Project description:The microbiota plays a major role in cancer. How the microbiota interacts with nutrients to produce regulatory metabolites is of significance for cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, we identified the metabolite 2-methylisocitrate to be produced and enriched in human tumor-associated microbiomes. 2-methylisocitrate exhibits anti-proliferative properties across genetically- and tissue-diverse cancer cell lines, 3D spheroids, and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Drug-metabolite screening traced the chemotherapeutic signatures indicating synergy between 5-fluorouracil and 2-methylisocitrate, and multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, building on nature’s template, we altered the chemical structure of 2-methylisocitrate, enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation, and their potential as promising co-adjuvants for cancer treatment.
Project description:Adverse effects of pharmaceutical agents are commonly attributed to direct drug toxicity. However, many drugs also disrupt gut microbial composition, and the resulting dysbiosis can influence drug metabolism, therapeutic efficacy, and host tissue responses. Disentangling microbiota-mediated effects from direct drug action remains a major challenge in understanding treatment-associated pathology. Here, we dissected the direct and microbiota-mediated effects of cytarabine (Ara-C), a widely used chemotherapeutic agent that frequently induces life-threatening gastrointestinal toxicity, on colonic barrier function and transcriptional responses. Using epithelial cell lines, ex vivo gut organ cultures, and in vivo models, we show that both Ara-C and its associated dysbiotic microbiota independently increase gut permeability, but through distinct molecular pathways: direct Ara-C exposure elicits interferon-driven inflammatory programs, whereas post-Ara-C microbiota activate mucosal defense and barrier-reinforcement gene sets. These findings establish chemotherapy-induced microbiota dysbiosis as an independent contributor to intestinal pathology and support microbiome-targeted strategies to mitigate gut toxicity.
Project description:Phloroglucinol is a key byproduct of gut microbial metabolism that has been widely used as a treatment for irritable bowel syndrome. Here, we demonstrate that phloroglucinol tempers macrophage responses to pro-inflammatory pathogens and stimuli. In vivo, phloroglucinol administration decreases gut and extraintestinal inflammation in murine models of inflammatory bowel disease and systemic infection. The metabolite induces modest modifications in the microbiota. However, the presence of an active microbiota is required to preserve its anti-inflammatory activity. Remarkably, the protective effect of phloroglucinol lasts partially at least 6 months. Single-cell transcriptomic analysis of bone marrow progenitors demonstrates the capacity of the metabolite to induce long-lasting innate immune training in hematopoietic lineages, at least partially through the participation of the receptor and transcription factor, aryl hydrocarbon receptor (AhR). Phloroglucinol induces alterations in metabolic and epigenetic pathways that are most prevalent in upstream progenitors as hallmarks of central trained immunity. These data identify phloroglucinol as a dietary-derived compound capable of inducing central trained immunity and modulating the response of the host to inflammatory insults.
Project description:Adverse effects of pharmaceutical agents are commonly attributed to direct drug toxicity. However, many drugs also disrupt gut microbial composition, and the resulting dysbiosis can influence drug metabolism, therapeutic efficacy, and host tissue responses. Disentangling microbiota-mediated effects from direct drug action remains a major challenge in understanding treatment-associated pathology. Here, we dissected the direct and microbiota-mediated effects of cytarabine (Ara-C), a widely used chemotherapeutic agent that frequently induces life-threatening gastrointestinal toxicity, on colonic barrier function and transcriptional responses. Using epithelial cell lines, ex vivo gut organ cultures, and in vivo models, we show that both Ara-C and its associated dysbiotic microbiota independently increase gut permeability, but through distinct molecular pathways: direct Ara-C exposure elicits interferon-driven inflammatory programs, whereas post-Ara-C microbiota activate mucosal defense and barrier-reinforcement gene sets. These findings establish chemotherapy-induced microbiota dysbiosis as an independent contributor to intestinal pathology and support microbiome-targeted strategies to mitigate gut toxicity.
Project description:We report the first case series of ICI associated colitis successfully treated with fecal microbiota transplantation (FMT), with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T cells (Tregs) within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
Project description:Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma, however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here we identify the gut microbiota as playing a previously unrecognized, critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances Tc1-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identified the transcription factor nuclear factor erythroid 2-related factor-2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we identify human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity and support its functional role in driving melanoma suppression.
Project description:A high-sugar diet induces lifestyle-associated metabolic diseases, such as obesity and diabetes, which may underlie the pro-tumor effects of a high-sugar diet. We supplied GL261 syngeneic glioblastoma (GBM) model mice with a short-term high-glucose diet (HGD) and found an increased survival rate with no evidence of metabolic disease. Modulation of the gut microbiota by an HGD was critical for enhancing the anti-tumor immune response. Single-cell RNA sequencing showed that modulation of the gut microbiota by an HGD increased the T cell-mediated anti-tumor immune response in GBM mice. We found that the cytotoxic CD4+ T cell population in GBM mice increased due to synergy with anti-PD-1 immune checkpoint inhibitors, but this depended on an HGD. Thus, we determined that an HGD enhanced anti-tumor immune responses in GBM mice through changes in the gut microbiota and suggest that the role of an HGD in GBM should be re-examined.
Project description:Modulation of the tumor promoting functions of cancer associated fibroblasts by PDE5 inhibition increases the efficacy of chemotherapy in human preclinical models of edophageal adenocarcinoma
Project description:Hesperidin, a citrus flavonoid glycoside, was investigated for its protective effects against high-fat diet (HFD)-induced metabolic syndrome in mice. Twelve weeks of supplementation markedly attenuated body weight gain, hepatic steatosis, adipocyte hypertrophy, dyslipidemia, and systemic inflammation, while enhancing glucose tolerance and insulin sensitivity. 16S rRNA sequencing demonstrated that hesperidin partially restored microbial diversity and selectively enriched beneficial taxa, including Lactobacillus, Bifidobacterium, and Akkermansia. Serum metabolomics revealed increased levels of microbial-derived metabolites such as cinnamic acid, hippuric acid, and sulfated phenolic acids, compounds associated with anti-obesity, antioxidant and anti-inflammatory activities. Transcriptomic profiling of inguinal white adipose tissue identified broad remodeling of metabolic pathways, with notable activation of calcium signaling, implicating both UCP1-dependent browning and UCP1-independent calcium futile cycling in thermogenesis. Importantly, antibiotic treatment abolished the metabolic benefits and suppressed the generation of bioactive metabolites, underscoring the indispensable role of gut microbiota in hesperidin bioactivity. Together, these findings delineate a microbiota–metabolite–adipose tissue axis through which hesperidin confers systemic metabolic protection, highlighting its potential as a microbiota-targeted dietary strategy for managing obesity-related disorders.