Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules1–3, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host. A microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for the characterization of gut-resident microorganisms and the interactions between microorganisms and their host.

A metabolomics pipeline for the mechanistic interrogation of the gut microbiome

Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis.

CRISPR-based detection of SARS-CoV-2: A review from sample to result.

Gut mucosal layers are crucial in maintaining the gut barrier function. Gut microbiota regulate homeostasis of gut mucosal layer via gut immune cells such as RORγt (+) IL-22(+) ILC3 cells, which can influence the proliferation of mucosal cells and the production of mucin. However, it is unclear how gut microbiota execute this regulation. Here we show that lactobacilli promote gut mucosal formation by producing L-Ornithine from arginine. L-Ornithine increases the level of aryl hydrocarbon receptor ligand L-kynurenine produced from tryptophan metabolism in gut epithelial cells, which in turn increases RORγt (+)IL-22(+) ILC3 cells. Human REG3A transgenic mice show an increased proportion of L-Ornithine producing lactobacilli in the gut contents, suggesting that gut epithelial REG3A favors the expansion of L-Ornithine producing lactobacilli. Our study implicates the importance of a crosstalk between arginine metabolism in Lactobacilli and tryptophan metabolism in gut epithelial cells in maintaining gut barrier. Qi, Li, Yun, Zhang et al.show that lactobacilli promote the generation of gut mucosa by facilitating the conversion of arginine to L-Ornithine. This study highlights the importance of a crosstalk between arginine metabolism in Lactobacilli and tryptophan metabolism in gut epithelial cells in maintaining a healthy gut barrier.

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Lactobacillus maintains healthy gut mucosa by producing L-Ornithine

Macrophages, which are functional plasticity cells, have the ability to phagocytize and digest foreign substances and acquire pro-(M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. The large number of macrophages in the intestinal tract, play a significant role in maintaining the homeostasis of microorganisms on the surface of the intestinal mucosa and in the continuous renewal of intestinal epithelial cells. They are not only responsible for innate immunity, but also participate in the development of intestinal inflammation. A clear understanding of the function of macrophages, as well as their role in pathogens and inflammatory response, will delineate the next steps in the treatment of intestinal inflammatory diseases. In this review, we discuss the origin and development of macrophages and their role in the intestinal inflammatory response or infection. In addition, the effects of macrophages in the occurrence and development of inflammatory bowel disease (IBD), and their role in inducing fibrosis, activating T cells, reducing colitis, and treating intestinal inflammation were also reviewed in this paper.

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Roles of Macrophages in the Development and Treatment of Gut Inflammation.

Macrophages are mainly divided into two populations, which play a different role in physiological and pathological conditions. The differentiation of these cells may be regulated by transcription factors. However, it is unclear how to modulate these transcription factors to affect differentiation of these cells. Here, we found that lncLy6C, a novel ultraconserved lncRNA, promotes differentiation of Ly6Chigh inflammatory monocytes into Ly6Clow/neg resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6Chigh pro-inflammatory monocytes and reduced Ly6Cneg resident macrophages. LncLy6C not only bound with transcription factor C/EBPβ but also bound with multiple lysine methyltransferases of H3K4me3 to specifically promote the enrichment of C/EBPβ and H3K4me3 marks on the promoter region of Nr4A1, which can promote Ly6Chigh into Ly6Cneg macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6Chigh inflammatory monocytes to differentiate into Ly6Cint/neg resident macrophages.

/pdf/lncrna-lncly6c-induced-by-microbiota-metabolite-butyrate-302n8373i8.pdf

LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6Chigh to Ly6Cint/neg macrophages through lncLy6C/C/EBPβ/Nr4A1 axis.

Gut microbiota may not only affect composition of local immune cells but also systemic immune cells. However, it is not completely clear how gut microbiota modulate these immune systems. We here found that there have expanded macrophage pools in huREG3γ tgIEC mice. REG3γ associated Lactobacillus, which is homology to Lactobacillus Taiwanese, could enlarge macrophage pools not only in the small intestinal lamina propria but also in the spleen and adipose tissues. STAT3 mediated signal(s) was a critical factor in the Lactobacillus mediated anti-inflammatory macrophages. We also offered evidence for critical cellular links among REG3γ associated Lactobacillus, tissue macrophages and obesity diseases. Anti-inflammatory macrophages in the lamina propria which are induced by REG3γ-associated Lactobacillus, may migrate into adipose tissues and are involved in resistance against high-fat diet mediated obesity. Thus, REG3γ-associated Lactobacillus induced anti-inflammatory macrophages in gut tissues may play a role in adipose tissue homeostasis.

/pdf/gut-reg3g-associated-lactobacillus-induces-anti-inflammatory-3lpwydulpl.pdf

Gut REG3γ-Associated Lactobacillus Induces Anti-inflammatory Macrophages to Maintain Adipose Tissue Homeostasis.

Background Chimeric antigen receptor T (CAR-T) cell therapy has made significant advances for hematological malignancies but encounters obstacles in the treatment of solid tumors mainly due to tumor immunosuppressive microenvironment. Methods Immunohistochemistry analysis was performed to examine the cellular expression of nectin cell adhesion molecule-4 (Nectin4) and fibroblast activation protein (FAP) in a variety of malignant solid tumors. Then, we engineered the fourth-generation Nectin4-targeted CAR-T (Nectin4-7.19 CAR-T) and FAP-targeted CAR-T (FAP-12 CAR-T) cells to evaluate their safety and efficacy in vitro and in vivo. Results In our study, we firstly demonstrated the aberrant overexpression of Nectin4 on both primary and metastatic solid tumors and FAP on cancer-associated fibroblasts. Then, we found that our fourth-generation Nectin4-7.19 CAR-T cells expressed IL-7 and CCL19 efficiently and exhibited superior proliferation, migration, and cytotoxicity compared to the second-generation Nectin4 CAR-T cells, while FAP-12 CAR-T cells exerted their ability of targeting both murine and human FAP effectively in vitro. In a fully immune-competent mouse model of metastatic colorectal cancer, lymphodepletion pretreated mice achieved complete remission with human Nectin4-targeted murine CAR-T (Nectin4 mCAR-T) cells. In the NSG mouse model of lung metastases, Nectin4-7.19 CAR-T cells eradicated metastatic tumors and prolonged survival in combination with FAP-12 CAR-T cells. Conclusions These findings showed that Nectin4-7.19 CAR-T cells had potential therapeutic efficacy and exerted a synergistic role with FAP-12 CAR-T cells, further demonstrating that Nectin4 and FAP were able to serve as promising targets for safe and effective CAR-T therapy of malignant solid tumors.

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Jiang Zhou

Papers

Lactobacillus maintains healthy gut mucosa by producing L-Ornithine

LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6Chigh to Ly6Cint/neg macrophages through lncLy6C/C/EBPβ/Nr4A1 axis.

Gut REG3γ-Associated Lactobacillus Induces Anti-inflammatory Macrophages to Maintain Adipose Tissue Homeostasis.

Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors