First-in-class microbial ecosystem therapeutics 4 (MET4) in metastatic solid cancer patients treated with immunotherapy: MET4-IO.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3098-3098 ◽  
Author(s):  
Daniel Vilarim Araujo ◽  
Marc Oliva Bernal ◽  
Tira Jing Ying Tan ◽  
Alya Abbas Heirali ◽  
Pierre H.H. Schneeberger ◽  
...  
Keyword(s):  
Cancer Patients ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Solid Cancer ◽  
Fecal Transplant ◽  
Additional Time ◽  
Microbial Ecosystem ◽  
Shannon Diversity ◽  
To Receive

3098 Background: Therapeutic augmentation of the intestinal microbiome to improve immunotherapy outcomes is an active area of investigation. Microbial Ecosystem Therapeutics (METs) are consortia of human-derived bacteria designed to be reproducible, scalable and safe alternatives to fecal transplant. MET4 is a first-in-class consortium of taxa associated with immune checkpoint inhibitor (ICI)-responsiveness. Here we describe preliminary results of MET4-IO, an interventional trial assessing the safety and ecological effects of MET4 in ICI recipients. Methods: MET4-IO is a randomized investigator-initiated trial, evaluating MET4 in solid cancer patients treated with ICI. MET4-IO involves 3 cohorts of 65 total patients: Group A, a safety cohort of 5 patients already on ICI; Group B, patients starting ICI, randomized 3:1 to receive MET4 or not; Group C, patients on ICI who experience radiological progression but not clinical deterioration, randomized 1:1 to receive MET4 or not. Stool and blood samples are collected at baseline and 4-5 additional time-points. For this interim analysis, 16S rRNA gene sequencing was performed on fecal specimens. Shannon diversity, relative abundance (RA), number and fold-change of MET4 taxa > RA 0.01 were assessed and compared to controls. Results: As of January 26, 2020, 21 patients were enrolled (A = 5,B = 12,C = 4), and 15 (71%) received MET4. The mean age was 65.9 years, 40% were females, 52% had head and neck cancer and 19% melanoma. Sixteen patients (76%) were treated with an anti-PD1 agent as monotherapy and 5 with a combination of anti-PD1 and anti-CTLA4 antibodies. G3-4 toxicities (CTCAEv5.0) attributed to ICI were observed in 13% vs. 17% of MET4 exposed and control patients, respectively. Three patients (20%) experienced toxicities attributed to MET4, all grade 1 except G2 dyspepsia in 1 patient. A greater number of MET4-associated taxa were detectable in MET4 recipients than controls (p < 0.01), with a trend towards higher cumulative RA (p = 0.10). No significant change in Shannon diversity after MET4 was observed, however controls were more likely to lose diversity overtime than MET4 recipients (p = 0.05). Colonization with MET4 varied by recipient and by taxon. Bifidobacterium, Collinsella and Enterococcus were significantly more common and abundant in MET4 recipients than controls. Conclusions: In this cohort, MET4 treatment was safe and associated with higher MET4-associated taxa in recipients than controls. Further analyses including peripheral blood immunophenotyping are ongoing. Clinical trial information: NCT03686202 .

scholarly journals The intestinal microbiome, weight, and metabolic changes in women treated by adjuvant chemotherapy for breast and gynecological malignancies

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Atara Uzan-Yulzari ◽  
Maya Morr ◽  
Hala Tareef-Nabwani ◽  
Oren Ziv ◽  
Dafna Magid-Neriya ◽  
...  
Keyword(s):  
Weight Gain ◽  
Adjuvant Chemotherapy ◽  
Fecal Microbiota Transplantation ◽  
Menopausal Status ◽  
16S Rrna Gene Sequencing ◽  
Metabolic Changes ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Fecal Transplant ◽  
Germ Free

Abstract Background Adjuvant chemotherapy induces weight gain, glucose intolerance, and hypertension in about a third of women. The mechanisms underlying these events have not been defined. This study assessed the association between the microbiome and weight gain in patients treated with adjuvant chemotherapy for breast and gynecological cancers. Methods Patients were recruited before starting adjuvant therapy. Weight and height were measured before treatment and 4–6 weeks after treatment completion. Weight gain was defined as an increase of 3% or more in body weight. A stool sample was collected before treatment, and 16S rRNA gene sequencing was performed. Data regarding oncological therapy, menopausal status, and antibiotic use was prospectively collected. Patients were excluded if they were treated by antibiotics during the study. Fecal transplant experiments from patients were conducted using Swiss Webster germ-free mice. Results Thirty-three patients were recruited; of them, 9 gained 3.5–10.6% of baseline weight. The pretreatment microbiome of women who gained weight following treatment was significantly different in diversity and taxonomy from that of control women. Fecal microbiota transplantation from pretreatment samples of patients that gained weight induced metabolic changes in germ-free mice compared to mice transplanted with pretreatment fecal samples from the control women. Conclusion The microbiome composition is predictive of weight gain following adjuvant chemotherapy and induces adverse metabolic changes in germ-free mice, suggesting it contributes to adverse metabolic changes seen in patients. Confirmation of these results in a larger patient cohort is warranted.

scholarly journals Changes in the Intestinal Microbiome during a Multispecies Probiotic Intervention in Compensated Cirrhosis

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1874 ◽  
Author(s):  
Angela Horvath ◽  
Marija Durdevic ◽  
Bettina Leber ◽  
Katharina di Vora ◽  
Florian Rainer ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Controlled Trial ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Microbiome Composition ◽  
Beneficial Effects ◽  
Compensated Cirrhosis ◽  
Gut Barrier Function ◽  
Probiotic Treatment

Probiotics have been used in trials to therapeutically modulate the gut microbiome and have shown beneficial effects in cirrhosis. However, their effect on the microbiome of cirrhosis patients is not fully understood yet. Here, we tested the effects of a multispecies probiotic on microbiome composition in compensated cirrhosis. The gut microbiome composition of 58 patients with compensated cirrhosis from a randomized controlled trial who received a daily dose of multispecies probiotics or placebo for six months was analysed by 16S rRNA gene sequencing. Microbiome composition of patients who received probiotics was enriched with probiotic strains and the abundance of Faecalibacterium prausnitzii, Syntrophococcus sucromutans, Bacteroides vulgatus, Alistipes shahii and a Prevotella species was increased in the probiotic group compared to the placebo group. Patients who had microbiome changes in response to probiotic treatment also showed a significant increase in neopterin and a significant decrease in faecal zonulin levels after intervention, which was not observed in placebo-treated patients or patients with unchanged microbiome compositions. In conclusion, multispecies probiotics may enrich the microbiome of compensated cirrhotic patients with probiotic bacteria during a six-month intervention and beneficially change the residential microbiome and gut barrier function.

scholarly journals The Vibrio cholerae T6SS is Dispensable for Colonization but Affects Pathogenesis and the Structure of Zebrafish Intestinal Microbiome

2021 ◽  
Author(s):  
Paul Breen ◽  
Andrew D. Winters ◽  
Kevin R. Theis ◽  
Jeffrey H. Withey
Keyword(s):  
Vibrio Cholerae ◽  
Model Organism ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Model Organisms ◽  
Rrna Gene ◽  
Composition And Structure ◽  
Aquatic Microbes ◽  
Host Microbe Interactions ◽  
Rrna Gene Sequencing

Zebrafish ( Danio rerio ) are an attractive model organism for a variety of scientific studies, including host-microbe interactions. The organism is particularly useful for the study of aquatic microbes that can colonize vertebrate hosts, including Vibrio cholerae , an intestinal pathogen. V. cholerae must colonize the intestine of an exposed host for pathogenicity to occur. While numerous studies have explored various aspects of the pathogenic effects of V. cholerae on zebrafish and other model organisms, few, if any, have examined how a V. cholerae infection alters the resident intestinal microbiome and the role of the type six secretion system (T6SS) in that process. In this study, 16S rRNA gene sequencing was utilized to investigate how strains of V. cholerae both with and without the T6SS alter the aforementioned microbial profiles following an infection. V. cholerae infection induced significant changes in the zebrafish intestinal microbiome, and while not necessary for colonization, the T6SS was essential for inducing mucin secretion, a marker for diarrhea. Additional salient differences to the microbiome were observed based on the presence or absence of the T6SS in the V. cholerae utilized for challenging the zebrafish hosts. We conclude that V. cholerae significantly modulates the zebrafish intestinal microbiome to enable colonization and that the T6SS is important for pathogenesis induced by the examined V. cholerae strains. Furthermore, presence or absence of T6SS differentially and significantly affected the composition and structure of the intestinal microbiome, with an increased abundance of other Vibrio bacteria observed in the absence of V. cholerae T6SS.

scholarly journals Effect of a Laminarin Rich Macroalgal Extract on the Caecal and Colonic Microbiota in the Post-Weaned Pig

Marine Drugs ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 157 ◽  
Author(s):  
Stafford Vigors ◽  
John V O’Doherty ◽  
Ruth Rattigan ◽  
Mary J McDonnell ◽  
Gaurav Rajauria ◽  
...  
Keyword(s):  
Feed Intake ◽  
Volatile Fatty Acids ◽  
Control Diet ◽  
Average Daily Gain ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Rrna Gene Sequencing ◽  
The Impact ◽  
Negative Relationships

Dietary supplementation with 300 ppm of a laminarin rich macroalgal extract reduces post-weaning intestinal dysfunction in pigs. A comprehensive analysis of the impact of laminarin on the intestinal microbiome during this period is essential to inform on the mode of action of this bioactivity. The objective of this study was to evaluate the effects of supplementing the diet of newly weaned pigs with 300 ppm of a laminarin rich extract, on animal performance, volatile fatty acids, and the intestinal microbiota using 16S rRNA gene sequencing. Pigs fed the laminarin-supplemented diet had higher average daily feed intake, growth rate, and body weight compared to pigs fed the control diet (p < 0.05). Pigs fed the laminarin-supplemented diet had reduced abundance of OTUs assigned to Enterobacteriaceae and increased abundance of OTUs assigned to the genus Prevotella (p < 0.05) compared to pigs fed the control diet. Enterobacteriaceae had negative relationships (p < 0.05) with average daily feed intake (ADFI), average daily gain (ADG), and butyric acid concentrations. In contrast, Prevotellaceae were positively correlated (p < 0.05) with ADFI, ADG, total VFA, acetic, propionic, butyric acids, and negatively correlated with isovaleric acid. Hence supplementation with a laminarin enriched extract potentially improves performance during the post-weaning period by promoting the proliferation of bacterial taxa such as Prevotella that favourably enhance nutrient digestion while reducing the load of potentially pathogenic bacterial taxa including Enterobacteriaceae.

scholarly journals Gut Microbiome Analysis As A Non-Invasive Tool for the Early Diagnosis of Cholangiocarcinoma

2021 ◽  
Author(s):  
Jialiang Li ◽  
Xueyan Li ◽  
Sina Zhang ◽  
Chen Jin ◽  
Zixia Lin ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Microbial Community Composition ◽  
Intestinal Flora ◽  
Alpha Diversity ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Non Invasive ◽  
Hepatobiliary Cancer

Abstract BACKGROUNDThe liver-microbiome axis is implicated in the pathogenesis of hepatobiliary cancer, and the role of the gut microbiota in cholangiocarcinoma (CCA) remains unclear.METHODWe conducted a case-control study on the intestinal flora of 33 CCA patients and 47 cholelithiasis individuals. We performed 16S rRNA gene sequencing to identify disease-related gut microbiota and assess the potential of the intestinal microbiome as a non-invasive biomarker for CCA.RESULTWe found that gut microbiome of CCA patients had a significantly higher alpha diversity (Shannon and Observed species indices, p = 0.006 and p = 0.02, respectively) and an overall different microbial community composition (p = 0.032). The genus Muribaculaceae_unclassified was most strongly associated with CCA (p < 0.001). We put forward a disease predictive model including twelve intestinal microbiome genera distinguished CCA patients from CF patients with an area under curve (AUC) of approximately 0.93 (95%CI, 0.85–0.987). The forecasting performance of this model was better than CA19-9. Moreover, genera Ezakiella and Garciella were only observed among intrahepatic cholangiocarcinoma patients. Further, we assessed predicted functional modules alternations CCA patients and uncovered a microbiota pattern specific to CCA.CONCLUSIONOur findings provide evidence of the intestinal microbiome as a non-invasive biomarker for CCA.

scholarly journals Psoriasis is associated with elevated gut IL-1α and intestinal microbiome alterations: results of a cross-sectional study from Central Asia.

2020 ◽  
Author(s):  
Sergey Yegorov ◽  
Dmitriy Babenko ◽  
Samat Kozhakhmetov ◽  
Lyudmila Akhmaltdinova ◽  
Irina Kadyrova ◽  
...  
Keyword(s):  
Microbial Diversity ◽  
Disease Status ◽  
16S Rrna Gene Sequencing ◽  
Cross Sectional Study ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Sectional Study ◽  
Cross Sectional ◽  
Dermatology Clinic ◽  
Chronic Inflammatory Condition

Objective: Psoriasis is a chronic inflammatory condition that predominantly affects the skin and is associated with extracutaneous disorders, such as inflammatory bowel disease and arthritis. Changes in gut immunology and microbiota are important drivers of proinflammatory disorders and could play a role in the pathogenesis of psoriasis. Therefore, we explored whether psoriasis in a Central Asian cohort is associated with alterations in select immunological markers and/or microbiota of the gut. Setting: We assessed correlates of psoriasis in a community from Kazakhstan. Participants: Outpatients, aged 30-45 years, of a dermatology clinic presenting with plaque, guttate or palmoplantar psoriasis (n=20), and age-sex matched subjects without psoriasis (n=20). Design: We undertook a cross-sectional study of stool samples. Stool supernatant was subjected to multiplex ELISA to assess the concentration of 47 cytokines and immunoglobulins and to 16S rRNA gene sequencing to characterize microbial diversity in both psoriasis+ participants and controls. Results: The psoriasis+ group tended to have higher concentrations of most analytes in stool (29/47=61.7%) and gut IL-1α was significantly elevated (4.19-fold, p=0.007) compared to controls. Psoriasis was associated with alterations in gut Firmicutes, including elevated Faecalibacterium and decreased Oscillibacter and Roseburia abundance, but no association was observed between gut microbial diversity or Firmicutes/Bacteroidetes ratios and disease status. Conclusions: Psoriasis may be associated with gut inflammation and dysbiosis. Studies are warranted to explore the use of gut microbiome-focused therapies in the management of psoriasis in this under-studied population.

scholarly journals IgA deficiency destabilizes immunological homeostasis towards intestinal microbiota and increases the risk of systemic immune dysregulation

2021 ◽  
Author(s):  
Peyton E Conrey ◽  
Lidiya Denu ◽  
Kaitlin C. O'Boyle ◽  
Jamal Green ◽  
Jeffrey Maslanka ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Intestinal Barrier ◽  
16S Rrna Gene Sequencing ◽  
Immune Dysregulation ◽  
Iga Deficiency ◽  
Fecal Microbiota ◽  
Intestinal Microbiome ◽  
Secretory Iga ◽  
Rrna Gene

Mammals produce large quantities of mucosal and systemic antibodies that maintain the intestinal barrier, shape the intestinal microbiome and promote lifelong mutualism with commensal microbes. Here, we developed an integrated host-commensal approach combining microbial flow cytometry and 16s rRNA gene sequencing to define the core microbes that induce mucosal and systemic antibodies in pediatric selective Immunoglobulin A (IgA) deficient and household control siblings with CyTOF analysis to determine the impacts of IgA deficiency on host cellular immune phenotype. In healthy controls, mucosal secretory IgA and IgM antibodies coat an overlapping subset of microbes, predominantly Firmicutes and Proteobacteria. Serum IgG antibodies target a similar consortium of fecal microbes, revealing connections between mucosal and systemic antibody networks. Unexpectedly, IgM provides limited compensation for IgA in children lacking intestinal IgA. Furthermore, we find broad systemic immune dysregulation in a subset of children and mice lacking IgA, including enhanced IgG targeting of fecal microbiota, elevated levels of inflammatory and allergic cytokines and alterations in T cell activation state. Thus, IgA tunes systemic interactions between the host and commensal microbiota. Understanding how IgA tunes baseline immune tone has implications for predicting and preventing autoimmune, inflammatory and allergic diseases broadly, as well as providing improved prognostic guidance to patients with IgA deficiency.

scholarly journals Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Catherine E Oldenburg ◽  
Ali Sié ◽  
Boubacar Coulibaly ◽  
Lucienne Ouermi ◽  
Clarisse Dah ◽  
...  
Keyword(s):  
Preschool Children ◽  
Diversity Index ◽  
Controlled Trial ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Once Daily ◽  
Microbiome Composition ◽  
Α Diversity ◽  
Rrna Gene Sequencing

Abstract Background Exposure to antibiotics may result in alterations to the composition of intestinal microbiota. However, few trials have been conducted, and observational studies are subject to confounding by indication. We conducted a randomized controlled trial to determine the effect of 3 commonly used pediatric antibiotics on the intestinal microbiome in healthy preschool children. Methods Children aged 6–59 months were randomized (1:1:1:1) to a 5-day course of 1 of 3 antibiotics, including amoxicillin (25 mg/kg/d twice-daily doses), azithromycin (10 mg/kg dose on day 1 and then 5 mg/kg once daily for 4 days), cotrimoxazole (240 mg once daily), or placebo. Rectal swabs were obtained at baseline and 5 days after the last dose and were processed using 16S rRNA gene sequencing. The prespecified primary outcome was inverse Simpson’s α-diversity index. Results Post-treatment Simpson’s diversity was significantly different across the 4 arms (P = .003). The mean Simpson’s α-diversity among azithromycin-treated children was significantly lower than in placebo-treated children (6.6; 95% confidence interval [CI], 5.5–7.8; vs 9.8; 95% CI, 8.7–10.9; P = .0001). Diversity in children treated with amoxicillin (8.3; 95% CI, 7.0–9.6; P = .09) or cotrimoxazole (8.3; 95% CI, 8.2–9.7; P = .08) was not significantly different than placebo. Conclusions Azithromycin affects the composition of the pediatric intestinal microbiome. The effect of amoxicillin and cotrimoxazole on microbiome composition was less clear. Clinical Trials Registration clinicaltrials.gov NCT03187834.

scholarly journals Dissection of the gut microbiota in mothers and children with chronic Trichuris trichiura infection in Pemba Island, Tanzania

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hongliang Chen ◽  
Matteo Mozzicafreddo ◽  
Elisa Pierella ◽  
Vanessa Carletti ◽  
Angela Piersanti ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neglected Tropical Diseases ◽  
16S Rrna Gene Sequencing ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Pemba Island ◽  
Life Years ◽  
Degrading Bacteria ◽  
Mothers And Children ◽  
Rrna Gene Sequencing

Abstract Background Soil-transmitted helminthiases are important neglected tropical diseases that result in a notably high number of disability-adjusted life years worldwide. Characterizing the interactions between the human intestinal microbiome and helminths is of interest in the development of alternative treatments that do not rely on chemotherapeutics and do not lead to drug resistance. Methods We recruited and obtained fecal samples from 32 pairs of mothers and children on Pemba Island and monitored their intestinal microbiota using 16S rRNA gene sequencing. Results We observed that microbial changes occur in the gut microbiota of infected mothers and children. Some short-chain fatty acid (SCFA)-producing bacteria and carbohydrate-degrading bacteria exhibited lower abundance in the infected individuals. Potentially pathogenic Campylobacter and proinflammatory Methanobrevibacter in infected mothers and opportunistic Enterococcus in infected children exhibited greater abundance. Conclusions Our findings could reveal the microbiota profiling in T. trichiura-infected individuals, indicate the potential roles of key microbiota in the host and aid to the development of novel strategies to control T. trichiura infection. Graphic abstract

scholarly journals Oral Vaccination against Lawsoniaintracellularis Changes the Intestinal Microbiome in Weaned Piglets

Animals ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 2082
Author(s):  
Robin B. Guevarra ◽  
Jae Hyoung Cho ◽  
Jin Ho Cho ◽  
Jun Hyung Lee ◽  
Hyeri Kim ◽  
...  
Keyword(s):  
Block Design ◽  
Alpha Diversity ◽  
16S Rrna Gene Sequencing ◽  
Fecal Microbiota ◽  
Negative Control ◽  
Intestinal Microbiome ◽  
Rrna Gene ◽  
Significant Shift ◽  
Diversity Analysis ◽  
Treatment Groups

Lawsoniaintracellularis, which causes porcine proliferative enteropathy (PPE), is a common swine intestinal pathogen that is prevalent in pig production sites worldwide. In this study, the alteration in the microbiome composition of weaned pigs was investigated in response to vaccination against L. intracellularis, using 16S rRNA gene sequencing. A total of 64 crossbred (Duroc × [Landrace × Yorkshire]) healthy weanling pigs weaned at 4 weeks of age were randomly assigned to four treatment groups (four pigs/pen; four pens/treatment), using a randomized complete block design for the 42-day trial. Pigs in the treatment groups were orally administered with three different doses (1 dose = 2 mL) of vaccine against L. intracellularis (Enterisol® Ileitis, Boehringer Ingelheim Vetmedica GmbH), namely the following: LAW1 (0.5 dose), LAW2 (1 dose), LAW3 (2 dose). A non-vaccinated group served as a negative control (CONT). Alpha diversity analysis revealed that vaccination led to significant changes in species evenness but not species richness of the gut microbiota. Beta diversity analysis revealed that vaccination against L. intracellularis caused a significant shift in the microbial community structure. At the genus level, there was a significant increase in Streptococcus and a significant decrease in Clostridium in the fecal microbiota of vaccinated pigs, regardless of dose.

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