Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

Zhang, Feiyu; Ferrero, Macarena; Dong, Ning; D’Auria, Giuseppe; Reyes-Prieto, Mariana; Herreros‐Pomares, Alejandro; Calabuig, Silvia; Duréndez, E.; Aparisi, Francisco; Blasco, Ana; Garcia, Clara B. Calderon; Camps, Carlos; Jantus‐Lewintre, Eloísa; Sirera, Rafael

doi:10.3390/cancers13112514

Cited by 23 publications

(20 citation statements)

References 69 publications

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“…Recent studies have demonstrated that gut microbiome is associated with NSCLC progression. Patients with higher gut microbiota alpha diversity ( Zhang C. et al., 2021 ), and those enriched in some microbes, such as Phascolarctobacterium ( Zhang F. et al., 2021 ), Ruminococcaceae UCG 13 , and Agathobacter ( Hakozaki et al., 2020 ), were found to have better PFS. In the current study, we found that the long-PFS group had the highest F/B value and significantly higher diversity in Fungi, Archaea, and Viruses among three groups.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Gut Microbiota Signature and Microbe-Disease Progression Associations in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Concurrent Chemoradiotherapy

Liu

Qiu

et al. 2022

Front. Cell. Infect. Microbiol.

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PurposeTo evaluate the association of gut microbiome signature and disease progression in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) by fecal metagenome analysis.MethodsMetagenome-wide association studies on baseline fecal samples from 18 LA-NSCLC patients before CCRT and 13 controls from healthy first-degree relatives were performed. Among the 18 LA-NSCLC patients, six patients were defined as the long progression-free survival (long-PFS) group (PFS≥11 months) while another 12 were in the short-PFS group (PFS<11 months). Alpha diversity, taxonomic composition, and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways were compared between groups.ResultsThe Firmicutes/Bacteroidetes value of long-PFS group was higher than those of short-PFS (p=0.073) and healthy individual groups (p=0.009). Meanwhile, long-PFS group had significantly higher diversities in Fungi, Archaea, and Viruses than short-PFS group. The KEGG pathways overrepresented in short-PFS group included fructose and mannose metabolism (p=0.028), streptomycin biosynthesis (p=0.028), acarbose and validamycin biosynthesis (p=0.013), ribosome biogenesis in eukaryotes (p=0.035), biosynthesis of vancomycin group antibiotics (p=0.004), apoptosis-fly (p=0.044), and tetracycline biosynthesis (p=0.044), while those overrepresented in long-PFS group included fatty acid biosynthesis (p=0.035), fatty acid metabolism (p=0.008), vancomycin resistance (p=0.008), longevity regulating pathway-worm (p=0.028), type II diabetes mellitus (p=0.004), and viral carcinogenesis (p=0.003). Further analysis of antibiotic resistome demonstrated that the short-PFS group had a trend with more antibiotic resistance genes than healthy control (p=0.070) and long-PFS groups (p=0.218). The vancomycin resistance sequences were significantly enriched in the long-PFS group compared to the short-PFS group (p=0.006).ConclusionsThe baseline gut microbiome composition and functionality might be associated with PFS in LA-NSCLC treated with CCRT. The outcome of CCRT might be modulated through bacterial metabolic pathways. The antibiotic resistance genes might play a role in disease progression and provide potential information on the relationship between the use of antibiotics and treatment efficacy of CCRT in LA-NSCLC.

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Section: Discussionmentioning

confidence: 99%

Analysis of Gut Microbiota Signature and Microbe-Disease Progression Associations in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Concurrent Chemoradiotherapy

Liu

Qiu

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Bacteroides vulgatus has been associated with the reduced risk of immune-related adverse events ( Usyk et al, 2021 ), including dermatological skin toxicity (where B. dorei anti-correlated) ( Zhang et al, 2021 ). Furthermore, B. vulgatus has been shown to be protective against Escherichia coli induced colitis of interleukin-2-deficient gnotobiotic mice ( Waidmann et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Short-Term Metformin Treatment Enriches Bacteroides dorei in an Obese Liver Steatosis Zucker Rat Model

et al. 2022

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Obesity is the leading cause of health-related diseases in the United States and World. Previously, we reported that obesity can change gut microbiota using the Zucker rat model. Metformin is an oral anti-hyperglycemic agent approved by the FDA to treat type 2 diabetes (T2D) in adults and children older than 10 years of age. The correlation of short-term metformin treatment and specific alterations to the gut microbiota in obese models is less known. Short-term metformin has been shown to reduce liver steatosis. Here we investigate the effects of short-term metformin treatment on population of gut microbiota profile in an obese rat model. Five week old obese (n = 12) female Zucker rats after 1 week of acclimation, received AIN-93 G diet for 8 weeks and then rats were randomly assigned into two groups (6 rats/group): (1) obese without metformin (ObC), or (2) obese with metformin (ObMet). Metformin was mixed with AIN-93G diet at 1,000 mg/kg of diet. Rats were weighed twice per week. All rats were sacrificed at the end of metformin treatment at 10 weeks and fecal samples were collected and kept at −80°C. Total microbial DNA was collected directly from the fecal samples used for shotgun-metagenomics sequencing and subsequently analyzed using MetaPlAn and HUMAnN. After stringent data filtering and quality control we found significant differences (p = 0.0007) in beta diversity (Aitchison distances) between the ObC vs. ObMet groups. Supervised and unsupervised analysis of the log-ratios Bacteroides dorei and B. massiliensis vs. all other Bacteroides spp., revealed that B. dorei and B. massiliensis were enriched in the ObMet group, while the remaining Bacteroides spp. where enriched in the ObC group (p = 0.002). The contributional diversity of pathways is also significantly associated by treatment group (p = 0.008). In summary, in the obese Zucker rat model, short-term metformin treatment changes the gut microbiota profile, particularly altering the composition Bacteroides spp. between ObC and ObMet.

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“…Strikingly, the researchers were able to demonstrate in this study that the response effect could be transferred to mice with a poor response via a fecal microbiome transplant. Furthermore, B. vulgatus was also increased in non-small cell lung cancer patients that did not experience dermatological irAE, following PD1-based ICB treatment [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma

Usyk

Pandey²,

Hayes

et al. 2021

Genome Med

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Background Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB. Methods Pre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch. Results Two natural GMB clusters with distinct community compositions were identified from the analysis of 16S rRNA data (R2 = 0.16, p < 0.001). In Cox-proportional hazard modeling, these two clusters showed a near 7-fold differential risk for developing irAEs within 1 year of initiating treatment (HR = 6.89 [95% CI: 1.33–35.58]). Using shotgun metagenomics, we further identified 37 bacterial strains differentially expressed between the risk groups, with specific dominance of Bacteroides dorei within the high-risk GMB cluster and Bacteroides vulgatus in the low-risk cluster. The high-risk cluster also appeared to have elevated expression of several functional pathways, including those associated with adenosine metabolism (all FDR < 0.05). A sub-analysis of samples (n = 10 participants) at baseline and 6 and 12 weeks after the start of treatment revealed that the microbiome remained stable over the course of treatment (R2 = 0.88, p < 0.001). Conclusions We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients.

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Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

Cited by 23 publications

References 69 publications

Analysis of Gut Microbiota Signature and Microbe-Disease Progression Associations in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Concurrent Chemoradiotherapy

Analysis of Gut Microbiota Signature and Microbe-Disease Progression Associations in Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Concurrent Chemoradiotherapy

Short-Term Metformin Treatment Enriches Bacteroides dorei in an Obese Liver Steatosis Zucker Rat Model

Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma

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