bims-nastce 2022-03-27 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2022‒03‒27
eight papers selected by
Petra Hirsova
Mayo Clinic College of Medicine

The Role of Gut-Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC.
Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role.
CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.
Hepatobiliary manifestations in inflammatory bowel disease: A practical approach.
Imaging Mass Spectrometry Reveals Alterations in N-linked glycosylation that are Associated with Histopathological Changes in Non-alcoholic Steatohepatitis in Mouse and Human.
The gut-liver axis: host microbiota interactions shape hepatocarcinogenesis.
Microvesicles released from activated CD4+ T cells alter microvascular endothelial cell function.
Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25.

Biomedicines. 2022 Feb 23. pii: 524. [Epub ahead of print]10(3):

The Role of Gut-Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC.

Qian Song, Xiang Zhang.

  Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses to hepatic inflammation, termed as non-alcoholic steatohepatitis (NASH), hepatic fibrosis/cirrhosis, and finally leading to NAFLD-related hepatocellular carcinoma (NAFLD-HCC). Accumulating evidence showed that the gut microbiome plays a vital role in the initiation and progression of NAFLD through the gut-liver axis. The gut-liver axis is the mutual communication between gut and liver comprising the portal circulation, bile duct, and systematic circulation. The gut microbiome dysbiosis contributes to NAFLD development by dysregulating the gut-liver axis, leading to increased intestinal permeability and unrestrained transfer of microbial metabolites into the liver. In this review, we systematically summarized the up-to-date information of gut microbiome dysbiosis and metabolomic changes along the stages of steatosis, NASH, fibrosis, and NAFLD-HCC. The components and functions of the gut-liver axis and its association with NAFLD were then discussed. In addition, we highlighted current knowledge of gut microbiome-based treatment strategies targeting the gut-liver axis for preventing NAFLD and its associated HCC.

Keywords:  gut microbiome; gut–liver axis; intestinal barrier; metabolites; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.3390/biomedicines10030524
Biomedicines. 2022 Feb 25. pii: 550. [Epub ahead of print]10(3):

Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role.

Haripriya Gupta, Byeong-Hyun Min, Raja Ganesan, Yoseph Asmelash Gebru, Satya Priya Sharma, Eunju Park, Sung-Min Won, Jin-Ju Jeong, Su-Been Lee, Min-Gi Cha, Goo-Hyun Kwon, Min-Kyo Jeong, Ji-Ye Hyun, Jung-A Eom, Hee-Jin Park, Sang-Jun Yoon, Mi-Ran Choi, Dong-Joon Kim, Ki-Tae Suk.

  Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut-liver axis.

Keywords:  NAFLD; microbial functions; microbiota; microbiota-based approach

DOI:  https://doi.org/10.3390/biomedicines10030550
Biomedicines. 2022 Mar 18. pii: 704. [Epub ahead of print]10(3):

CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.

Kiara V Whitley, Claudia M Tellez Freitas, Carlos Moreno, Christopher Haynie, Joshua Bennett, John C Hancock, Tyler D Cox, Brett E Pickett, K Scott Weber.

  Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found on their surface. CD5 is a T cell co-receptor that regulates thymocyte selection and peripheral T cell activation. The removal of CD5 enhances T cell activation and proliferation, but how this is accomplished is not well understood. We examined how CD5 specifically affects CD4+ T cell metabolic function and systemic metabolome by analyzing serum and T cell metabolites from CD5WT and CD5KO mice. We found that CD5 removal depletes certain serum metabolites, and CD5KO T cells have higher levels of several metabolites. Transcriptomic analysis identified several upregulated metabolic genes in CD5KO T cells. Bioinformatic analysis identified glycolysis and the TCA cycle as metabolic pathways promoted by CD5 removal. Functional metabolic analysis demonstrated that CD5KO T cells have higher oxygen consumption rates (OCR) and higher extracellular acidification rates (ECAR). Together, these findings suggest that the loss of CD5 is linked to CD4+ T cell metabolism changes in metabolic gene expression and metabolite concentration.

Keywords:  CD5; RNA-Seq; T cell co-receptor; T cell metabolism; bioinformatics; helper T cell; metabolomics

DOI:  https://doi.org/10.3390/biomedicines10030704
World J Hepatol. 2022 Feb 27. 14(2): 319-337

Hepatobiliary manifestations in inflammatory bowel disease: A practical approach.

Paulina Núñez F, Fabiola Castro, Gabriel Mezzano, Rodrigo Quera, Diego Diaz, Lorena Castro.

  Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. They can occur at any moment in the course of the disease or associated with the treatment. The prevalence of liver dysfunction can reach up to 50% in different studies. Nonalcoholic fatty liver disease is considered the most common hepatobiliary complication in IBD, while primary sclerosing cholangitis is the most specific. Management of hepatic manifestations in IBD involves a multidisciplinary approach that includes a high index of suspicion and joint management with hepatologists. The medical confrontation with abnormal liver tests must include an exhaustive study to determine if these patterns can be related to IBD, associated diseases or to the therapies used.

Keywords:  Extraintestinal manifestations; Hepatic steatosis; Inflammatory bowel disease; Liver toxicity; Sclerosing primary cholangitis

DOI:  https://doi.org/10.4254/wjh.v14.i2.319
Mol Cell Proteomics. 2022 Mar 21. pii: S1535-9476(22)00033-0. [Epub ahead of print] 100225

Imaging Mass Spectrometry Reveals Alterations in N-linked glycosylation that are Associated with Histopathological Changes in Non-alcoholic Steatohepatitis in Mouse and Human.

Shaaron Ochoa-Rios, Ian P O'Connor, Lindsey N Kent, Julian M Clouse, Yannis Hadjiyannis, Christopher Koivisto, Thierry Pecot, Peggi Angel, Richard R Drake, Gustavo Leone, Anand S Mehta, Don C Rockey.

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) and is characterized by inflammation, hepatocyte injury, and fibrosis. Further, NASH is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). Previous research demonstrated that serum N-glycan profiles can be altered in NASH patients. Here, we hypothesized that these N-glycan modifications may be associated with specific liver damage in NAFLD and NASH. To investigate the N-glycome profile in tissue, Imaging Mass Spectrometry (IMS) was used for a qualitative and quantitative in situ N-linked glycan analysis of mouse and human NAFLD/NASH tissue. A murine model was used to induce NAFLD and NASH through ad libitum feeding with either a high-fat diet (HFD) or a Western diet (WD), respectively. Mice fed a HFD or WD developed inflammation, steatosis, and fibrosis, consistent with NAFLD/NASH phenotypes. Induction of NAFLD/NASH for 18 months using high caloric diets resulted in increased expression of mannose, complex/fucosylated, and hybrid N-glycan structures compared to control mouse livers. To validate the animal results liver biopsy specimens from 51 human NAFLD/NASH patients representing the full range of NASH CRN (Clinical Research Network) fibrosis stages were analyzed. Importantly, the same glycan alterations observed in mouse models were observed in human NASH biopsies and correlated with the degree of fibrosis. In addition, spatial glycan alterations were localized specifically to histopathological changes in tissue like fibrotic and fatty areas. We demonstrate that the use of standard staining's combined with IMS provide a full profile of the origin of N-glycan modifications within the tissue. These results indicate that the spatial distribution of abundances of released N-glycans correlate with regions of tissue steatosis associated with NAFLD/NASH.

DOI: https://doi.org/10.1016/j.mcpro.2022.100225
Trends Cancer. 2022 Mar 21. pii: S2405-8033(22)00045-0. [Epub ahead of print]

The gut-liver axis: host microbiota interactions shape hepatocarcinogenesis.

Maruhen A D Silveira, Steve Bilodeau, Tim F Greten, Xin Wei Wang, Giorgio Trinchieri.

  Although their etiologies vary, tumors share a common trait: the control of an oncogenic transcriptional program that is regulated by the interaction of the malignant cells with the stromal and immune cells in the tumor microenvironment (TME). The TME shows high phenotypic and functional heterogeneity that may be modulated by interactions with commensal microbes (the microbiota) both systemically and locally. Unlike host cells, the microbiota adapts after environmental perturbations, impacting host-microbe interactions. In the liver, the bidirectional relationship in the gut and its associated microbiota creates an interdependent environment. Therefore, the gut microbiota and its metabolites modulate liver gene expression directly and indirectly, causing an imbalance in the gut-liver axis, which may result in disease, including carcinogenesis.

Keywords:  dysbiosis; gut–liver axis; liver cancer; microbiota; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2022.02.009
Eur J Clin Invest. 2022 Mar 22. e13769

Microvesicles released from activated CD4+ T cells alter microvascular endothelial cell function.

Daria Vdovenko, Carolina Balbi, Dario Di Silvestre, Giulia Passignani, Yustina M Puspitasari, Martina Zarak-Crnkovic, Pierluigi Mauri, Giovanni G Camici, Thomas F Lüscher, Urs Eriksson, Giuseppe Vassalli.

  BACKGROUND: Microvesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.METHODS: CD4+ T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28 coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated (MV.Act) and non-activated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency=100%, which were selected by both LDA (P<0.01) and MaxQUANT (P<0.01) workflows, were defined as "high-confidence" differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.
RESULTS: T cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n=2110 and n=851 proteins in MV.Act and MV.NAct, respectively). Protein-protein-interaction network models reconstructed from both differentially expressed proteins (n=594; LDA P≤0.01) and "high-confidence" differentially expressed proteins (n=98; P≤0.01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organization, and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key pro-inflammatory pathway related to effector CD4+ T-cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment, and endothelial monolayer barrier disruption.
CONCLUSIONS: T-cell receptor-mediated activation of CD4+ T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.

Keywords:  T cells; endothelial cell; extracellular vesicle; microvesicle; proteomics

DOI:  https://doi.org/10.1111/eci.13769
J Exp Med. 2022 May 02. pii: e20200795. [Epub ahead of print]219(5):

Lymph node fibroblastic reticular cells regulate differentiation and function of CD4 T cells via CD25.

Dongeon Kim, Mingyo Kim, Tae Woo Kim, Yong-Ho Choe, Hae Sook Noh, Hyun Min Jeon, HyunSeok Kim, Youngeun Lee, Gayeong Hur, Kyung-Mi Lee, Kihyuk Shin, Sang-Il Lee, Seung-Hyo Lee.

Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the α chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses.

DOI: https://doi.org/10.1084/jem.20200795