The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages

Schulthess, Julie; Pandey, Sumeet; Capitani, Melania; Rue-Albrecht, Kévin; Arnold, Isabelle C.; Franchini, Fanny; Chomka, Agnieszka; Ilott, Nicholas E.; Johnston, Daniel; Pires, Elisabete; McCullagh, James; Sansom, Stephen N.; Arancibia‐Cárcamo, Carolina V.; Uhlig, Holm H.; Powrie, Fiona

doi:10.1016/j.immuni.2018.12.018

Cited by 647 publications

(533 citation statements)

References 60 publications

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“…In the current study, we observed that the S.E WT strain with AvrA expression and complementary strain induced weak autophagic activity, compared to the autophagic activity following S.E AvrA muant strain infection. Numerous lines of evidence indicate that Salmonella infection can activate robust host cell autophagy (37)(38)(39). This difference maybe due to the serotype difference.…”

Section: Discussionmentioning

confidence: 99%

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Jiao

Zhang

Lin

et al. 2020

Preprint

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Autophagy is a cellular process to clear pathogens. Salmonella enterica serovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens.However, major studies still focus on Salmonella enterica serovar Typhimurium. Here, we reported that AvrA, a S. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. In S.E-AvrA--infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression.In addition, AvrA protein interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses. Importance:Salmonella Enteritidis is an important pathogen with a public health concern and farm production risk, yet the host-pathogen interactions that govern the survival of S.Enteritidis infections are incompletely understood. Anti-bacterial autophagy provides potent cell-autonomous immunity against bacterial colonization. Here, we report that a new role for effector AvrA of S. Enteritidis in the reduction of Beclin-1 protein expression through the JNK pathway and the attenuation of the autophagic response in intestinal epithelial cells. This finding not only indicates an important role of S. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.3

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Section: Discussionmentioning

confidence: 99%

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Jiao

Zhang

Lin

et al. 2020

Preprint

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“…These effects were also mediated by alterations in macrophage metabolism, through inhibition of histone deacetylase 3 to inhibit mammalian target of rapamycin signalling and glycolysis. 58 These two studies demonstrate a novel role for butyrate in shaping macrophage metabolism in the intestine, which has a profound effect on macrophage function. 59 The small intestine contains high concentrations of dietary vitamin A and its active metabolite RA, an important modulator of intestinal immune responses.…”

Section: Compartmentalization Of Macrophage Function In the Intestinementioning

confidence: 91%

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

Scott

Mann

2019

Immunology

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Summary Mucosal tissues contain distinct microbial communities that differ drastically depending on the barrier site, and as such, mucosal immune responses have evolved to be tailored specifically for their location. Whether protective or regulatory immune responses against invading pathogens or the commensal microbiota occur is controlled by local mononuclear phagocytes (MNPs). Comprising macrophages and dendritic cells (DCs), the functions of these cells are highly dependent on the local environment. For example, the intestine contains the greatest bacterial load of any site in the body, and hence, intestinal MNPs are hyporesponsive to bacterial stimulation. This is thought to be one of the major mechanisms by which harmful immune responses directed against the trillions of harmless bacteria that line the gut lumen are avoided. Regulation of MNP function by the microbiota has been characterized in the most depth in the intestine but there are several mucosal sites that also contain their own microbiota. In this review, we present an overview of how MNP function is regulated by the microbiota at mucosal sites, highlighting recent novel pathways by which this occurs in the intestine, and new studies elucidating these interactions at mucosal sites that have been characterized in less depth, including the urogenital tract.

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“…Mechanistically, microbial metabolites have been shown to mediate many of these effects. Short‐chain fatty acids, products of microbial fermentation in the gut, promote Treg cell accumulation, in addition to regulating many other immune effector functions . Microbiota‐derived ATP can stimulate Th17 development, and tryptophan breakdown products like indole‐3‐lactic acid promote the development of intraepithelial CD4 + CD8αα + T cells through stimulation of the aryl hydrocarbon receptor .…”

Section: Of Mice and Menmentioning

confidence: 99%

Understanding immune–microbiota interactions in the intestine

Ahern

Maloy

2019

Immunology

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Summary The past two decades have seen an explosion in research that aims to understand how the dynamic interplay with the gut microbiota impacts host health and disease, establishing a role for the gut microbiota in a plethora of pathologies. Understanding how health‐promoting microbiota are established and how beneficial host–microbiota interactions are maintained is of immense biomedical importance. Despite the enormous progress that has been made, our knowledge of the specific microbiota members that mediate these effects and the mechanisms underlying these interactions is rudimentary. The dearth of information regarding the nature of advantageous host–microbiota interactions, and the factors that cause these relationships to go awry, has hampered our ability to realize the therapeutic potential of the microbiota. Here we discuss key issues that limit current knowledge and describe a path forwards to improving our understanding of the contributions of the microbiota to host health.

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The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages

Cited by 647 publications

References 60 publications

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

Understanding immune–microbiota interactions in the intestine

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