BMDCs). Comp treatment exhibited strong dose dependent inhibition of IL-12 p40 and IL-6 cytokine production with IC₅₀ values of 7.85 ± 0.32 and 7.86 ± 0.18, respectively in LPS-stimulated BMDCs. Treatment of Comp inhibited MAPKs and NF-κB pathways in LPS-stimulated BMDCs by inhibiting the phosphorylation of ERK1/2, JNK1/2, p38 and IκB. Thus, these results suggest that Comp have a significant anti-inflammatory property and affirm further studies concerning the potentials of Comp for medicinal use.

Acrosorium polyneurum Extract Inhibits the LPS-Induced Inflammatory Response by Impairing the MAPK and NF-κB Pathways

Marine algae exhibit broad spectrum anti-bacterial and anti-inflammatory activities. Acrosorium polyneurum (A. polyneurum) is a marine red alga and belongs to the family Delesseriaceae. The present research evaluates the antiinflammatory effects of A. polyneurum extract (APE) on pro-inflammatory cytokine production. APE demonstrated substantial inhibitory effects on production of pro-inflammatory cytokine in bone marrow-derived macrophages (BMDMs). APE pre-treatment in the lipopolysaccharide (LPS)-stimulated BMDMs exhibited a robust inhibitory effect on production of interleukin (IL)-12, IL-6 and tumor necrosis factor (TNF)-α. It revealed a robust inhibitory effect on phosphorylation of ERK1/2, JNK1/2 and p38. APE also showed remarkable inhibitory effect on phosphorylation and degradation of IκBα. Furthermore, APE pre-treatment demonstrated substantial inhibition of LPS-induced production of nitric oxide and inducible nitric oxide synthase. Collectively, these data suggest that APE has a noteworthy anti-inflammatory property and deserve further studies concerning its potential use as a medicinal agent for inflammation-related disorders.

High-fat-diet-modulated Gut Microbiota Promotes Intestinal Carcinogenesis

Gut microbiota play a critical role in the development of intestinal cancer. Dietary changes cause dysbiosis of gut microbiota that mediates production of dietary factors triggering intestinal cancer. Genetic and dietary factors work in different combinatorial ways in initiation and progression of intestinal cancer, one of which is changes in gut microbiota. Recently, it has been found that high-fat-diet promote intestinal tumorigenesis in a genetically susceptible K-ras(G12Dint) mice without induction of obesity. High-fat-diet along with oncogene activation dampened paneth-cell mediated immunity and thus shift bacterial communities in such a way that promotes intestinal cancer.