Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells

Bachem, Annabell; Makhlouf, Christina; Binger, Katrina J.; Souza, David P De; Tull, Dedreia; Hochheiser, Katharina; Whitney, Paul G.; Fernandez‐Ruiz, Daniel; Dähling, Sabrina; Kastenmüller, Wolfgang; Jönsson, Johanna; Gressier, Elise; Lew, Andrew M.; Perdomo, Carolina; Kupz, Andreas; Figgett, William A.; Mackay, Fabienne; Oleshansky, Moshe; Russ, Brendan E.; Parish, Ian A.; Kallies, Axel; McConville, Malcolm J.; Turner, Stephen J.; Gebhardt, Thomas; Bedoui, Sammy

doi:10.1016/j.immuni.2019.06.002

Cited by 469 publications

(357 citation statements)

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“…Here signi cant elevation of SCFAs indicated activation of intestinal bacterial fermentation process by icariside I, which further con rmed with up-regulation of colonic Gpr41 and Gpr43 mRNAs. Previous studies also showed that microbiota-derived SCFAs can enhance cellular metabolism and memory potential of antigen-activated CD8 + T cells in participating in the immune response against intracellular pathogens and tumors [45], as well as promoting activity and differentiation of CD4 + T cells [46]. Most of microbiota-derived indole derivatives are endogenous ligands of AhR, which is involved in host immunometabolism and multiple pathophysiological processes of metabolic diseases such as obesity and cancer [47].…”

Section: Discussionmentioning

confidence: 99%

Immunological Anti-Tumor Activity of Icariside I by Regulating Gut Microbiota and Its Derived Metabolites in a Melanoma Mouse Model

Chen

Cao

Shi

et al. 2020

Preprint

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Background Emerging evidence has shown that gut microbiome plays important roles in antitumor immunotherapy by shaping systemic immune responses. Specifically, Lactobacillus spp. and Bifidobacterium spp. were previously reported to enhance host immunity and inhibit tumor growth. Furthermore, microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and indole derivatives are gradually regarded as immunomodulatory molecules involved in metabolic signaling pathways. Methods A B16F10 melanoma model was selected as a tumor-bearing animal for the investigation of immunological anti-tumor activity of Icariside I. Gut microbiota structure and composition in cecal content of mice was firstly analyzed by 16S rRNA gene sequence with the goal of screening those bacteria highly associated with tumor immunotherapy. Subsequently, targeted metabolomics approach was employed to quantitatively determine microbiota-derived metabolites such as SCFAs and indole derivatives. The population of multiple lymphocyte subsets in peripheral blood were measured with flowcytometry to evaluate changes of host immunity. Results Icariside I significantly inhibited B16F10 melanoma growth in vivo through regulation of gut microbiota and host immune. Oral administration of icariside I improved the altered gut microbiota community with marked restoration of Lactobacillus spp. and Bifidobacterium spp. abundance. Icariside I was also able to improve the levels of microbiota-derived metabolites such as short-chain fatty acids (SCFAs) and indole derivatives, consequently repairing intestinal barrier and systemic inflammation of tumor-bearing mice. Furthermore, icariside I up-regulated multiple lymphocyte subsets including CD4 + and CD8 + T cells or NK and NKT cells in peripheral blood. Conclusions These results suggested that icariside I may be developed as a novel and natural anticancer adjuvant via microbiome remodeling and host immune regulation.

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Section: Discussionmentioning

confidence: 99%

Immunological Anti-Tumor Activity of Icariside I by Regulating Gut Microbiota and Its Derived Metabolites in a Melanoma Mouse Model

Chen

Cao

Shi

et al. 2020

Preprint

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“…The microbiome can even influence the metabolic profile of cells. Normal commensal flora ferment dietary fibre to produce short‐chain fatty acids like butyrate, which strongly promotes FAO, OXPHOS and memory T cell development . While many nutrients are imported, it should be noted that autophagy can also be a source of macromolecules and is essential for the resolution of an immune response, to establish a memory cell population …”

Section: Nutrient Sensing In T Cellsmentioning

confidence: 99%

The clock is ticking: the impact of ageing on T cell metabolism

et al. 2019

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It is now clear that access to specific metabolic programmes controls the survival and function of various immune cell populations, including T cells. Efficient naïve and memory T cell homoeostasis requires the use of specific metabolic pathways and differentiation requires rapid and dramatic metabolic remodelling. While we are beginning to appreciate the crucial role of metabolic programming during normal T cell physiology, many of the potential impacts of ageing on metabolic homoeostasis and remodelling in T cells remain unexplored. This review will outline our current understanding of T cell metabolism and explore age‐related metabolic changes that are postulated or have been demonstrated to impact T cell function.

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“…The interaction between gut microbiota and the host immune system is mainly mediated by microbiota-produced small diffusible metabolites[14]. Short chain fatty acids (SCFAs), the most abundant microbial metabolites in the intestine, play crucial roles in both immune regulation[15, 16, 17, 18, 19] and microbiota-gut-brain communication[20]. Interestingly, many recent studies identified gut microbiota dysbiosis in schizophrenia[21, 22, 23, 24].…”

Section: Introductionmentioning

confidence: 99%

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

Zhu

Wang

et al. 2020

Preprint

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Objective: Gut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia. Design: Gut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse. Results: Both microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, Gut microbiota chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors.Conclusion: microbiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia. Summary Significance of this study What is already known about this subject?Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA).Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms. Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters. What are the new findings?

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Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells

Cited by 469 publications

References 53 publications

Immunological Anti-Tumor Activity of Icariside I by Regulating Gut Microbiota and Its Derived Metabolites in a Melanoma Mouse Model

Immunological Anti-Tumor Activity of Icariside I by Regulating Gut Microbiota and Its Derived Metabolites in a Melanoma Mouse Model

The clock is ticking: the impact of ageing on T cell metabolism

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

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