Abstract The human gut microbiome is increasingly viewed as an active regulator of host physiology, extending beyond earlier taxonomy‐centered descriptions of a complex microbial community. Accumulating evidence supports an organ‐like conceptual framework in which the gut microbiome exhibits spatially structured organization, extensive metabolic capacity, and continuous bidirectional communication with host systems. Through the production of bioactive metabolites with endocrine‐like, immunomodulatory, and neuromodulatory properties, the microbiome contributes to metabolic, immune, and neuroendocrine regulation, thereby influencing systemic homeostasis and disease susceptibility. Recent advances in multi‐omics, spatial biology, and computational modeling are moving the field from taxonomic association toward functional interpretation, mechanistic insight, and causal inference. These approaches are beginning to reveal microbiome‐derived functional modules and host–microbe signaling networks that are shaped by host genetics, diet, medications, feeding patterns, circadian rhythms, and environmental exposures. In this review, we synthesize current mechanistic and translational evidence to conceptualize the gut microbiome as an organ‐like functional system, delineate its structural and functional organization, and propose a framework for mapping, modeling, and therapeutically targeting microbiome‐derived circuits to support precision medicine in metabolic, inflammatory, and selected gut–brain axis‐related disorders.
Yang Bi, Wei-Bin Song, Maria Glymenaki et al.· iMeta· 0 citations
Metastasis remains the principal cause of cancer mortality, with the lungs representing one of the most frequent and clinically challenging sites. The tumor microenvironment, particularly tumor-associated macrophages (TAMs), plays a pivotal role in establishing and maintaining metastatic niches. Yet, how host ketone bodies influence the immune microenvironment to govern metastatic progression is poorly defined. Pan-cancer gene expression analysis on the Home for Researchers platform to assess the activity of enzymes involved in acetoacetate synthesis and catabolism. Two murine metastatic Lung Cancer models were established to evaluate the role of acetoacetate in metastatic progression. Flow cytometry and immunohistochemistry were used to assess immune cell infiltration, particularly TAMs. Molecular modeling, Drug Affinity Responsive Target Stability, Cellular Thermal Shift Assay, receptor activation assays, inhibitor and small interfering RNA experiments were used to examine the interaction between acetoacetate and the G protein-coupled receptor 43 (GPR43). Immunofluorescence, RNA sequencing, quantitative PCR, Transwell, cytokine supplementation, dot and western blotting, methylated DNA immunoprecipitation–qPCR, and enzyme-linked immunosorbent assay were performed to investigate how acetoacetate regulates interleukin-6 (IL-6) and colony-stimulating factor 1 (CSF1), as well as the underlying epigenetic mechanisms. We uncover a previously unappreciated collapse of acetoacetate homeostasis in lung cancer, driven by the coordinated suppression of ketogenesis and increased ketolysis, resulting in a systemic acetoacetate deficiency. Restoring acetoacetate significantly limits metastatic lung cancer spread and reduces TAM infiltration within the tumor microenvironment. Mechanistically, we identify acetoacetate as an endogenous ligand for GPR43, linking metabolic sensing to immune regulation. Disruption of GPR43 signaling abolishes the anti-metastatic effects of acetoacetate, confirming a reliance on this pathway. Strikingly, acetoacetate–GPR43 signaling increases methionine adenosyltransferase 2A (MAT2A) and S-adenosylmethionine levels and induces region-specific DNA hypermethylation of pro-inflammatory cytokine genes, including IL6 and CSF1, thereby silencing their transcription. Restoring IL-6 and CSF1 reestablishes TAMs’ proliferation and migration, reactivating a pro-metastatic environment. Our findings reveal a novel “metabolic–epigenetic–immune” axis, in which acetoacetate, through GPR43 signaling, reprograms the monocyte epigenome via DNA hypermethylation to suppress pro-metastatic inflammation. This study identifies the acetoacetate–GPR43 axis as a mechanistically grounded, potential therapeutic strategy for metastatic lung cancer and offers new insights into overcoming the limitations of current TAM-targeted therapies.
Shuying Yuan, Biying Xiao, Shuaishuai Ni et al.· Journal of Translational Med...· 0 citations
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