Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor ...immunity are unclear. In this study, we isolated three bacterial species-
,
, and
species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal
modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A
receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a ...major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn's disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.
Eradication of pathogens from the bloodstream is critical to prevent disseminated infections and sepsis. Kupffer cells in the liver form an intravascular firewall that captures and clears pathogens ...from the blood. Here, we show that the catching and killing of circulating pathogens by Kupffer cells in vivo are promoted by the gut microbiota through commensal-derived D-lactate that reaches the liver via the portal vein. The integrity of this Kupffer cell-mediated intravascular firewall requires continuous crosstalk with gut commensals, as microbiota depletion with antibiotics leads to a failure of pathogen clearance and overwhelming disseminated infection. Furthermore, administration of purified D-lactate to germ-free mice, or gnotobiotic colonization with D-lactate-producing commensals, restores Kupffer cell-mediated pathogen clearance by the liver firewall. Thus, the gut microbiota programs an intravascular immune firewall that protects against the spread of bacterial infections via the bloodstream.
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•The gut microbiota promotes clearance of pathogens from the bloodstream by the liver•Commensal D-lactate programs Kupffer cells to capture and kill circulating pathogens•Dysbiosis causes impaired Kupffer cell function, leading to disseminated infection
McDonald et al., used gnotobiotic mice and in vivo imaging to show that clearance of circulating pathogens by Kupffer cells in the liver is governed by the gut microbiota and its production of D-lactate, which reaches the liver via the portal vein and programs Kupffer cells to capture and kill pathogens in the bloodstream.
IntroductionAthletes are not immune to mental health issues but are less likely to seek help than non-athletes and experience barriers including lack of access to services, lack of knowledge as to ...how to access services and negative past experiences for help-seeking. Formal (eg, university counsellors, general practitioners and psychologists) and semi-formal (eg, academic tutor, sports coach and physiotherapist) sources of support provided in healthcare, the sport context and higher education are key places for athletes to seek help for mental health, and there is a need to synthesise the evidence on athletes’ access, attitudes to and experiences of these services, to understand how to improve these services specific to athletes’ mental health needs. This protocol outlines a scoping review that will be used to map the evidence, identify gaps in the literature and summarise findings on athletes’ access, attitudes to and experiences of help-seeking for their mental health.Methods and analysisThe methodological frameworks of Arksey and O’Malley (2005), Levac et al (2010) and the Joanna Briggs Institute (2020 and 2021) were used to inform this scoping review protocol alongside the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols checklist and published scoping review protocols within sport and health. The six stages of Arksey and O’Malley’s (2005) framework have been used for this scoping review. The searches were conducted between 30 March 2022 and 3 April 2022 in the following databases: APA PsycINFO (via OVID), Embase (via Ovid), MEDLINE (via Ovid), APA PsycArticles Full Text (via OVID), Web of Science Core Collection, SPORTDiscus (via EBSCO), CINAHL (via EBSCO), Scopus, ProQuest (Education Database), ProQuest (Education Collection), ProQuest (Health & Medical Collection), ProQuest (Nursing & Allied Health database), ProQuest (Psychology Database), ProQuest (Public Health Database) and ProQuest (Sports Medicine & Education). The main inclusion criteria of this review are: papers that focus on past help-seeking behaviour, attitudes towards help-seeking and future behavioural intentions, papers that refer to formal and semi-formal sources of support and peer-reviewed literature, primary research articles, systematic or scoping reviews and interventions. During title and abstract screening and full-text review, at least two reviewers will be involved. Data to be extracted from studies includes: details of the study population, whether the paper focuses on formal and/or semi-formal sources of support and whether the focus is on access, attitudes or experiences to help-seeking for mental health.Ethics and disseminationThe evidence will be mapped numerically and through content analysis to describe studies and highlight key concepts, themes and gaps in the literature. The published scoping review will be disseminated to relevant stakeholders and policymakers including those in healthcare, the sporting context and the higher education system. The resulting outputs will be in the form of both peer-reviewed and non-peer reviewed publications (eg, multimedia in the form of a blog post and at conferences). The dissemination plan will be informed by patient and public involvement. Ethics approval was not required for this study.
While the ontogeny and recruitment of the intestinal monocyte/macrophage lineage has been studied extensively, their precise localization and function has been overlooked. Here we show by imaging the ...murine small and large intestines in steady-state that intestinal CX3CR1
macrophages form an interdigitated network intimately adherent to the entire mucosal lamina propria vasculature. The macrophages form contacts with each other, which are disrupted in the absence of microbiome, monocyte recruitment (Ccr2
), or monocyte conversion (Nr4a1
). In dysbiosis, gaps exist between the perivascular macrophages correlating with increased bacterial translocation from the lamina propria into the bloodstream. The recruitment of monocytes and conversion to macrophages during intestinal injury is also dependent upon CCR2, Nr4a1 and the microbiome. These findings demonstrate a relationship between microbiome and the maturation of lamina propria perivascular macrophages into a tight anatomical barrier that might function to prevent bacterial translocation. These cells are also critical for emergency vascular repair.
Commensal bacteria are major contributors to mammalian metabolism. We used liquid chromatography mass spectrometry to study the metabolomes of germ-free, gnotobiotic, and specific-pathogen-free mice, ...while also evaluating the influence of age and sex on metabolite profiles. Microbiota modified the metabolome of all body sites and accounted for the highest proportion of variation within the gastrointestinal tract. Microbiota and age explained similar amounts of variation the metabolome of urine, serum, and peritoneal fluid, while age was the primary driver of variation in the liver and spleen. Although sex explained the least amount of variation at all sites, it had a significant impact on all sites except the ileum. Collectively, these data illustrate the interplay between microbiota, age, and sex in the metabolic phenotypes of diverse body sites. This provides a framework for interpreting complex metabolic phenotypes and will help guide future studies into the role that the microbiome plays in disease.
Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA) and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been ...shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil) and diets supplemented with ω-3 PUFA (corn oil+fish oil) for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection-induced responses resulting in sepsis. We conclude that as an anti-inflammatory agent, ω-3 PUFA supplementation during infection may prove detrimental when host inflammatory responses are critical for survival.
Living in a hard water area is associated with an increased risk of atopic dermatitis (AD). Greater skin barrier impairment after exposure to surfactants in wash products, combined with the high ...calcium levels of hard water and/or high chlorine levels, is a compelling mechanism for this increase. The purpose of this study was to investigate this mechanism in individuals with and without a predisposition to skin barrier impairment. We recruited 80 participants: healthy control subjects and AD patients with and without FLG mutations. The skin of each participant was washed with sodium lauryl sulfate in water of varying hardness levels and chlorine concentrations, rinsed, and covered with chambers to determine the effects of surfactant residues. Sites washed with hard water had significantly increased sodium lauryl sulfate deposits. These deposits increased transepidermal water loss and caused irritation, particularly in AD patients carrying FLG mutations. A clear effect of chlorine was not observed. Water softening by ion-exchange mitigated the negative effects of hard water. Barrier impairment resulting from the interaction between hard water and surfactants is a contributory factor to the development of AD. Installation of a water softener in early life may be able to prevent AD development. An intervention study is required to test this hypothesis.
In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained ...largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or β-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal
and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G
and CD68
cells, while increasing the relative amount of IgGκ
B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens
serovar Typhimurium and
, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections.
Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly ...understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS.
We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively.
Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients.
In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS.
The study protocol was registered with PROSPERO CRD42021282074 in October 2021 and published in BMJ Open in 2022.
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