Microbiome-Modulated Metabolites at the Interface of Host Immunity

Blacher, Eran; Levy, Maayan; Tatirovsky, Evgeny; Elinav, Eran

doi:10.4049/jimmunol.1601247

Cited by 280 publications

(225 citation statements)

References 99 publications

(124 reference statements)

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“…Of note, a part of unabsorbed flavanols is excreted into the feces (33, 38, 39). In this framework, it is worthwhile emphasizing that microbiota-derived metabolites of ingested polyphenols in view of their healthy effects are object of intensive investigation (40, 41). For instance, with special reference to consumers of cocoa polyphenols, a comparison between regular consumers of chocolate and low consumers has clearly shown a significant difference in terms of metabolite profiles (42).…”

Section: Introductionmentioning

confidence: 99%

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications

2017

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It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.

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Section: Introductionmentioning

confidence: 99%

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications

2017

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“…Comparisons of pathway enrichment across these groups showed changes in metabolic functions, with anabolic functions predominating in R including amino acid biosynthesis (Fig. 3E), which may promote host immunity (36), whereas catabolic functions predominated in NR (Fig. 3E, fig.…”

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confidence: 99%

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Gopalakrishnan¹,

Spencer²,

Nezi³

et al. 2018

Science

3,398

3,135

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Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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“…Recent advances in our understanding of the microbiome-immunity axis has spurred interest in how gut microbiota and their metabolic products, especially short chain fatty acids, can contribute to health outcomes and potentially be used for clinical purposes (3,(68)(69)(70)(71)(72)(73)(74). In order to fully appreciate the mechanisms by which gut metabolites like butyrate exert their immunomodulatory effects, it is necessary to understand how butyrate directly influences immune programs that contribute to infection and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Short chain fatty acid butyrate promotes virus infection by repressing interferon stimulated genes

Chemudupati

Smith

Fillinger

et al. 2020

Preprint

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Butyrate is an abundant metabolite produced by the gut microbiota and is known to modulate multiple immune system pathways and inflammatory diseases. However, studies of its effects on virus infection of cells are limited and enigmatic. We found that butyrate increases cellular infection and virus replication in influenza virus, reovirus, and human immunodeficiency virus infections. Further exploring this phenomenon, we found that addition of butyrate to cells deficient in type I interferon (IFN) signaling did not increase susceptibility to virus infection. Accordingly, we discovered that butyrate suppressed levels of specific IFN stimulated gene (ISG) products in human and mouse cells. Butyrate did not inhibit IFN-induced phosphorylation of transcription factors STAT1 and STAT2 or their translocation to the nucleus, indicating that IFN signaling was not disrupted. Rather, our data are suggestive of a role for inhibition of histone deacetylase activity by butyrate in limiting ISG induction. Global transcript analysis revealed that butyrate increases expression of more than 800 cellular genes, but represses IFN-induced expression of 60% of ISGs. Overall, we identify a new mechanism by which butyrate promotes virus infection via repression of ISGs. Our findings also add to the growing body of evidence showing that individual ISGs respond differently to type I IFN induction depending on the cellular environment, including the presence of butyrate. ImportanceButyrate is a lipid produced by intestinal bacteria that can regulate inflammation throughout the body. Here we show for the first time that butyrate influences the innate antiviral immune response mediated by type I IFNs. A majority of antiviral genes induced

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Microbiome-Modulated Metabolites at the Interface of Host Immunity

Cited by 280 publications

References 99 publications

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Short chain fatty acid butyrate promotes virus infection by repressing interferon stimulated genes

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