Production of α-Galactosylceramide by a Prominent Member of the Human Gut Microbiota

Brown, Laura C.; Peñaranda, Cristina; Kashyap, Purna C.; Williams, Brianna B.; Clardy, Jon; Kronenberg, Mitchell; Sonnenburg, Justin L.; Comstock, Laurie E.; Bluestone, Jeffrey A.; Fischbach, Michael A.

doi:10.1371/journal.pbio.1001610

Cited by 222 publications

(265 citation statements)

References 36 publications

Supporting

Mentioning

252

Contrasting

Unclassified

Order By: Relevance

“…Of note, the ApoE −/− mouse atherosclerosis model is dependent on NK-T cell activation through CD1d [88], a restriction element for many self and microbial lipids in this model. Of note, the gut microbe Bacteroides fragilis was identified as a source of the Cd1d ligand α-galactosylceramide [89], which could be an interesting link between microbiota and atherogenesis. As the leakage of gut microbial products into the circulation is enhanced under highfat diet and the gut microbiota represents the major source of metabolic endotoxemia [3], microbiota-dependent activation of pattern recognition receptors could be involved in cardiovascular disease development at multiple levels.…”

Section: Gut Microbial Ligands Promote Cvd Development and Arterial Tmentioning

confidence: 99%

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

2018

View full text Add to dashboard Cite

Commensal gut microbiota have recently been implicated in cardiovascular disease (CVD) and cerebrovascular disease. Atherosclerotic plaque formation depends on the colonization status of the host. In addition to host nutrition and the related microbiota-dependent metabolic changes, activation of innate immune pathways triggers the development of atherosclerosis and supports arterial thrombosis. Gnotobiotic mouse models have uncovered that activation of Toll-like receptor-2 by gut microbial ligands supports von Willebrand factor-integrin mediated platelet deposition to the site of vascular injury. Depending on nutritional factors, the microbiota-derived choline-metabolite trimethylamine Noxide (TMAO) increases atherosclerotic plaque size, triggers prothrombotic platelet function and promotes arterial thrombus growth. Hence, the composition of the commensal microbiota is an emerging risk factor for CVD. Here, we provide an overview on microbiota-dependent pathomechanisms that drive the development of CVD and arterial thrombosis.Keywords: Arterial thrombosis r Atherosclerosis r Cardiovascular disease r Microbiota r Toll-like receptors IntroductionAt birth, our body surfaces are colonized by microbial communities (microbiota), representing one of the most densely colonized microbial ecosystems [1]. This process is strongly influenced by genetic, nutritional, and environmental factors [2]. The commensal microbiota constitutes a permanent inflammatory stimulus [3], which is kept in check by the host's immune responses [4]. The microbiota can be viewed as an organ that impacts host physiology [5,6]. Changes in gut microbiota composition were associated with intestinal diseases (e.g. inflammatory bowel disease, colon cancer) and cardiometabolic disease states, such as diet-induced obesity, type 2 diabetes, atherosclerosis, and arterial thrombosis [7]. The results from recent experimental and clinical studies have led to the assumption that Correspondence: Christoph Reinhardt e-mail: Christoph.Reinhardt@unimedizin-mainz.de molecules synthesized by the intestinal microbiota are involved in the development of cardiovascular disease (CVD) [8] and may increase the risk of arterial thrombosis [9, 10] as well as the outcome of ischemic stroke [11]. Experimental evidence from germ-free mouse studies and metagenomics analyses have associated the gut microbiota with obesity [12][13][14][15], type 2 diabetes [3, 16, 17], stroke [11, 18], and CVD [8, 9, 19]. Therefore, targeting the composition and metabolic function of the intestinal microbiota may represent a therapeutic option that in the future may allow prevention and treatment of cardiometabolic diseases [20].Here, we provide a comprehensive overview on the emerging link between gut microbiota and CVD. We delineate the contribution of this complex microbial ecosystem to metabolic inflammation and its impact on host metabolism. The main focus of this review is to highlight how gut microbiota may contribute to the development of CVD, cerebrovascular disease and arterial thromb...

show abstract

Section: Gut Microbial Ligands Promote Cvd Development and Arterial Tmentioning

confidence: 99%

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

2018

View full text Add to dashboard Cite

show abstract

“…This chemokine regulation has been shown to occur through epigenetic changes involving the reduction of methylation pattern of the CXCl16 gene and in so doing reducing the number of invariant NK T cells in the colonic lamina propria (Olszak et al, 2012). Bacteroides fragilis (B. fragilis) provides another example of a factor critical for the normal function of the immune system by producing glycosphingolipid which in turn inhibits natural killer T cells proliferation in the colonic lamina propria (Wieland Brown et al, 2013). B. fragilis polysaccharide A (PSA) is recognized by TLR2 on DCs and this interaction induces colonic regulatory T cells (Tregs) (Round and Mazmanian, 2009).…”

Section: Microbes and Immunitymentioning

confidence: 99%

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Dinan

Cryan

2016

Neuropsychopharmacol

201

121

View full text Add to dashboard Cite

There is now a large volume of evidence to support the view that the immune system is a key communication pathway between the gut and brain, which plays an important role in stress-related psychopathologies and thus provides a potentially fruitful target for psychotropic intervention. The gut microbiota is a complex ecosystem with a diverse range of organisms and a sophisticated genomic structure. Bacteria within the gut are estimated to weigh in excess of 1 kg in the adult human and the microbes within not only produce antimicrobial peptides, short chain fatty acids, and vitamins, but also most of the common neurotransmitters found in the human brain. That the microbial content of the gut plays a key role in immune development is now beyond doubt. Early disruption of the host-microbe interplay can have lifelong consequences, not just in terms of intestinal function but in distal organs including the brain. It is clear that the immune system and nervous system are in continuous communication in order to maintain a state of homeostasis. Significant gaps in knowledge remain about the effect of the gut microbiota in coordinating the immune-nervous systems dialogue. However, studies using germ-free animals, infective models, prebiotics, probiotics, and antibiotics have increased our understanding of the interplay. Early life stress can have a lifelong impact on the microbial content of the intestine and permanently alter immune functioning. That early life stress can also impact adult psychopathology has long been appreciated in psychiatry. The challenge now is to fully decipher the molecular mechanisms that link the gut microbiota, immune, and central nervous systems in a network of communication that impacts behavior patterns and psychopathology, to eventually translate these findings to the human situation both in health and disease. Even at this juncture, there is evidence to pinpoint key sites of communication where gut microbial interventions either with drugs or diet or perhaps fecal microbiota transplantation may positively impact mental health.

show abstract

“…The spleen contains a large population of NKT cells distributed throughout the parenchyma in the steady-state (7). Type I NKT cells expressing an invariant TCR Va14 chain coupled with a limited TCR Vb-chain repertoire can recognize bacterial glycolipids (8)(9)(10) or upregulated expression of endogenous glycolipids (11) in the context of the MHC class I-like molecule CD1d on APCs. Once stimulated, NKT cells consolidate in the marginal zone (MZ) and from this location can provoke a powerful cascade of molecular and cellular interactions that can influence effector outcomes throughout the spleen (7,12).…”

mentioning

confidence: 99%

Activated NKT Cells Can Condition Different Splenic Dendritic Cell Subsets To Respond More Effectively to TLR Engagement and Enhance Cross-Priming

Osmond

Farrand

Painter

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

The function of dendritic cells (DCs) can be modulated through multiple signals, including recognition of pathogen-associated molecular patterns, as well as signals provided by rapidly activated leukocytes in the local environment, such as innate-like T cells. In this article, we addressed the possibility that the roles of different murine DC subsets in cross-priming CD8+ T cells can change with the nature and timing of activatory stimuli. We show that CD8α+ DCs play a critical role in cross-priming CD8+ T cell responses to circulating proteins that enter the spleen in close temporal association with ligands for TLRs and/or compounds that activate NKT cells. However, if NKT cells are activated first, then CD8α− DCs become conditioned to respond more vigorously to TLR ligation, and if triggered directly, these cells can also contribute to priming of CD8+ T cell responses. In fact, the initial activation of NKT cells can condition multiple DC subsets to respond more effectively to TLR ligation, with plasmacytoid DCs making more IFN-α and both CD8α+ and CD8α− DCs manufacturing more IL-12. These results suggest that different DC subsets can contribute to T cell priming if provided appropriately phased activatory stimuli, an observation that could be factored into the design of more effective vaccines.

show abstract

Production of α-Galactosylceramide by a Prominent Member of the Human Gut Microbiota

Abstract: A common human gut bacterium, Bacteroides fragilis, produces a sphingolipid ligand for the conserved host receptor CD1d and can modulate natural killer T cell activity.

Cited by 222 publications

References 36 publications

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

Activated NKT Cells Can Condition Different Splenic Dendritic Cell Subsets To Respond More Effectively to TLR Engagement and Enhance Cross-Priming

Contact Info

Product

Resources

About