scholarly journals The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients

Science ◽  
2018 ◽  
Vol 359 (6371) ◽  
pp. 104-108 ◽  
Author(s):  
Vyara Matson ◽  
Jessica Fessler ◽  
Riyue Bao ◽  
Tara Chongsuwat ◽  
Yuanyuan Zha ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Antitumor Immunity ◽  
Human Cancer ◽  
Quantitative Polymerase Chain Reaction ◽  
Bacterial Species ◽  
Bifidobacterium Longum ◽  
Tumor Control ◽  
Microbial Composition ◽  
Stool Samples ◽  
Melanoma Patients

Anti–PD-1–based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients’ microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti–PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.

Plasma concentrations of dabrafenib and trametinib (PCD/T) monitoring in advanced BRAFV600mut melanoma patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9541-9541
Author(s):  
Elisa Funck-Brentano ◽  
Margot Raynal ◽  
Jean-Claude Alvarez ◽  
Alain Beauchet ◽  
Christian Funck-Brentano ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Response ◽  
Interindividual Variability ◽  
Plasma Concentrations ◽  
Stage Iv ◽  
Tumor Control ◽  
Active Metabolites ◽  
Pharmacological Interactions ◽  
High Interindividual Variability ◽  
Melanoma Patients

9541 Background: Dabrafenib (D) and trametinib (T) are highly ative in BRAFV600mut melanoma pts. One previous study suggested high PCD to be associated with adverse effects (AE) but not with tumor response. We investigated the relationship between PCD/T and tumor control or AE. Methods: PCD/T were evaluated with high-performance liquid chromatography/mass spectrometry in D+T-treated metastatic melanoma patients. We analyzed results at steady state (≥2 d for D, 24 d for T after introduction or dose modification) and far from peak concentrations (8 to 14.5 h for D and 20-28 h for T). We collected data of tumor assessments (RECIST 1.1) prospectively stored in our database and AE (CTCAE 4.0) blinded to PCD/T results. Each AE was associated with the closest sample harvested to the beginning of AE, or in the absence of AE with the highest PCD/T level for each patient. Results: We analyzed 75 D and 58 T assays from 36 pts (19M/17F), treated with D+T for metastatic melanoma (Stage IV: N = 35), mostly in first line (69.4%). Initial D dose was 300 mg/d and 2 mg/d for T, reduced in 10 patients (27.7%) for AE: to 30% of D (N = 8) and 25% of T (N = 8). High interindividual variability of PCD (range: 4-945ng/mL, median 70.0) and of PCT (5-25ng/mL, median 8.6) was observed. No differences between mean PCD/T at the time of evaluations showing progressive disease (PD) compared to those without PD pts (146.6±111.6 and 9.3±2.1) and pts with complete (N = 11), partial (N = 1) or stable response (N = 1) (160.6±127.9, P = 0.81 and 10.6ng/mL±2.6, P = 0.29) were observed. No significant relationship was shown between PCD/T and body mass index (r = 0.22 and -0.31), age (p = 0.19 and 0.26), or between PCD/T and D (p = 0.11) or T (p = 0.17) doses, neither between elevated mean PCD/T and any most common AE. Conclusions: This study shows a high interindividual variability but failed to show a relationship between PCD or T and tumor response nor AE. One limit is we did not explore PC of D active metabolites (hydroxy-and desmethylD). It has been shown that there is an auto-induction of D; T inhibits P-gp, a D substrate, suggesting synergistic pharmacological interactions. Thus, D pharmacokinetic seems to be too complex to be easily monitored.

scholarly journals Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Science ◽  
2017 ◽  
Vol 359 (6371) ◽  
pp. 97-103 ◽  
Author(s):  
V. Gopalakrishnan ◽  
C. N. Spencer ◽  
L. Nezi ◽  
A. Reuben ◽  
M. C. Andrews ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Human Cancer ◽  
Alpha Diversity ◽  
Fecal Microbiome ◽  
Functional Differences ◽  
Programmed Cell Death 1 ◽  
Melanoma Patients ◽  
Immune Profiling

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

scholarly journals Dynamic Evolution and Correlation between Metabolites and Microorganisms during Manufacturing Process and Storage of Fu Brick Tea

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 703
Author(s):  
Jing Li ◽  
Ran Xu ◽  
Lixuan Zong ◽  
Joseph Brake ◽  
Lizeng Cheng ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Bacterial Species ◽  
Critical Factor ◽  
Tea Polyphenols ◽  
Dynamic Evolution ◽  
Manufacturing Processes ◽  
Microbial Fermentation ◽  
Microbial Composition ◽  
Tea Polysaccharides ◽  
Positive Correlations

Fu brick tea (FBT) is one of the major brands of dark tea. Microbial fermentation is considered the key step in the development of the special characteristics of FBT. The systemic corelationship of the microbiome and metabolomics during manufacture of Fu brick tea is not fully understood. In this study, we comprehensively explored the microbiome and metabolite dynamic evolution during the FBT manufacturing processes, and revealed decisive factors for the quality and safety of FBT based on the grouped methods of metabolomics combined with biochemical measurements, microbiome sequencing combined with quantitative polymerase chain reaction (PCR), and multiplex analysis. Both the microbiome and quantitative PCR showed that fungi displayed concentrated distribution characteristics in the primary dark tea samples, while bacterial richness increased during the flowering processes and ripening period. All microorganism species, as well as dominant fungi and bacteria, were identified in the distinct processes periods. A total of 178 metabolites were identified, and 34 of them were characterized as critical metabolites responsible for metabolic changes caused by the corresponding processes. Metabolic analysis showed that most metabolites were decreased during the FBT manufacturing processes, with the exception of gallic acid. Multivariate analysis verified that the critical metabolites were correlated with specific dominant microbial species. All the top fungal species except unclassified_g_ Aspergillus showed positive correlations with six critical metabolites (L-The, epigallocatechin (EGC), Gln, tea polyphenol (TP), tea polysaccharides (TPs) and caffeine). Five of the top bacteria species (Cronobacter, Klebsiella, Pantoea, Pluralibacter, and unclassified_ f_Entero-bacteriaceae) showed positive correlations with epigallocatechins and tea polyphenols, while the other 11 top bacterial species correlated negatively with all the critical metabolites. The content of amino acids, tea polyphenols, tea polysaccharides, and flavonoids was reduced during microbial fermentation. In conclusion, our results reveal that microbial composition is the critical factor in changing the metabolic profile of FBT. This discovery provides a theoretical basis for improving the quality of FBT and enhancing its safety.

scholarly journals Cross-feeding between Bifidobacterium infantis and Anaerostipes caccae on lactose and human milk oligosaccharides

2018 ◽  
Author(s):  
Loo Wee Chia ◽  
Marko Mank ◽  
Bernadet Blijenberg ◽  
Roger S. Bongers ◽  
Steven Aalvink ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Human Milk ◽  
Early Life ◽  
Bacterial Species ◽  
Bifidobacterium Longum ◽  
Human Milk Oligosaccharides ◽  
Microbial Composition ◽  
Milk Oligosaccharides ◽  
Important Species ◽  
Key Species

AbstractThe establishment of the gut microbiota immediately after birth is a dynamic process that may impact lifelong health. At this important developmental stage in early life, human milk oligosaccharides (HMOS) serve as specific substrates to promote the growth of gut microbes, particularly the group of Actinobacteria (bifidobacteria). Later in life, this shifts to the colonisation of Firmicutes and Bacteroidetes, which generally dominate the human gut throughout adulthood. The well-orchestrated transition is important for health, as an aberrant microbial composition and/or SCFA production are associated with colicky symptoms and atopic diseases in infants. Here, we study the trophic interactions between an HMOS-degrader, Bifidobacterium longum subsp. infantis and the butyrogenic Anaerostipes caccae using carbohydrate substrates that are relevant in this early life period, i.e. lactose and HMOS. Mono-and co-cultures of these bacterial species were grown at pH 6.5 in anaerobic bioreactors supplemented with lactose or total human milk carbohydrates (containing both lactose and HMOS). A cac was not able to grow on these substrates except when grown in co-culture with B. inf, leading concomitant butyrate production. Cross-feeding was observed, in which A. cac utilised the liberated monosaccharides as well as lactate and acetate produced by B. inf. This microbial cross-feeding is indicative of the key ecological role of bifidobacteria in providing substrates for other important species to colonise the infant gut. The symbiotic relationship between these key species contributes to the gradual production of butyrate early in life that could be important for host-microbial cross-talk and gut maturation.ImportanceThe establishment of a healthy infant gut microbiota is crucial for the immune, metabolic and neurological development of infants. Recent evidence suggests that an aberrant gut microbiota early in life could lead to discomfort and predispose infants to the development of immune related diseases. This paper addresses the ecosystem function of two resident microbes of the infant gut. The significance of this research is the proof of cross-feeding interactions between HMOS-degrading bifidobacteria and a butyrate-producing microorganism. Bifidobacteria in the infant gut that support the growth and butyrogenesis of butyrate-producing bacteria, could orchestrated an important event of maturation for both the gut ecosystem and physiology of infant.

scholarly journals Gut microbial communities modulate efficacy of albendazole-ivermectin against soil-transmitted helminthiases

2021 ◽  
Author(s):  
Pierre H.H. Schneeberger ◽  
Morgan Gueuning ◽  
Sophie Welsche ◽  
Eveline Hürlimann ◽  
Julian Dommann ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Combination Therapy ◽  
Bacterial Species ◽  
Trichuris Trichiura ◽  
Post Treatment ◽  
Rrna Gene ◽  
Microbial Composition ◽  
Stool Samples ◽  
Pre Treatment ◽  
Cure Rates

AbstractBackgroundSoil-transmitted helminth infections represent a large burden across the globe with over a quarter of the world’s population at risk. The outcome of available treatments is species-specific with a large proportion of unexplained treatment failure. Administration of albendazole is the standard of care, but because of low cure rates (CR) observed in treating Trichuris trichiura infections, a significantly more efficacious alternative therapy combining albendazole and ivermectin is being investigated.Methods80 patients from the village of Pak-Khan, in Laos, with confirmed STH infections (Trichuris trichiura and hookworms), received either albendazole (400 mg) or albendazole (400 mg) and ivermectin (200 µg/kg) together. A pre-treatment stool sample was collected as well as daily post-treatment stool samples for up to 28 days to measure treatment efficacy. Taxonomic profiling of pre-treatment stool samples was conducted using 16S rRNA gene sequencing, target-specific and total bacteria qPCR, as well as shotgun sequencing.ResultsThree bacterial communities, or enterotypes (ET) 1-3, were identified. No association with pre-treatment enterotype and treatment outcome of both Trichuris trichiura and hookworm were found in the monotherapy arm with overall cure rates (CR) of 7.5% and 50%, respectively. Pre-treatment enterotype was strongly associated with efficacy of the combination therapy for both, T. trichiura (CRoverall = 33.3%; CRET1 = 5.8%; CRET2 = 16.6%; CRET3 = 68.5%) and hookworm (CRoverall = 47.2%; CRET1 = 31.2%; CRET2 = 16.6%; CRET3 = 78.5%) infections. Daily post-treatment egg per gram of stool counts recapitulated these observations and faster and increased egg reduction was observed in ET3 when compared to failure-associated ET1 and ET2. Species-level comparisons of these enterotypes highlighted a set of ten differentially enriched bacterial species.ConclusionTaxonomically distinct gut microbiota communities were found in this setting in terms of both, relative and absolute abundances, of specific bacterial taxa. Pre-treatment enterotype was relevant for treatment outcome of the combination therapy, albendazole and ivermectin, for T. trichiura as well as for hookworm infections. These observations indicate that pre-treatment microbial composition of stool samples should be monitored to ensure evidence-based administration of albendazole-ivermectin to treat these diseases.

scholarly journals Transient Effect of Infant Formula Supplementation on the Intestinal Microbiota

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 807
Author(s):  
Ning Chin ◽  
Gema Méndez-Lagares ◽  
Diana H. Taft ◽  
Victoria Laleau ◽  
Hung Kieu ◽  
...  
Keyword(s):  
16S Rrna ◽  
Gut Microbiome ◽  
Bacterial Species ◽  
Bifidobacterium Longum ◽  
The United States ◽  
16S Rrna Sequencing ◽  
T Cell Subsets ◽  
Rrna Sequencing ◽  
Stool Samples ◽  
The Impact

Breastfeeding is the gold standard for feeding infants because of its long-term benefits to health and development, but most infants in the United States are not exclusively breastfed in the first six months. We enrolled 24 infants who were either exclusively breastfed or supplemented with formula by the age of one month. We collected diet information, stool samples for evaluation of microbiotas by 16S rRNA sequencing, and blood samples for assessment of immune development by flow cytometry from birth to 6 months of age. We further typed the Bifidobacterium strains in stool samples whose 16S rRNA sequencing showed the presence of Bifidobacteriaceae. Supplementation with formula during breastfeeding transiently changed the composition of the gut microbiome, but the impact dissipated by six months of age. For example, Bifidobacterium longum, a bacterial species highly correlated with human milk consumption, was found to be significantly different only at 1 month of age but not at later time points. No immunologic differences were found to be associated with supplementation, including the development of T-cell subsets, B cells, or monocytes. These data suggest that early formula supplementation, given in addition to breast milk, has minimal lasting impact on the gut microbiome or immunity.

Galacto- and Fructo-oligosaccharides Utilized for Growth by Cocultures of Bifidobacterial Species Characteristic of the Infant Gut

2020 ◽  
Author(s):  
Ian Sims ◽  
GW Tannock
Keyword(s):  
Breast Milk ◽  
Bacterial Species ◽  
Bifidobacterium Longum ◽  
Well Being ◽  
Bifidobacterium Bifidum ◽  
Child Rearing ◽  
Potential Growth ◽  
Human Infants ◽  
Infant Diet ◽  
Growth Substrates

Copyright © 2020 American Society for Microbiology. Bifidobacterial species are common inhabitants of the gut of human infants during the period when milk is a major component of the diet. Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium longum subspecies longum, and B. longum subspecies infantis have been detected frequently in infant feces, but B. longum subsp. infantis may be disadvantaged numerically in the gut of infants in westernized countries. This may be due to the different durations of breast milk feeding in different countries. Supplementation of the infant diet or replacement of breast milk using formula feeds is common in Western countries. Formula milks often contain galacto- and/or fructo-oligosaccharides (GOS and FOS, respectively) as additives to augment the concentration of oligosaccharides in ruminant milks, but the ability of B. longum subsp. infantis to utilize these potential growth substrates when they are in competition with other bifidobacterial species is unknown. We compared the growth and oligosaccharide utilization of GOS and FOS by bifidobacterial species in pure culture and coculture. Short-chain GOS and FOS (degrees of polymerization [DP] 2 and 3) were favored growth substrates for strains of B. bifidum and B. longum subsp. longum, whereas both B. breve and B. longum subsp. infantis had the ability to utilize both short- and longer-chain GOS and FOS (DP 2 to 6). B. breve was nevertheless numerically dominant over B. longum subsp. infantis in cocultures. This was probably related to the slower use of GOS of DP 3 by B. longum subsp. infantis, indicating that the kinetics of substrate utilization is an important ecological factor in the assemblage of gut communities.IMPORTANCE The kinds of bacteria that form the collection of microbes (the microbiota) in the gut of human infants may influence health and well-being. Knowledge of how the composition of the infant diet influences the assemblage of the bacterial collection is therefore important because dietary interventions may offer opportunities to alter the microbiota with the aim of improving health. Bifidobacterium longum subspecies infantis is a well-known bacterial species, but under modern child-rearing conditions it may be disadvantaged in the gut. Modern formula milks often contain particular oligosaccharide additives that are generally considered to support bifidobacterial growth. However, studies of the ability of various bifidobacterial species to grow together in the presence of these oligosaccharides have not been conducted. These kinds of studies are essential for developing concepts of microbial ecology related to the influence of human nutrition on the development of the gut microbiota.

Gamma knife radiosurgery for intracranial metastatic melanoma: a 6-year experience

2002 ◽  
Vol 97 ◽  
pp. 494-498 ◽  
Author(s):  
Jorge Gonzalez-martinez ◽  
Laura Hernandez ◽  
Lucia Zamorano ◽  
Andrew Sloan ◽  
Kenneth Levin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Gamma Knife Radiosurgery ◽  
Tumor Control ◽  
Karnofsky Performance Scale ◽  
Content Type ◽  
Significant Difference ◽  
The Mean ◽  
Fine Print

Object. The purpose of this study was to evaluate retrospectively the effectiveness of stereotactic radiosurgery for intracranial metastatic melanoma and to identify prognostic factors related to tumor control and survival that might be helpful in determining appropriate therapy. Methods. Twenty-four patients with intracranial metastases (115 lesions) metastatic from melanoma underwent radiosurgery. In 14 patients (58.3%) whole-brain radiotherapy (WBRT) was performed, and in 12 (50%) chemotherapy was conducted before radiosurgery. The median tumor volume was 4 cm3 (range 1–15 cm3). The mean dose was 16.4 Gy (range 13–20 Gy) prescribed to the 50% isodose at the tumor margin. All cases were categorized according to the Recursive Partitioning Analysis classification for brain metastases. Univariate and multivariate analyses of survival were performed to determine significant prognostic factors affecting survival. The mean survival was 5.5 months after radiosurgery. The analyses revealed no difference in terms of survival between patients who underwent WBRT or chemotherapy and those who did not. A significant difference (p < 0.05) in mean survival was observed between patients receiving immunotherapy or those with a Karnofsky Performance Scale (KPS) score of greater than 90. Conclusions. The treatment with systemic immunotherapy and a KPS score greater than 90 were factors associated with a better prognosis. Radiosurgery for melanoma-related brain metastases appears to be an effective treatment associated with few complications.

scholarly journals Ingestion of probiotic (Lactobacillus helveticus and Bifidobacterium longum) alters intestinal microbial structure and behavioral expression following social defeat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katherine A. Partrick ◽  
Anna M. Rosenhauer ◽  
Jérémie Auger ◽  
Amanda R. Arnold ◽  
Nicole M. Ronczkowski ◽  
...  
Keyword(s):  
Social Stress ◽  
Bifidobacterium Longum ◽  
Social Defeat ◽  
Lactobacillus Helveticus ◽  
Rrna Gene ◽  
Social Avoidance ◽  
Social Defeat Stress ◽  
Microbial Structure ◽  
Microbial Composition ◽  
Anti Inflammatory

AbstractSocial stress exacerbates anxious and depressive behaviors in humans. Similarly, anxiety- and depressive-like behaviors are triggered by social stress in a variety of non-human animals. Here, we tested whether oral administration of the putative anxiolytic probiotic strains Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces the striking increase in anxiety-like behavior and changes in gut microbiota observed following social defeat stress in Syrian hamsters. We administered the probiotic at two different doses for 21 days, and 16S rRNA gene amplicon sequencing revealed a shift in microbial structure following probiotic administration at both doses, independently of stress. Probiotic administration at either dose increased anti-inflammatory cytokines IL-4, IL-5, and IL-10 compared to placebo. Surprisingly, probiotic administration at the low dose, equivalent to the one used in humans, significantly increased social avoidance and decreased social interaction. This behavioral change was associated with a reduction in microbial richness in this group. Together, these results demonstrate that probiotic administration alters gut microbial composition and may promote an anti-inflammatory profile but that these changes may not promote reductions in behavioral responses to social stress.

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