Tryptophan metabolism in health and disease

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(8), P. 1304 - 1326

Published: June 22, 2023

Language: Английский

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Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment

Cell, Journal Year: 2023, Volume and Issue: 186(9), P. 1846 - 1862.e26

Published: April 1, 2023

Language: Английский

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Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Nature, Journal Year: 2023, Volume and Issue: 615(7950), P. 168 - 174

Published: Feb. 22, 2023

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing high incidence of metastatic disease and limited responses treatment1,2. Less than half all patients respond primary treatment for PDAC, chemotherapy3,4, genetic alterations alone cannot explain this5. Diet an environmental factor that can influence response therapies, but its role in PDAC unclear. Here, using shotgun metagenomic sequencing metabolomic screening, we show microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) enriched who treatment. Faecal microbiota transplantation, short-term dietary manipulation oral 3-IAA administration increase efficacy chemotherapy humanized gnotobiotic mouse models PDAC. Using a combination loss- gain-of-function experiments, licensed neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which with induces downregulation reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 7. All this results accumulation ROS autophagy cells, compromises their metabolic fitness and, ultimately, proliferation. In humans, observed significant correlation between levels therapy two independent cohorts. summary, identify has clinical implications provide motivation considering nutritional interventions during cancer.

Language: Английский

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Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(11), P. 1112 - 1140

Published: Sept. 7, 2022

Abstract Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among most abundant immune cells infiltrating TME and present at all stages cancer progression, targeting TAMs has become one favored immunotherapy strategies. In addition, distinct origins. At early stage cancer, can provide niche for maintenance stem cells. contrast, (CSCs) or poorly differentiated key factors modulating macrophage activation. review, we first propose origin connection between precursor Macrophages undergo dynamic phenotypic transition during carcinogenesis. this course such transition, it is critical to determine appropriate timing therapy block specific markers suppress pro‐tumoral TAMs. The review provides more detailed discussion trends surface than previous reviews. Complex crosstalk occurs play indispensable roles angiogenesis, autophagy due their heterogeneity robust plasticity. interact with other by directing cell‐to‐cell contact secreting various effector molecules. Similarly, combined drive recruitment polarization. Despite latest achievements advancements treatment strategies following studies, comprehensive discussions on communication currently lacking. discussed interactions (from cell maturation), therapeutic (including chimeric antigen receptor macrophages), clinical trials hepatocellular carcinoma (HCC) intrahepatic cholangiocarcinoma (iCCA) rationale further investigation as potential target treating patients

Language: Английский

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Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis

Cells, Journal Year: 2022, Volume and Issue: 11(15), P. 2296 - 2296

Published: July 25, 2022

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic (IAA), indole-3-acetaldehyde Kyn produced by intestinal microorganisms through direct Trp transformation also, partly, kynurenine (Kyn) pathway. These play a critical role maintaining homeostasis of systematic immunity also potentially affect occurrence development diseases inflammatory bowel diseases, tumors, obesity metabolic syndrome, nervous system, infectious vascular inflammation cardiovascular hepatic fibrosis. They not only promote differentiation function anti-inflammatory macrophages, Treg cells, CD4

Language: Английский

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Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 16, 2023

Abstract Microorganisms, including bacteria, viruses, fungi, and other eukaryotes, play critical roles in human health. An altered microbiome can be associated with complex diseases. Intratumoral microbial components are found multiple tumor tissues closely correlated cancer initiation development therapy efficacy. The intratumoral microbiota may contribute to promotion of the progression cancers by DNA mutations, activating carcinogenic pathways, promoting chronic inflammation, complement system, initiating metastasis. Moreover, not only enhance antitumor immunity via mechanisms STING signaling activation, T NK cell TLS production, microbiota-derived antigen presenting, but also decrease immune responses promote through pathways upregulation ROS, an anti-inflammatory environment, inactivation, immunosuppression. effect on is dependent composition, crosstalk between cancer, status cancers. regulate physiology response different β-catenin, TLR, ERK, NF-κB, STING, among others. These viewpoints help identify as diagnosis or prognosis evaluation cancers, new therapeutic strategy potential targets for therapy.

Language: Английский

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Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 793 - 793

Published: March 2, 2023

The gut microbiota, including bacteria, archaea, fungi, viruses and phages, inhabits the gastrointestinal tract. This commensal microbiota can contribute to regulation of host immune response homeostasis. Alterations have been found in many immune-related diseases. metabolites generated by specific microorganisms such as short-chain fatty acids (SCFAs), tryptophan (Trp) bile acid (BA) metabolites, not only affect genetic epigenetic but also impact metabolism cells, immunosuppressive inflammatory cells. cells (such tolerogenic macrophages (tMacs), dendritic (tDCs), myeloid-derived suppressive (MDSCs), regulatory T (Tregs), B (Breg) innate lymphocytes (ILCs)) Macs (iMacs), DCs, CD4 helper (Th)1, CD4Th2, Th17, natural killer (NK) NK neutrophils) express different receptors for SCFAs, Trp BA from microorganisms. Activation these promotes differentiation function inhibits causing reprogramming local systemic system maintain homeostasis individuals. We here will summarize recent advances understanding effects on homeostasis, especially functions

Language: Английский

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The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer

Science Immunology, Journal Year: 2022, Volume and Issue: 7(75)

Published: Sept. 9, 2022

The composition of the gut microbiome can control innate and adaptive immunity has emerged as a key regulator tumor growth, especially in context immune checkpoint blockade (ICB) therapy. However, underlying mechanisms for how affects growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory therapy, including ICB. Using nontargeted, liquid chromatography–tandem mass spectrometry–based metabolomic screen, we identified microbe–derived metabolite trimethylamine N -oxide (TMAO), which enhanced antitumor PDAC. Delivery TMAO intraperitoneally or via dietary choline supplement orthotopic PDAC-bearing mice reduced associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, activated effector T cell response microenvironment. Mechanistically, potentiated type I interferon (IFN) pathway conferred effects IFN–dependent manner. Delivering TMAO-primed macrophages intravenously produced similar effects. Combining ICB (anti-PD1 and/or anti-Tim3) mouse model PDAC significantly burden improved survival beyond alone. Last, levels bacteria containing CutC (an enzyme that generates trimethylamine, precursor) correlated long-term patients anti-PD1 melanoma. Together, our study identifies microbial driver lays groundwork potential therapeutic strategies targeting TMAO.

Language: Английский

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Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 13, 2023

Abstract In the past period, due to rapid development of next-generation sequencing technology, accumulating evidence has clarified complex role human microbiota in cancer and therapeutic response. More importantly, available seems indicate that modulating composition gut improve efficacy anti-cancer drugs may be feasible. However, intricate complexities exist, a deep comprehensive understanding how interacts with is critical realize its full potential treatment. The purpose this review summarize initial clues on molecular mechanisms regarding mutual effects between development, highlight relationship microbes immunotherapy, chemotherapy, radiation therapy surgery, which provide insights into formulation individualized strategies for management. addition, current emerging microbial interventions as well their clinical applications are summarized. Although many challenges remain now, great importance cannot overstated strategies, it necessary explore holistic approach incorporates modulation cancer.

Language: Английский

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Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: June 5, 2023

Abstract Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the response. Regarding metabolic reprogramming in tumor microenvironment, dysregulation of amino acid consumption is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered metabolism tightly linked outgrowth, metastasis, therapeutic resistance through governing fate various cells. During these processes, concentration free acids, their membrane bound transporters, key enzymes, sensors such as mTOR GCN2 play critical roles controlling cell differentiation function. As such, anti-cancer responses could be enhanced by supplement specific essential or targeting enzymes sensors, thereby developing novel adjuvant modalities. To further dissect regulation immunity, this review summarizes regulatory mechanisms effects on phenotypes functions tumor-infiltrating propose approaches exploited rewire enhance cancer immunotherapy.

Language: Английский

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