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Cancer Cell Nov 2023Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome...
Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.
Topics: Female; Humans; Lactic Acid; Uterine Cervical Neoplasms; Lactobacillus; Microbiota; Tumor Microenvironment
PubMed: 37863066
DOI: 10.1016/j.ccell.2023.09.012 -
Gut Nov 2023Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving...
OBJECTIVE
Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC).
DESIGN
The effects of in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites.
RESULTS
significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. synergised with anti-PD1 therapy by reducing Foxp3 CD25 regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8 T cells. -derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4 T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation.
CONCLUSION
-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. is a potential adjuvant to augment anti-PD1 efficacy against CRC.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Kynurenine; Receptors, Aryl Hydrocarbon; T-Lymphocytes, Regulatory; Lactobacillus; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Bacterial Lysates
PubMed: 37770127
DOI: 10.1136/gutjnl-2023-329543 -
Microorganisms Aug 2023The role of the gut microbiota in modulating the risk of respiratory infections has garnered increasing attention. However, conventional clinical trials have faced...
The role of the gut microbiota in modulating the risk of respiratory infections has garnered increasing attention. However, conventional clinical trials have faced challenges in establishing the precise relationship between the two. In this study, we conducted a Mendelian randomization analysis with single nucleotide polymorphisms employed as instrumental variables to assess the causal links between the gut microbiota and respiratory infections. Two categories of bacteria, family and genus , were causally associated with the occurrence of upper respiratory tract infections (URTIs). Four categories of gut microbiota existed that were causally associated with lower respiratory tract infections (LRTIs), with order and genus showing a positive association and genus and genus showing a negative association. The metabolites and metabolic pathways only played a role in the development of LRTIs, with the metabolite deoxycholine acting negatively and menaquinol 8 biosynthesis acting positively. The identification of specific bacterial populations, metabolites, and pathways may provide new clues for mechanism research concerning therapeutic interventions for respiratory infections. Future research should focus on elucidating the potential mechanisms regulating the gut microbiota and developing effective strategies to reduce the incidence of respiratory infections. These findings have the potential to significantly improve global respiratory health.
PubMed: 37630668
DOI: 10.3390/microorganisms11082108 -
Microbiology (Reading, England) Dec 2023The bacterial family (the lactobacilli) occupy a unique role in microbiology due to their beneficial role in both human cultural history and biology, from the food...
The bacterial family (the lactobacilli) occupy a unique role in microbiology due to their beneficial role in both human cultural history and biology, from the food preservation of hunter gatherers-turned-farmers, through the prevention of scurvy in seafarers exploring new worlds, and the health-promoting properties of species that colonize the human body as well as animals that are important for agriculture and pollination. The almost bewildering phenotypic and genomic complexity of the former genus was recently reconciled with molecular taxonomy and phylogeny to establish robust genera comprising the , whose main features are summarized in this Microbe Profile.
Topics: Lactobacillaceae; Probiotics
PubMed: 38088348
DOI: 10.1099/mic.0.001414 -
Medicina (Kaunas, Lithuania) Aug 2023Contrary to popular belief, we have known for many years that the endometrium is not a sterile environment and is considered to be a low-biomass milieu compared to the... (Review)
Review
Contrary to popular belief, we have known for many years that the endometrium is not a sterile environment and is considered to be a low-biomass milieu compared to the vagina. Numerous trials and studies have attempted to establish a valid sampling method and assess its physiological composition, but no consensus has been reached. Many factors, such as ethnicity, age and inflammation, can influence the microbiome. Moreover, it possesses a higher alpha-diversity and, therefore, contains more diverse bacteria than the vagina. For instance, has been shown to be a predominant genus in the vaginal microbiome of healthy women. Consequently, even if a majority of scientists postulate that a predominance of inside the uterus improves reproductive outcomes, vaginal contamination by these bacteria during sampling cannot be ruled out. Certain pathologies, such as chronic endometritis, have been identified as inflammation perpetrators that hinder the embryo implantation process. This pro-inflammatory climate created by dysbiosis of the endometrial microbiota could induce secondary inflammatory mediators via Toll-like receptors, creating an environment conducive to the development of endometriosis and even promoting carcinogenesis. However, studies to this day have focused on small populations. In addition, there is no clearly defined healthy uterine composition yet. At most, only a few taxa have been identified as pathogenic. As sampling and analysis methods become increasingly precise, we can expect the endometrial microbiota to be incorporated into future diagnostic tools and treatments for women's health.
Topics: Female; Humans; Endometrium; Uterus; Carcinogenesis; Inflammation; Lactobacillus; Microbiota
PubMed: 37763663
DOI: 10.3390/medicina59091540 -
Frontiers in Immunology 2023Frequent use of hormones and drugs may be associated with side-effects. Recent studies have shown that probiotics have effects on the prevention and treatment of... (Review)
Review
Frequent use of hormones and drugs may be associated with side-effects. Recent studies have shown that probiotics have effects on the prevention and treatment of immune-related diseases. () had regulatory effects on intestinal microbiota, host epithelial cells, immune cells, cytokines, antibodies (Ab), toll-like receptors (TLRs), tryptophan (Try) metabolism, antioxidant enzymes, and expression of related genes, and exhibits antibacterial and anti-inflammatory effects, leading to alleviation of disease symptoms. Although the specific composition of the cell-free supernatant (CFS) of has not been clarified, its efficacy in animal models has drawn increased attention to its potential use. This review summarizes the effects of on intestinal flora and immune regulation, and discusses the feasibility of its application in atopic dermatitis (AD), asthma, necrotizing enterocolitis (NEC), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), and provides insights for the prevention and treatment of immune-related diseases.
Topics: Animals; Limosilactobacillus reuteri; Immunomodulation; Anti-Bacterial Agents; Antibodies; Antioxidants
PubMed: 37638038
DOI: 10.3389/fimmu.2023.1228754 -
Cell Communication and Signaling : CCS Jun 2023Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation of the exocrine gland. An imbalance of gut microbiota has been linked to SS. However, the...
BACKGROUND
Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation of the exocrine gland. An imbalance of gut microbiota has been linked to SS. However, the molecular mechanism is unclear. We investigated the effects of Lactobacillus acidophilus (L. acidophilus) and propionate on the development and progression of SS in mouse model.
METHODS
We compared the gut microbiomes of young and old mice. We administered L. acidophilus and propionate up to 24 weeks. The saliva flow rate and the histopathology of the salivary glands were investigated, and the effects of propionate on the STIM1-STING signaling pathway were evaluated in vitro.
RESULTS
Lactobacillaceae and Lactobacillus were decreased in aged mice. SS symptoms were ameliorated by L. acidophilus. The abundance of propionate-producing bacterial was increased by L. acidophilus. Propionate ameliorated the development and progression of SS by inhibiting the STIM1-STING signaling pathway.
CONCLUSIONS
The findings suggest that Lactobacillus acidophilus and propionate have therapeutic potential for SS. Video Abstract.
Topics: Animals; Mice; Sjogren's Syndrome; Lactobacillus acidophilus; Propionates; Inflammation; Signal Transduction
PubMed: 37316856
DOI: 10.1186/s12964-023-01141-0 -
Cell Reports May 2023Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation,...
Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms in vitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments in vitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV.
Topics: Female; Humans; Proteomics; Vagina; Vaginosis, Bacterial; Lactobacillus; Metabolome; TOR Serine-Threonine Kinases; Microbiota; Inflammation
PubMed: 37149863
DOI: 10.1016/j.celrep.2023.112474 -
Clinical and Translational Medicine Jul 2023Common treatments for metastatic/unresectable HER2-negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune...
BACKGROUND
Common treatments for metastatic/unresectable HER2-negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune checkpoint inhibitor. However, significant drug resistance exists regardless of the treatment regimen.
METHODS
Patients with metastatic/unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma were enrolled. All patients were divided into three groups according to the treatment regimen and were further divided into responders and non-responders according to efficacy evaluation. Metagenomics sequencing were performed to analyze gut microbiome signature of patients receiving different treatments at baseline and throughout treatment.
RESULTS
One hundred seventeen patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma receiving chemotherapy alone, anti PD-1/PD-L1 immunotherapy alone or combined regimen were included in this study. Microbiome signatures related to clinical response are distinct among the three treatment groups. Among which, 14, 8 and 13 species were significantly different between responders and non-responders in immunotherapy, immunotherapy plus chemotherapy and chemotherapy group, respectively. Patients with higher relative abundance of Lactobacillus possessed higher microbiome diversity and significantly better response to anti-PD-1/PD-L1 immunotherapy and had a trend to achieve better progression-free survival. Another cohort of 101 patients has been used as an external validation set to confirm the stability and reliability of these findings.
CONCLUSIONS
Gut microbiome affects response of treatments in HER2-negative advanced gastric cancer in a treatment-specific way, immunotherapy plus chemotherapy did not equal to a simple superposition of immunotherapy and chemotherapy. Lactobacillus is expected to become a novel choice as an adjuvant agent in promoting the efficacy of immunotherapy in gastric cancer.
Topics: Humans; Gastrointestinal Microbiome; B7-H1 Antigen; Stomach Neoplasms; Immune Checkpoint Inhibitors; Reproducibility of Results; Adenocarcinoma; Lactobacillus
PubMed: 37381590
DOI: 10.1002/ctm2.1312 -
Gut Microbes Dec 2023Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the...
Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for -mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by . This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.
Topics: Humans; Animals; Mice; Secretin; Oxytocin; Gastrointestinal Microbiome; Gastrointestinal Hormones; Intestinal Mucosa; Limosilactobacillus reuteri
PubMed: 37698879
DOI: 10.1080/19490976.2023.2256043