Marion Thibaudin, Jean-David Fumet, Benoist Chibaudel, Jaafar Bennouna, Christophe Borg, Jerome Martin-Babau, Romain Cohen, Marianne Fonck, Julien Taieb, Emeric Limagne, Julie Blanc, Elise Ballot, Léa Hampe, Marjorie Bon, Susy Daumoine, Morgane Peroz, Hugo Mananet, Valentin Derangère, Romain Boidot, Henri-Alexandre Michaud, Caroline Laheurte, Olivier Adotevi, Aurélie Bertaut, Caroline Truntzer, François Ghiringhelli <<<

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 . <<<

Nicolas Vallet, Maud Salmona, Jeanne Malet-Villemagne, Maxime Bredel, Louise Bondeelle, Simon Tournier, Séverine Mercier-Delarue, Stéphane Cassonnet, Brian Ingram, Régis Peffault de Latour, Anne Bergeron, Gérard Socié, Jérome Le Goff, Patricia Lepage, David Michonneau <<<

Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells. <<<

Wenchao Wei, Chi Chun Wong, Zhongjun Jia, Weixin Liu, Changan Liu, Fenfen Ji, Yasi Pan, Feixue Wang, Guoping Wang, Liuyang Zhao, Eagle S H Chu, Xiang Zhang, Joseph J Y Sung, Jun Yu <<<

Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by C-inulin. Integration of C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease. <<<

Jessica Roelands, Peter J K Kuppen, Eiman I Ahmed, Raghvendra Mall, Tariq Masoodi, Parul Singh, Gianni Monaco, Christophe Raynaud, Noel F C C de Miranda, Luigi Ferraro, Tatiana C Carneiro-Lobo, Najeeb Syed, Arun Rawat, Amany Awad, Julie Decock, William Mifsud, Lance D Miller, Shimaa Sherif, Mahmoud G Mohamed, Darawan Rinchai, Marc Van den Eynde, Rosalyn W Sayaman, Elad Ziv, Francois Bertucci, Mahir Abdulla Petkar, Stephan Lorenz, Lisa Sara Mathew, Kun Wang, Selvasankar Murugesan, Damien Chaussabel, Alexander L Vahrmeijer, Ena Wang, Anna Ceccarelli, Khalid A Fakhro, Gabriele Zoppoli, Alberto Ballestrero, Rob A E M Tollenaar, Francesco M Marincola, Jérôme Galon, Souhaila Al Khodor, Michele Ceccarelli, Wouter Hendrickx, Davide Bedognetti <<<

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches. <<<

Individual amino acids are widely popular as supplements because of various perceived and real health benefits. However, currently, there are no recommendations set by national health agencies for tolerable upper intake levels (UL) for amino acids because of a lack of well-conducted human dose-response trials. In the past decade, under the initiative of the International Council on Amino Acid Science, a nonprofit organization, a series of UL human clinical studies were conducted. The goal of this narrative review is to summarize the studies on 6 essential amino acids (leucine, tryptophan, methionine, lysine, histidine, and phenylalanine), 2 nonessential amino acids (arginine and serine), and 2 nonproteinogenic amino acids (ornithine and citrulline) and provide the first set of ULs. A brief background of the concept of the DRI framework of UL, the concept of UL for amino acids, and a perspective of the results are also provided. The data suggest that in relatively healthy adult individuals, the tested amino acids are well tolerated, and ULs, or the no-observed-adverse-effect-level (NOAEL), lowest-observed-adverse-effect-level (LOAEL), can be determined. The ULs were for leucine-young (35 g/d), tryptophan (4.5 g/d), and leucine-elderly (30 g/d); NOAEL and LOAEL for methionine at 3.2 and 6.4 g/d, respectively; NOAEL for arginine (30 g/d); NOAEL and LOAEL for lysine at 6 and 7.5 g/d, respectively; NOAEL and LOAEL for histidine at 8 and 12 g/d, respectively; and NOAEL for phenylalanine (12 g/d), serine (12 g/d), ornithine (12 g/d) and citrulline (24 g/d). This first set of human UL data are hoped to help national and international agencies set safety standards for supplemental amino acids. <<<

Xiao Guo, Yuemeng Zhu, Lu Guo, Yiwen Qi, Xiaocheng Liu, Jinhui Wang, Jiangtao Zhang, Linlin Cui, Yueyang Shi, Qichu Wang, Cenxi Liu, Guangxing Lu, Yilian Liu, Tao Li, Shangyu Hong, Yingying Qin, Xuelian Xiong, Hao Wu, Lin Huang, He Huang, Chao Gu, Bin Li, Jin Li <<<

Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone. Though POI affects many aspects of women's health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch-chain amino acid (BCAA) insufficiency-related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57BL/6J mice. A mechanism study revealed that the BCAA insufficiency-induced POI is associated with abnormal activation of the ceramide-reactive oxygen species (ROS) axis and consequent impairment of ovarian granulosa cell function. Significantly, the dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI. <<<

Ming Sun, Josef Fritz, Christel Häggström, Tone Bjørge, Gabriele Nagel, Jonas Manjer, Anders Engeland, Emanuel Zitt, Bethany van Guelpen, Pär Stattin, Hanno Ulmer, Tanja Stocks <<<

BACKGROUND: Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce.METHODS: We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided.RESULTS: Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55-3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05).CONCLUSIONS: This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention. <<<

Simona Ceglia, Alyssa Berthelette, Kelsey Howley, Yun Li, Benedikt Mortzfeld, Shakti K Bhattarai, Nicole K H Yiew, Ying Xu, Robert Brink, Jason G Cyster, Lora V Hooper, Gwendalyn J Randolph, Vanni Bucci, Andrea Reboldi <<<

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection. <<<

Vaccines are one of the greatest successes of public health, preventing millions of cases of disease and death in children each year. However, the efficacy of many vaccines can vary greatly between infants from geographically and socioeconomically distinct locations. Differences in the composition of the intestinal microbiome have emerged as one of the main factors that can account for variations in immunisation outcomes. In this Review, we assess the influence of the gut microbiota upon early life immunity, focusing on two important members of the microbiota with health-promoting and immunomodulatory properties: Bifidobacterium and Bacteroides. Additionally, we discuss their immune stimulatory microbial properties, interactions with the host, and their effect on vaccine responses and efficacy in infants. We also provide an overview of current microbiota-based approaches to enhance vaccine outcomes, and describe novel microbe-derived components that could lead to safer, more effective vaccines and vaccine adjuvants. <<<

An orchestrated cellular network, including adaptive lymphocytes and group 3 innate lymphoid cells (ILC3s), maintains intestinal barrier integrity and homeostasis. T cells can monitor environmental insults through constitutive circulation, scanning tissues and forming immunological contacts, a process named immunosurveillance. In contrast, the dynamics of intestinal ILC3s are unknown. Using intravital imaging, we observed that villus ILC3s were largely immotile at steady state but acquired migratory 'patrolling' attributes and enhanced cytokine expression in response to inflammation. We showed that T cells, the chemokine CCL25 and bacterial ligands regulated intestinal ILC3 behavior and that loss of patrolling behavior by interleukin-22 (IL-22)-producing ILC3s altered the intestinal barrier through increased epithelial cell death. Collectively, we identified notable differences between the behavior of ILC3s and T cells, with a prominent adaptation of intestinal ILC3s toward mucosal immunosurveillance after inflammation. <<<

BACKGROUND: Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear.METHODS: We performed integrated microbiome-metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action.RESULTS: Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE-/- mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels.CONCLUSIONS: Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD. <<<