Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity

Meng, Xiang; Zhou, Hangcheng; Shen, Hui‐Hui; Lufumpa, Eniya; Li, Xiaomei; Guo, Baolei; Li, Baozhu

doi:10.1016/j.autrev.2019.03.006

Cited by 37 publications

(19 citation statements)

References 303 publications

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“…Gut microbiota depletion alters profiles of cecum metabolomics and gut microbiomes. As previously described, the way that the microbiota modulates host immunity and susceptibility to infection depends largely on metabolites (35)(36)(37)(38). To definitely determine the metabolic profiles of antibiotic-treated mice, we performed in-depth untargeted metabolomics sequencing of cecum samples by liquid chromatography-mass spectrometry (LC-MS).…”

Section: Resultsmentioning

confidence: 99%

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

et al. 2020

mSystems

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ABSRTACT Klebsiella pneumoniae is a common cause of human-pneumonia-derived sepsis with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis. The mechanisms by which the gut microbiota affects the host defenses in the respiratory system systematically, however, remain poorly understood. Here, we show that gut microbiota depletion increases susceptibility to extracellular K. pneumoniae infections in terms of increased bacterial burdens in lung and decreased survival rates. Oral supplementation with gut microbiota-derived short-chain fatty acids (SCFAs), subsequently activating G protein-coupled receptor 43 (GPCR43), enhances a macrophage’s capacity to phagocytose invading K. pneumoniae. Furthermore, SCFAs and GPR43 increase macrophage bacterial clearance by upregulating LAMTOR2, which is further identified as an antibacterial effector and elucidated to facilitate phagosome-lysosome fusion and extracellular signal-regulated kinase (ERK) phosphorylation. Lastly, conditional ablation of Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation. IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.

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Section: Resultsmentioning

confidence: 99%

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

et al. 2020

mSystems

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“…The mammalian immune system has a complex and dynamic bidirectional relationship with the microbiome (38). As previously described, the gut microbiota regulates the host immune systems, in part by producing metabolites (39,40). To assess the specific metabolomic profiles of K. pneumonia-challenged mice, we performed in-depth untargeted metabolomics sequencing of cecal contents by liquid chromatography-mass spectrometry (LC-MS) at Beijing Genomics Institute, Shenzhen.…”

Section: Alterations In the Cecal Metabolome Of K Pneumoniae-infectementioning

confidence: 99%

Alterations in the Gut Microbiome and Cecal Metabolome During Klebsiella pneumoniae-Induced Pneumosepsis

et al. 2020

Front. Immunol.

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Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis in human and is associated with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis during bacterial infections. However, the mechanisms by which the gut microbiota affects immune responses in the lung still remain poorly understood. Here, we performed cecal metabolomics sequencing and fecal 16s rRNA sequencing in K. pneumoniae-infected mice and uninfected controls and showed that K. pneumoniae infection led to profound alterations in the gut microbiome and thus the cecal metabolome. We observed that the levels of Lactobacillus reuteri and Bifidobacterium pseudolongum were significantly decreased in K. pneumoniae-infected mice. Spearman correlation analysis showed that alterations in the richness and composition of the gut microbiota were associated with profound changes in host metabolite concentrations. Further, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, were detected in cecal contents and serum by gas chromatography-mass spectrometry (GC-MS). We observed that the concentrations of these three SCFAs were all lower in the infected groups than in the untreated controls. Lastly, oral supplementation with these three SCFAs reduced susceptibility to K. pneumoniae infections, as indicated by lower bacterial burdens in the lung and higher survival rates. Our data highlight the protective roles of gut microbiota and certain metabolites in K. pneumoniae-pneumonia and suggests that it is possible to intervene in this bacterial pneumonia by targeting the gut microbiota.

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“…A beneficial anti-inflammatory role for a high fiber diet is well-described for a large range of largely non-infectious disease settings in murine models (1–7). The use of high fiber diets to ameliorate human diseases is thus being actively pursued (8, 9), in particularly for autoimmune conditions (10, 11). Some evidence for benefit in humans has emerged, although results have often been inconclusive (12).…”

Section: Introductionmentioning

confidence: 99%

“…A high fiber diet changes the gut microbiome, with a number of studies in mice (3, 13, 14) and humans (15, 16) detailing the changes in bacterial species compositions. Bacterial fermentation of fiber (primarily undigested and/or indigestible carbohydrate) results in the production of short chain fatty acids (SCFA) such as acetate, propionate and butyrate, which enter the circulation and are believed to be the key players in dietary fiber-mediated systemic anti-inflammatory activities (8, 10, 17). SCFAs mediate effects on a number of cells including T cells (18, 19) particularly regulatory T cells (20), macrophages (21–23) and endothelial cells (24).…”

Section: Introductionmentioning

confidence: 99%

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate

et al. 2019

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Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus associated with a robust systemic infection and an acute inflammatory rheumatic disease. A high fiber diet has been widely promoted for its ability to ameliorate inflammatory diseases. Fiber is fermented in the gut into short chain fatty acids such as acetate, propionate, and butyrate, which enter the circulation providing systemic anti-inflammatory activities. Herein we show that mice fed a high fiber diet show a clear exacerbation of CHIKV arthropathy, with increased edema and neutrophil infiltrates. RNA-Seq analyses illustrated that a high fiber diet, in this setting, promoted a range of pro-neutrophil responses including Th17/IL-17. Gene Set Enrichment Analyses demonstrated significant similarities with mouse models of inflammatory psoriasis and significant depression of macrophage resolution phase signatures in the CHIKV arthritic lesions from mice fed a high fiber diet. Supplementation of the drinking water with butyrate also increased edema after CHIKV infection. However, the mechanisms involved were different, with modulation of AP-1 and NF-κB responses identified, potentially implicating deoptimization of endothelial barrier repair. Thus, neither fiber nor short chain fatty acids provided benefits in this acute infectious disease setting, which is characterized by widespread viral cytopathic effects and a need for tissue repair.

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Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity

Cited by 37 publications

References 303 publications

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages

Alterations in the Gut Microbiome and Cecal Metabolome During Klebsiella pneumoniae-Induced Pneumosepsis

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate

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