Publications by authors named "Bertrand Routy"

55 Publications

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

Cell Death Differ 2021 May 7. Epub 2021 May 7.

Gustave Roussy Cancer Center, Villejuif, France.

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.
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http://dx.doi.org/10.1038/s41418-021-00784-1DOI Listing
May 2021

First clinical proof-of-concept that FMT can overcome resistance to ICIs.

Nat Rev Clin Oncol 2021 Mar 19. Epub 2021 Mar 19.

Hematology-Oncology Division, Department of Medicine, University of Montreal Healthcare Centre (CHUM), Montreal, Quebec, Canada.

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http://dx.doi.org/10.1038/s41571-021-00502-3DOI Listing
March 2021

Improvement of EGFR Testing over the Last Decade and Impact of Delaying TKI Initiation.

Curr Oncol 2021 Feb 26;28(2):1045-1055. Epub 2021 Feb 26.

Hematology and Medical Oncology Service, Centre Hospitalier Universitaire de Montreal, University of Montreal, Montreal, QC H2X 3E4, Canada.

Background: Epidermal growth factor receptor (EGFR) is the most common oncogenic mutation in lung adenocarcinoma and tyrosine kinase inhibitors (TKIs) have been considered standard treatment for more than a decade. However, time to initiation of TKIs (TTIT) from diagnosis is often delayed and represents a challenge for clinicians. We aimed to assess the impact of TTIT on clinical outcomes and complications.

Method: TTIT was defined as the time between confirmed advanced diagnosis and the initiation of a TKI. Complications during this pre-TKI period were retrospectively collected from all patients with EGFR-mutant non small cell lung cancer (NSCLC) in our institution.

Results: 102 patients were diagnosed with EGFR mutated NSCLC between 2006 and 2019. The median PFS and OS were 12.9 and 22.5 months, respectively. TTIT was 5.7 months (95% CI 3.4-8) with a significant decrease in the latter years of this cohort. During the pre-TKI period, 23 patients received chemotherapy as first line treatment, of which 5 developed severe adverse events and 3 were not fit to receive TKI thereafter. Additionally, 29 patients had rapid clinical deterioration before initiation of first line TKI and 16 had to be hospitalized. Among the patients presenting a performance status deterioration, their prognosis was markedly affected compared to the remainder of the cohort ( = 0.01).

Conclusion: Our real-world evidence study supports the concept that a delay to treat EGFR mutant NSCLC with TKIs is associated with adverse events, patient progression, hospitalization, and decreased overall survival. Rapid molecular diagnosis, including access to ctDNA technology may circumvent these deleterious delays.
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http://dx.doi.org/10.3390/curroncol28020102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025752PMC
February 2021

A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors.

Clin Cancer Res 2021 May 16;27(9):2571-2583. Epub 2021 Feb 16.

The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%-30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.

Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies ( = 303 unique patients) using a uniform computational approach.

Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis ( < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers ( = 105).

Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4834DOI Listing
May 2021

Survival Impact of Aggressive Treatment and PD-L1 Expression in Oligometastatic NSCLC.

Curr Oncol 2021 Jan 20;28(1):593-605. Epub 2021 Jan 20.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.

Background: Studies have shown that aggressive treatment of non-small cell lung cancer (NSCLC) with oligometastatic disease improves the overall survival (OS) compared to a palliative approach and some immunotherapy checkpoint inhibitors, such as anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death protein 1 (PD-1), and T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitors are now part of the standard of care for advanced NSCLC. However, the prognostic impact of PD-L1 expression in the oligometastatic setting remains unknown.

Methods: Patients with oligometastatic NSCLC were identified from the patient database of the Centre hospitalier de l'Université de Montréal (CHUM). "Oligometastatic disease" definition chosen is one synchronous metastasis based on the M1b staging of the eight IASLC (The International Association for the Study of Lung Cancer) Classification (within sixth months of diagnosis) or up to three cerebral metastasis based on the methodology of the previous major phase II randomized study of Gomez et al. We compared the OS between patients receiving aggressive treatment at both metastatic and primary sites (Group A) and patients receiving non-aggressive treatment (Group B). Subgroup analysis was performed using tumor PD-L1 expression.

Results: Among 643 metastatic NSCLC patients, we identified 67 patients with oligometastasis (10%). Median follow-up was 13.3 months. Twenty-nine patients (43%) received radical treatment at metastatic and primary sites (Group A), and 38 patients (57%) received non-aggressive treatment (Group B). The median OS (mOS) of Group A was significantly longer than for Group B (26 months vs. 5 months, = 0.0001). Median progression-free survival (mPFS) of Group A was superior than Group B (17.5 months vs. 3.4 months, = 0.0001). This difference was still significant when controlled for primary tumor staging: stage I ( = 0.316), stage II ( = 0.024), and stage III ( = 0.001). In the cohort of patients who were not treated with PD-L1 inhibitors, PD-L1 expression negatively correlated with mOS.

Conclusions: Aggressive treatments of oligometastatic NSCLC significantly improve mOS and mPFS compared to a more palliative approach. PD-L1 expression is a negative prognostic factor which suggests a possible role for immunotherapy in this setting.
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http://dx.doi.org/10.3390/curroncol28010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924378PMC
January 2021

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer.

J Cancer 2021 1;12(4):1125-1132. Epub 2021 Jan 1.

Infectious Disease and Immunity in Global Health Program, Research Institute of McGill University Health Centre, Montreal, QC, Canada.

Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer.
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http://dx.doi.org/10.7150/jca.50376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797663PMC
January 2021

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

Cell Death Differ 2020 Dec 1. Epub 2020 Dec 1.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.
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http://dx.doi.org/10.1038/s41418-020-00684-wDOI Listing
December 2020

Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: A real-world multicentre study.

Eur J Cancer 2021 01 24;142:83-91. Epub 2020 Nov 24.

Centre de Recherche Du Centre Hospitalier de L'Université de Montréal (CRCHUM), 900, Rue Saint-Denis, Pavillon R, H2X 0A9, Montreal, Quebec, Canada; Cedars Cancer Center, McGill University Healthcare Center (MUHC), 1001, Boulevard Décarie, H4A 3J1, Montreal, Quebec, Canada; Segal Cancer Center, Jewish General Hospital, 3755, Chemin de La Côte-Sainte-Catherine, H3T 1E2, Montreal, Quebec, Canada. Electronic address:

Background: The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups.

Methods: In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use.

Results: Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression <1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006).

Conclusions: This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.
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http://dx.doi.org/10.1016/j.ejca.2020.10.008DOI Listing
January 2021

Angiotensin-converting enzyme (ACE) inhibitor prescription affects non-small-cell lung cancer (NSCLC) patients response to PD-1/PD-L1 immune checkpoint blockers.

Oncoimmunology 2020 10 27;9(1):1836766. Epub 2020 Oct 27.

Department of Medical Oncology, GF Leclerc Centre, Dijon, France.

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients' co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, = .01 (HR = 1.8 CI95% 1.1-2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. , the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.
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http://dx.doi.org/10.1080/2162402X.2020.1836766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595630PMC
October 2020

The role of the gut microbiome on radiation therapy efficacy and gastrointestinal complications: A systematic review.

Radiother Oncol 2021 03 1;156:1-9. Epub 2020 Nov 1.

Centre de recherche de l'Université de Montréal, (CRCHUM), Montréal, QC, Canada; Centre hospitalier de l'Université de Montréal, (CHUM), Montréal, QC, Canada. Electronic address:

Radiation therapy (RT) is an essential component of therapy either curative or palliative armamentarium in oncology, but its efficacy varies considerably among patients through many extrinsic and intrinsic mechanisms of the tumour, which are beginning to be better understood. Recent studies have shown that the gut microbiome represents a key factor in the modulation of the systemic immune response and consequently on patients' outcome. Moreover, the emergence of biomarkers that are derived from the gut microbiota has fuelled the development of adjuvant strategies for patients treated with immunotherapy in combination or not with RT. Despite progress in development of more precise radiotherapy techniques, almost all patients undergoing RT to the abdomen, pelvis, or rectum develop acute adverse events as a consequence of several dose-limiting parameters such as the location of irradiation that may subsequently damage normal tissue including the intestinal epithelium. Several lines of evidence in preclinical models identified that vancomycin improves RT-induced gastrointestinal toxicities such as diarrhea and oral mucositis. In order to gain further insight into this rapidly evolving field, we have systematically reviewed the studies that have described how the gut microbiome may directly or indirectly modulate RT efficacy and its gastro-intestinal toxicities. Lastly, we outline current knowledge gaps and discuss potentially more satisfactory therapeutic options to restore the functionality of the gut microbiome of patients treated with RT.
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http://dx.doi.org/10.1016/j.radonc.2020.10.033DOI Listing
March 2021

Physiologic colonic uptake of F-FDG on PET/CT is associated with clinical response and gut microbiome composition in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

Eur J Nucl Med Mol Imaging 2021 May 31;48(5):1550-1559. Epub 2020 Oct 31.

Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Québec, Canada.

Background: Immune checkpoint inhibitors (ICI) represent the backbone treatment for advanced non-small cell lung cancer (NSCLC). Emerging data suggest that increased gut microbiome diversity is associated with favorable response to ICI and that antibiotic-induced dysbiosis is associated with deleterious outcomes. F-FDG physiologic colonic uptake on PET/CT increases following treatment with antibiotics (ATB) and could act as a surrogate marker for microbiome composition and predict prognosis. The aim of this study was to determine if F-FDG physiologic colonic uptake prior to ICI initiation correlates with gut microbiome profiling and clinical outcomes in patients with advanced NSCLC.

Methods: Seventy-one patients with advanced NSCLC who underwent a PET/CT prior to ICI were identified. Blinded colonic contouring was performed for each colon segment and patients were stratified according to the median of the average colon SUV as well as for each segment in low vs. high SUV groups. Response rate, progression-free survival (PFS), and overall survival (OS) were compared in the low vs. high SUV groups. Gut microbiome composition was analyzed for 23 patients using metagenomics sequencing.

Results: The high colon SUV group had a higher proportion of non-responders (p = 0.033) and significantly shorter PFS (4.1 vs. 11.3 months, HR 1.94, 95% CI 1.11-3.41, p = 0.005). High caecum SUV correlated with numerically shorter OS (10.8 vs. 27.6 months, HR 1.85, 95% CI 0.97-3.53, p = 0.058). Metagenomics sequencing revealed distinctive microbiome populations in each group. Patients with low caecum SUV had higher microbiome diversity (p = 0.046) and were enriched with Bifidobacteriaceae, Lachnospiraceae, and Bacteroidaceae.

Conclusions: Lower colon physiologic F-FDG uptake on PET/CT prior to ICI initiation was associated with better clinical outcomes and higher gut microbiome diversity in patients with advanced NSCLC. Here, we propose that F-FDG physiologic colonic uptake on PET/CT could serve as a potential novel marker of gut microbiome composition and may predict clinical outcomes in this population.
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http://dx.doi.org/10.1007/s00259-020-05081-6DOI Listing
May 2021

High mortality among hospital-acquired COVID-19 infection in patients with cancer: A multicentre observational cohort study.

Eur J Cancer 2020 11 3;139:181-187. Epub 2020 Sep 3.

Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Department of Hematology-Oncology, Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada. Electronic address:

Introduction: Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centres have undertaken efforts to care for patients with cancer in COVID-free units. Nevertheless, the frequency and relevance of nosocomial transmission of COVID-19 in patients with cancer remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify predictive factors for COVID-19 severity in patients with cancer.

Methods: Patients with cancer and a laboratory-confirmed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3rd and May 23rd, 2020 in the provinces of Quebec and British Columbia in Canada. Patient's baseline characteristics including age, sex, comorbidities, cancer type and type of anticancer treatment were collected. The exposure of interest was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 ≥ 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalisation, supplemental oxygen, intensive-care unit (ICU) admission and/or mechanical ventilation.

Results: A total of 252 patients (N = 249 adult and N = 3 paediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N = 233). One hundred and six patients (42.1%) received active anticancer treatment in the last 3 months before COVID-19 diagnosis. During a median follow-up of 25 days, 33 (13.1%) required admission to the ICU, and 71 (28.2%) died. Forty-seven (19.1%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection than that in a contemporary community-acquired population (27 days versus unreached, hazard ratio (HR) = 2.3, 95% CI: 1.2-4.4, p = 0.0006. Multivariate analysis demonstrated that hospital-acquired COVID-19, age, Eastern Cooperative Oncology Group status and advanced stage of cancer were independently associated with death.

Interpretation: Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free units. We also validated that age and advanced cancer were negative predictive factors for COVID-19 severity in patients with cancer.
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http://dx.doi.org/10.1016/j.ejca.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470707PMC
November 2020

Repurposing Metformin in Nondiabetic People With HIV: Influence on Weight and Gut Microbiota.

Open Forum Infect Dis 2020 Sep 11;7(9):ofaa338. Epub 2020 Sep 11.

Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, Québec, Canada.

Background: People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio.

Methods: In the Lilac pilot trial, we recruited 23 nondiabetic PWH receiving ART for more than 2 years with a low CD4/CD8 ratio (<0.7). Blood and stool samples were collected during study visits at baseline, after a 12-week metformin treatment, and 12 weeks after discontinuation. Microbiota composition was analyzed by 16S rDNA gene sequencing, and markers of inflammation were assessed in plasma.

Results: Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective

Conclusions: Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH.
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http://dx.doi.org/10.1093/ofid/ofaa338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489545PMC
September 2020

The Link Between the Gut Microbiome and Response to Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Eur Urol 2021 01 16;79(1):1-2. Epub 2020 Sep 16.

Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montreal, Montreal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2020.09.001DOI Listing
January 2021

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors.

Oncoimmunology 2020 07 20;9(1):1794423. Epub 2020 Jul 20.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1794423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466864PMC
July 2020

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

Oncoimmunology 2020 06 3;9(1):1774298. Epub 2020 Jun 3.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1774298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466862PMC
June 2020

COVID-19: a challenge for oncology services.

Oncoimmunology 2020 05 5;9(1):1760686. Epub 2020 May 5.

Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.

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http://dx.doi.org/10.1080/2162402X.2020.1760686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458620PMC
May 2020

Tumor Infiltrating Lymphocytes Signature as a New Pan-Cancer Predictive Biomarker of Anti PD-1/PD-L1 Efficacy.

Cancers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Cancer Biology Transfer Platform, Georges-François Leclerc Cancer Center, 1 rue du Professeur Marion, F-21000 Dijon, France.

Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers12092418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564481PMC
August 2020

The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non-Small Cell Lung Cancer.

Cancer Immunol Res 2020 10 27;8(10):1243-1250. Epub 2020 Jul 27.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo City, Tokyo, Japan.

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non-small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti-PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3-V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of UCG 13 and When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, UCG 13 and were enriched in patients with favorable ORR and PFS >6 months. UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI..
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0196DOI Listing
October 2020

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.

Science 2020 08;369(6506):936-942

Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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http://dx.doi.org/10.1126/science.aax0701DOI Listing
August 2020

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion.

Oncologist 2020 11 8;25(11):916-920. Epub 2020 Sep 8.

Thoracic Oncology Unit, Le Centre Hospitalier de l'Université de Montréal, Montreal, Canada.

Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. KEY POINTS: To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.
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http://dx.doi.org/10.1634/theoncologist.2020-0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648335PMC
November 2020

Arterial thrombosis and coronavirus disease 2019 in a patient with cancer.

Eur J Cancer 2020 07 18;134:1-2. Epub 2020 May 18.

Centre Hospitalier de l'Université de Montréal, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231757PMC
July 2020

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Nat Med 2020 06 25;26(6):919-931. Epub 2020 May 25.

Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

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.
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http://dx.doi.org/10.1038/s41591-020-0882-8DOI Listing
June 2020

New pathways in immune stimulation: targeting OX40.

ESMO Open 2020 02 9;5(1). Epub 2020 Feb 9.

INSERM U1015, Gustave Roussy Institute, Villejuif, France

Immune checkpoint blockers (ICB) reinvigorate the immune system by removing the molecular brakes responsible for the scarce activity of immune phenotypes against malignant cells. After having proven their remarkable role as monotherapy, combinations of anti-Programmed cell death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) agents with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, chemotherapy and/or anti-angiogenic compounds provide unprecedented results and durable responses across a variety of tumour types. Nevertheless, the main drawbacks of ICB are represented by primary and acquired resistance, translating into disease progression, as well as by immune-related toxicities. In this sense, novel strategies to foster the immune system through its direct stimulation are being tested in order to provide additional clinical improvements in patients with cancer. In this scenario, the co-stimulatory molecule OX40 (CD134) belongs to the next generation of immune therapeutic targets. Preliminary results of early clinical trials evaluating OX40 stimulation by means of different agents are encouraging. Here we review the rationale of OX40 targeting, highlighting the combination of OX40-directed therapies with different anticancer agents as a potential strategy to foster the immune system against malignant phenotypes.
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http://dx.doi.org/10.1136/esmoopen-2019-000573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046367PMC
February 2020

Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.

Eur Urol 2020 08 4;78(2):195-206. Epub 2020 May 4.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Background: 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.

Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.

Design, Setting, And Participants: 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.

Outcome Measurements And Statistical Analysis: 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.

Results And Limitations: 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).

Conclusions: 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.

Patient Summary: 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.
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http://dx.doi.org/10.1016/j.eururo.2020.04.044DOI Listing
August 2020

Tumor CD155 Expression Is Associated with Resistance to Anti-PD1 Immunotherapy in Metastatic Melanoma.

Clin Cancer Res 2020 07 28;26(14):3671-3681. Epub 2020 Apr 28.

Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Queensland, Australia.

Purpose: Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.

Experimental Design: Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival.

Results: High pretreatment CD155 tumor levels correlated with high parenchymal PD1CD8/CD8 T-cell ratios (PD1) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy.

Conclusions: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1CD8 T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3925DOI Listing
July 2020

The Bacterium : A Sentinel for Gut Permeability and Its Relevance to HIV-Related Inflammation.

Front Immunol 2020 9;11:645. Epub 2020 Apr 9.

Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada.

Gut dysbiosis, namely dysregulation of the intestinal microbiota, and increased gut permeability lead to enhanced inflammation and are commonly seen in chronic conditions such as obesity and aging. In people living with HIV (PLWH), several lines of evidence suggest that a depletion of gut CD4 T-cells is associated with gut dysbiosis, microbial translocation and systemic inflammation. Antiretroviral therapy (ART) rapidly controls viral replication, which leads to CD4 T-cell recovery and control of the disease. However, gut dysbiosis, epithelial damage and microbial translocation persist despite ART, increasing risk of developing inflammatory non-AIDS comorbidities such as cardiovascular disease, diabetes mellitus, liver steatosis and cancer. In addition to ART, an emerging research priority is to discover strategies to improve the gut microbial composition and intestinal barrier function. Probiotic interventions have been extensively used with controversial benefits in humans. Encouragingly, within the last decade, the intestinal symbiotic bacterium has emerged as the "sentinel of the gut." A lower abundance of has been shown in diabetic and obese people as well as in PLWH. Interventions with high levels of polyphenols such as tea or diets rich in fruit, the antibiotic vancomycin and the antidiabetic drug metformin have been shown to increase abundance, contributing to improved metabolic function in diabetic and obese individuals. We hypothesize that gut microbiota rich in can reduce microbial translocation and inflammation, preventing occurrences of non-AIDS comorbidities in PLWH. To this aim, we will discuss the protective effect of and its potential applications, paving the way toward novel therapeutic strategies to improve gut health in PLWH.
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http://dx.doi.org/10.3389/fimmu.2020.00645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160922PMC
March 2021

Moving towards personalized treatments of immune-related adverse events.

Nat Rev Clin Oncol 2020 08 3;17(8):504-515. Epub 2020 Apr 3.

Department of Immunology and Rheumatology, Cleveland Clinic, Cleveland, OH, USA.

The enhancement of immune responses upon treatment with immune checkpoint inhibitors can have the desired outcome of reinvigorating antitumour immune surveillance, but often at the expense of immune-related adverse events (irAEs). This novel disease entity often prompts comparisons with, and extrapolation of treatment approaches from, primary autoimmune disorders. Accordingly, current treatment guidelines for irAEs make generic recommendations adapted from the literature describing primary autoimmune diseases, without taking into consideration the substantial disparity of the immunohistopathological findings within each organ affected by an irAE. The treatment modalities themselves are complex and have many potential drawbacks, such as serious and rarely fatal infections, drug toxicities overlapping with irAEs and the risk of compromising cancer immune surveillance. Herein, we provide an overview of key cellular and soluble immunological factors mediating irAEs and propose a model integrating this knowledge with the immunohistopathological findings of the affected organs for a personalized decision-making process for each patient.
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http://dx.doi.org/10.1038/s41571-020-0352-8DOI Listing
August 2020

Metformin effect on gut microbiota: insights for HIV-related inflammation.

AIDS Res Ther 2020 03 10;17(1):10. Epub 2020 Mar 10.

Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, 1001 Blvd Décarie, Montréal, QC, Canada.

The gut microbiota is emerging as a prominent player in maintaining health through several metabolic and immune pathways. Dysregulation of gut microbiota composition, also known as dysbiosis, is involved in the clinical outcome of diabetes, inflammatory bowel diseases, cancer, aging and HIV infection. Gut dysbiosis and inflammation persist in people living with HIV (PLWH) despite receiving antiretroviral therapy, further contributing to non-AIDS comorbidities. Metformin, a widely used antidiabetic agent, has been found to benefit microbiota composition, promote gut barrier integrity and reduce inflammation in human and animal models of diabetes. Inspired by the effect of metformin on diabetes-related gut dysbiosis, we herein critically review the relevance of metformin to control inflammation in PLWH. Metformin may improve gut microbiota composition, in turn reducing inflammation and risk of non-AIDS comorbidities. This review will pave the way towards innovative strategies to counteract dysregulated microbiota and improve the lives of PLWH.
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http://dx.doi.org/10.1186/s12981-020-00267-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063824PMC
March 2020