Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota.In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of ...potentially pathogenic bacteria(i.e.,gram negative species)and a decrease in autochthonous familiae.Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences.We therefore described the features of the complex interaction between gut microbiota and cirrhotic host,the so called"gut-liver axis",with a particular attention to the acquired risk of bacterial translocation,systemic inflammation and the relationship with systemic infections in the cirrhotic patient.Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.
Rebuilding the Gut Microbiota Ecosystem Gagliardi, Antonella; Totino, Valentina; Cacciotti, Fatima ...
International journal of environmental research and public health,
08/2018, Letnik:
15, Številka:
8
Journal Article
Recenzirano
Odprti dostop
A microbial ecosystem in which bacteria no longer live in a mutualistic association is called dysbiotic. Gut microbiota dysbiosis is a condition related with the pathogenesis of intestinal illnesses ...(irritable bowel syndrome, celiac disease, and inflammatory bowel disease) and extra-intestinal illnesses (obesity, metabolic disorder, cardiovascular syndrome, allergy, and asthma). Dysbiosis status has been related to various important pathologies, and many therapeutic strategies aimed at restoring the balance of the intestinal ecosystem have been implemented. These strategies include the administration of probiotics, prebiotics, and synbiotics; phage therapy; fecal transplantation; bacterial consortium transplantation; and a still poorly investigated approach based on predatory bacteria. This review discusses the various aspects of these strategies to counteract intestinal dysbiosis.
The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain ...unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC.
To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.
We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.
Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors.
Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae).
The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers.
We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.
Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.
The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T
) cells and the efficacy of chemotherapy-induced immune responses. It remains ...unclear whether gut microbes contribute to the elicitation of T
cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T
cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1
T
cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics ...was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recently demonstrated in the sputum or saliva, suggesting how the shedding of viral RNA outlasts the end of ...symptoms. Recent data from transcriptome analysis show that the oral cavity mucosa harbors high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), highlighting its role as a double-edged sword for SARS-CoV-2 body entrance or interpersonal transmission. Here, we studied the oral microbiota structure and inflammatory profile of 26 naive severe coronavirus disease 2019 (COVID-19) patients and 15 controls by 16S rRNA V2 automated targeted sequencing and magnetic bead-based multiplex immunoassays, respectively. A significant diminution in species richness was observed in COVID-19 patients, along with a marked difference in beta-diversity. Species such as
Prevotella salivae
and
Veillonella infantium
were distinctive for COVID-19 patients, while
Neisseria perflava
and
Rothia mucilaginosa
were predominant in controls. Interestingly, these two groups of oral species oppositely clustered within the bacterial network, defining two distinct Species Interacting Groups (SIGs). COVID-19-related pro-inflammatory cytokines were found in both oral and serum samples, along with a specific bacterial consortium able to counteract them. We introduced a new parameter, named CytoCOV, able to predict COVID-19 susceptibility for an unknown subject at 71% of power with an Area Under Curve (AUC) equal to 0.995. This pilot study evidenced a distinctive oral microbiota composition in COVID-19 subjects, with a definite structural network in relation to secreted cytokines. Our results would be usable in clinics against COVID-19, using bacterial consortia as biomarkers or to reduce local inflammation.
Celiac Disease (CD) is an autoimmune disorder of the small intestine in which dietary gluten ingestion leads to a chronic enteropathy. Recently, scientific evidence suggested a potential role of gut ...microbiota in CD. To have a snapshot of dominant duodenal microbiota we analyzed the mucosa-associated microbiota of 20 children with CD, before and after a gluten-free diet (GFD) regimen, and of 10 controls. Total DNA was extracted from duodenal biopsies and amplification products of 16S ribosomal DNA were compared by temporal temperature gradient gel electrophoresis (TTGE). TTGE profiles were analyzed by statistical multivariate analysis.
The average number of bands in TTGE profiles was significantly higher (P < 0.0001) in active (n.b. 16.7 +/- 0.7) and inactive states (n.b. 13.2 +/- 0.8) than in controls (n.b. 3.7 +/- 1.3). Mean interindividual similarity index was 54.9% +/- 14.9% for active disease, 55.6% +/- 15.7% for remission state and 21.8% +/- 30.16% for controls. Similarity index between celiac children before and after GFD treatment was 63.9% +/- 15.8%. Differences in microbiota biodiversity were among active and remission state (P = 0.000224) and amid active CD and controls (P < 0.001). Bacteroides vulgatus and Escherichia coli were detected more often in CD patients than in controls (P < 0.0001).
Overall, the results highlighted a peculiar microbial TTGE profile and a significant higher biodiversity in CD pediatric patients' duodenal mucosa. The possible pathophysiological role of these microbial differences needs further characterization.
Microbiota are microorganismal communities colonizing human tissues exposed to the external environment, including the urogenital tract. The bacterial composition of the vaginal microbiota has been ...established and is partially related to obstetric outcome, while the uterine microbiota, considered to be a sterile environment for years, is now the focus of more extensive studies and debates. The characterization of the microbiota contained in the reproductive tract (RT) of asymptomatic and infertile women, could define a specific RT microbiota associated with implantation failure. In this pilot study, 34 women undergoing personalized hormonal stimulation were recruited and the biological samples of each patient, vaginal fluid, and endometrial biopsy, were collected immediately prior to oocyte-pick up, and sequenced. Women were subsequently divided into groups according to fertilization outcome. Analysis of the 16s rRNA V4-V5 region revealed a significant difference between vaginal and endometrial microbiota. The vaginal microbiota of pregnant women corroborated previous data, exhibiting a lactobacilli-dominant habitat compared to non-pregnant cases, while the endometrial bacterial colonization was characterized by a polymicrobial ecosystem in which lactobacilli were exclusively detected in the group that displayed unsuccessful
fertilization. Overall, these preliminary results revisit our knowledge of the genitourinary microbiota, and highlight a putative relationship between vaginal/endometrial microbiota and reproductive success.
Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in ...intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
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