This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

Metagenomic biomarker discovery and explanation

Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-derived metabolites play complex roles in supporting cancer progression and suppressing immune responses. Preclinical and clinical studies have shown that manipulating cholesterol metabolism inhibits tumour growth, reshapes the immunological landscape and reinvigorates anti-tumour immunity. Here, we review cholesterol metabolism in cancer cells, its role in cancer progression and the mechanisms through which cholesterol metabolites affect immune cells in the tumour microenvironment. We also discuss therapeutic strategies aimed at interfering with cholesterol metabolism, and how the combination of such approaches with existing anti-cancer therapies can have synergistic effects, thus offering new therapeutic opportunities.

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

The present invention provides a method for treating cancer using a proteasome inhibitor. The present invention also provides a method of treating a patient suffering from cancer based on an increase in the expression level of NFκB as measured by the H score of the patient's tumor sample using the NFκB p65 IHC assay. The present invention also provides a method for determining whether to treat a patient with a proteasome inhibitor based on the level of NFκB p65 in the patient's tumor sample. The present invention relates to the discovery that patients suffering from cancer respond to treatment with proteasome inhibitors. [Selection] Figure 1

How to treat cancer

A healthy gut microbiota not only has beneficial effects on the activity of the immune system, but also on thyroid function. Thyroid and intestinal diseases prevalently coexist—Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the most common autoimmune thyroid diseases (AITD) and often co-occur with Celiac Disease (CD) and Non-celiac wheat sensitivity (NCWS). This can be explained by the damaged intestinal barrier and the following increase of intestinal permeability, allowing antigens to pass more easily and activate the immune system or cross-react with extraintestinal tissues, respectively. Dysbiosis has not only been found in AITDs, but has also been reported in thyroid carcinoma, in which an increased number of carcinogenic and inflammatory bacterial strains were observed. Additionally, the composition of the gut microbiota has an influence on the availability of essential micronutrients for the thyroid gland. Iodine, iron, and copper are crucial for thyroid hormone synthesis, selenium and zinc are needed for converting T4 to T3, and vitamin D assists in regulating the immune response. Those micronutrients are often found to be deficient in AITDs, resulting in malfunctioning of the thyroid. Bariatric surgery can lead to an inadequate absorption of these nutrients and further implicates changes in thyroid stimulating hormone (TSH) and T3 levels. Supplementation of probiotics showed beneficial effects on thyroid hormones and thyroid function in general. A literature research was performed to examine the interplay between gut microbiota and thyroid disorders that should be considered when treating patients suffering from thyroid diseases. Multifactorial therapeutic and preventive management strategies could be established and more specifically adjusted to patients, depending on their gut bacteria composition. Future well-powered human studies are warranted to evaluate the impact of alterations in gut microbiota on thyroid function and diseases.

https://www.mdpi.com/2072-6643/12/6/1769/pdf

Thyroid-Gut-Axis: How Does the Microbiota Influence Thyroid Function?

Association between fecal microbiota and generalized anxiety disorder: Severity and early treatment response.

Background: Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease in which both genetic predisposition and environmental factors serve as disease triggers. Many studies have indicate...

Alterations of the Gut Microbiota in Hashimoto's Thyroiditis Patients

Colorectal cancer (CRC) is a common cancer worldwide with complex etiology. Fusobacterium nucleatum (F. nucleatum), an oral symbiotic bacterium, has been linked with CRC in the past decade. A series of gut microbiota studies show that CRC patients carry a high abundance of F. nucleatum in the tumor tissue and fecal, and etiological studies have clarified the role of F. nucleatum as a pro-carcinogenic bacterium in various stages of CRC. In this review, we summarize the biological characteristics of F. nucleatum and the epidemiological associations between F. nucleatum and CRC, and then highlight the mechanisms by which F. nucleatum participates in CRC progression, metastasis, and chemoresistance by affecting cancer cells or regulating the tumor microenvironment (TME). We also discuss the research gap in this field and give our perspective for future studies. These findings will pave the way for manipulating gut F. nucleatum to deal with CRC in the future.

/pdf/fusobacterium-nucleatum-acts-as-a-pro-carcinogenic-bacterium-4ilqqo2nwf.pdf

Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality.

Chimeric antigen receptor-modified T cell (CART) therapy has been demonstrated to have significant effect on hematologic tumor in patients. However, many persistent obstacles and challenges still limit the application. It is known that CD8 T cells are a key component of antitumor immunity. An avasimibe-induced inhibition of cholesterol esterification has been shown to improve the antitumor response of CD8 T cells in mice. In this study, using human CD19-directed CART cells as effector cells and CD19-overexpressing K562 cells as target cells, we detected whether cholesterol acyltransferase inhibition by avasimibe can enhance the antitumor effect of human CART cells. After avasimibe treatment, the infection rate was dropped by up to 50% (P<0.05). The cytotoxic effect of CART cells was significantly increased than the control group in a dose-dependent manner. Moreover, the level of secreted interferon-γ increased in almost half of the cases (P<0.05); the ratio of CD8CD4 T cells was increased among the total T cells and the CART cells in some of cases (P<0.05). Our study suggests that inhibition of cholesterol acyltransferase can promote the antitumor effect of CART cells, and provides a new option for a combination therapy by regulating T-cell metabolism to enhance antitumor effects.

Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells.

Dysbiosis of gut microbiota and metabolome is a frequently encountered condition in liver cirrhosis (LC) patients. The severity of liver dysfunction was found to be correlated with the degree of microbial dysbiosis. Several clinical studies have indicated liver function improvement after therapeutic splenectomy for LC induced hypersplenism. We sought to determine whether such post-splenectomy outcome is pertinent to modulation of the abnormal gut microenvironment in LC patients. A cross-sectional study including 12 LC patients and 16 healthy volunteers was first conducted, then a before-after study in the cohort of patients was carried out before and six months after splenectomy. Faecal samples were collected in hospital. Temporal bacterial (n=40) and metabolomics (n=30) profiling was performed using 16s rRNA gene sequencing and UPLC/MS respectively. Our results revealed that microbial composition in patients was clearly different from that in healthy controls, evidenced by considerable taxonomic variation. Along with improved liver function (Child-Pugh score), the patients also displayed similar gut microbiota profile and predicted metagenome function to that of healthy controls after splenectomy. Enterobacteriaceae and Streptococcaceae, two LC-enriched families showing positive relation with Child-Pugh score, exhibited significantly decreased abundance after splenectomy. At the genus level, 11 genera were differentially abundant between patients and healthy controls, but 9 genera of them restituted to normal levels by certain degree after splenectomy. PICRUSt analysis showed the relative abundance of 17 KEGG pathways were partially restored after splenectomy. Four of them were Amino acid related pathways: Lysine degradation, Tryptophan degradation, Amino acid metabolism and Protein digestion and absorption. These findings were supported by metabonomics results which showed that relative abundance of Amino acid and corresponding catabolites changed towards normal. In addition to the variations in the relative abundances of bacteria and metabolites, the correlation between them also altered in patients after splenectomy. Dysbiosis in gut microbiome and related metabolism of LC patients were partially corrected after splenectomy. Whether the improved gut microenvironment could prevent LC related complications and delay the progress of liver cirrhosis is a propitious objective for future study.

/pdf/splenectomy-leads-to-amelioration-of-altered-gut-microbiota-1c6ucccmxk.pdf

Splenectomy Leads to Amelioration of Altered Gut Microbiota and Metabolome in Liver Cirrhosis Patients

Disturbance of the gut microbiota is common in liver cirrhosis (LC) patients, the underlying mechanisms of which are yet to be unfolded. This study aims to explore the relationship between small bowel transit (SBT) and gut microbiota in LC patients. Cross-sectional design was applied with 36 LC patients and 20 healthy controls (HCs). The gut microbiota was characterized by 16S rRNA gene sequencing. The Firmicutes/Bacteroidetes (F/B) ratio and the Microbial Dysbiosis index (MDI) were used to evaluate the severity of microbiota dysbiosis. The scintigraphy method was performed in patients to describe the objective values of SBT. Patients were then subdivided according to the Child-Pugh score (threshold = 5) or SBT value (threshold = 0.6) for microbiota analysis. LC patients were characterized by an altered gut microbiota; F/B ratios and MDI were higher than HC in both Child_5 (14.00 ± 14.69 vs. 2.86 ± 0.99, p F) = 0.0068, pMANOVA], with higher F/B ratios and MDI in SBT_0.6- patients (19.71 ± 16.62 vs. 7.33 ± 6.65, p < 0.01; 1.02 ± 0.97 vs. 0.20 ± 0.58, p < 0.01). Similar results were observed between the SBT_0.6- and SBT_0.6+ sub-groups of patients with normal liver function and a Child-Pugh score of 5. SBT was negatively correlated with both the F/B ratio and MDI (r = -0.34, p < 0.05; r = -0.38, p < 0.05). Interestingly, an increased capacity for the inferred pathway "bacterial invasion of epithelial cells" in patients, was highly negatively correlated with SBT (r = -0.57, p < 0.01). The severity of microbiota dysbiosis in LC patients depends on SBT rather than Child-Pugh score. SBT per se might be significantly related to the gut microbiota abnormalities observed in patients with LC.

/pdf/small-bowel-transit-and-altered-gut-microbiota-in-patients-22gx1hocwd.pdf

Jun Li

Papers

Alterations of the Gut Microbiota in Hashimoto's Thyroiditis Patients

Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality.

Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells.

Splenectomy Leads to Amelioration of Altered Gut Microbiota and Metabolome in Liver Cirrhosis Patients

Small Bowel Transit and Altered Gut Microbiota in Patients With Liver Cirrhosis