The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIIIgamma, a secreted C-type lectin. RegIIIgamma binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. We show that RegIIIgamma and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. We propose that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships.
The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load. To address this question we studied Paneth cells, a key small intestinal epithelial lineage. We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria. Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis. Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface.commensal bacteria ͉ epithelium ͉ innate immunity ͉ intestine ͉ toll-like receptors H umans harbor nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of coevolution have molded this human-microbe interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment (1). However, bacterial invasion of tissue can result in breakdown of this symbiotic association and lead to pathologies such as inflammatory bowel disease (2). Intestinal epithelia constitute the major interface between the microbiota and internal host tissues. Despite the enormous numbers of commensal bacteria, microbial incursions across mucosal surfaces are relatively rare, suggesting that intestinal epithelia harbor highly effective mechanisms for controlling microbial interactions with the host mucosal interface. However, little is known about how intestinal epithelial cells maintain homeostasis with vast, complex populations of enteric bacteria.The Paneth cell is a specialized small intestinal epithelial lineage that resides at the base of crypts of Lieberkühn and contributes to intestinal innate immunity by secreting a diverse repertoire of antimicrobial proteins (3). Several antimicrobial factors in Paneth cells are expressed under the control of indigenous microorganisms (4, 5). In addition, ex vivo studies on isolated small intestinal crypts indicate that secretion of antimicrobial products is triggered by bacterial signals (3). However, itis not yet clear whether Paneth cells detect bacteria through cell-autonomous mechanisms. Furthermore, although Paneth cells are known to secrete abundant antimicrobial factors (3), the in vivo functional role of Paneth cells in maintaining homeostasis with commensal bacterial populations has not been established.In this report, we show that Paneth cells detect enteric bacteria through cell-autonomous MyD88 activation, triggering expression of multiple antimicrobial factors. We show that Paneth cell-intrinsic MyD88 signaling limits bacterial penetration of host tissues, disclo...
Summary Inflammatory diseases of the gastrointestinal tract are frequently associated with changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria), a common signature of dysbiosis (1–8). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum cofactor-dependent microbial respiratory pathways that are only operational during episodes of inflammation. In contrast, tungstate treatment caused no overt changes in the microbiota composition under homeostatic conditions. Importantly, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in murine models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the setting of gut inflammation.
The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. Here we show that γδ intraepithelial lymphocytes (γδ IEL) of the small intestine produce innate antimicrobial factors in response to resident bacterial "pathobionts" that penetrate the intestinal epithelium. γδ IEL activation was dependent on epithelial cell-intrinsic MyD88, suggesting that epithelial cells supply microbe-dependent cues to γδ IEL. Finally, γδ T cells protect against invasion of intestinal tissues by resident bacteria specifically during the first few hours after bacterial encounter, indicating that γδ IEL occupy a unique temporal niche among intestinal immune defenses. Thus, γδ IEL detect the presence of invading bacteria through cross-talk with neighboring epithelial cells and are an essential component of the hierarchy of immune defenses that maintain homeostasis with the intestinal microbiota.antibacterial defense | mucosal immunity | microbiota
SUMMARY Intestinal inflammation is frequently associated with an alteration of the gut microbiota, termed dysbiosis, which is characterized by a reduced abundance of obligate anaerobic bacteria and an expansion of Proteobacteria such as commensal E. coli. The mechanisms enabling the outgrowth of Proteobacteria during inflammation are incompletely understood. Metagenomic sequencing revealed bacterial formate oxidation and aerobic respiration to be overrepresented metabolic pathways in a chemically-induced murine model of colitis. Dysbiosis was accompanied by increased formate levels in the gut lumen. Formate was of microbial origin since no formate was detected in germ-free mice. Complementary studies using commensal E. coli strains as model organisms indicated that formate dehydrogenase and terminal oxidase genes provided a fitness advantage in murine models of colitis. In vivo, formate served as electron donor in conjunction with oxygen as the terminal electron acceptor. This work identifies bacterial formate oxidation and oxygen respiration as metabolic signatures for inflammation-associated dysbiosis.
Summary Toxoplasma gondii is a universally-distributed pathogen that infects over 1 billion people worldwide. Host resistance to this protozoan parasite depends on the potent production of IL-12 and IFN-γ. Although Toll-like receptor 11 (TLR11) plays a major role in controlling Th1 immunity to this pathogen in mice, this innate immune receptor is not functional in humans, and the mechanisms of TLR11-independent sensing of T. gondii remain elusive. Here, we show that both mucosal innate and adaptive immune responses to T. gondii rely on the indirect stimulation of dendritic cells by normal gut microflora. We identify a novel function for commensal bacteria in which they provide an immunostimulatory effect on dendritic cells during parasitic infection. Our results reveal that indirect immunostimulation by gut commensals provides protection against T. gondii in the absence of TLR11.
The intestinal mucosal surface is in direct contact with a vast beneficial microbiota. The symbiotic nature of this relationship is threatened when the surface epithelium is injured, yet little is known about how mucosal surfaces maintain homeostasis with commensal microbes following damage. ␥␦ Intraepithelial lymphocytes (␥␦ IEL) reside at the gut epithelial surface, where they stimulate mucosal healing following acute injury. A genome-wide analysis of the ␥␦ IEL response to dextran sulfate sodium-induced colonic damage revealed induction of a complex transcriptional program, including coordinate regulation of cytoprotective, immunomodulatory, and antibacterial factors. Studies in germfree mice demonstrated that commensal microbiota regulate key components of this transcriptional program, thus revealing a dialogue between commensal bacteria and ␥␦ IEL in injured epithelia. Analysis of TCR␦-deficient mice indicated that ␥␦ T cells are essential for controlling mucosal penetration of commensal bacteria immediately following dextran sulfate sodium-induced damage, suggesting that a key function of ␥␦ IEL is to maintain host-microbial homeostasis following acute mucosal injury. Taken together, these findings disclose a reciprocal relationship between ␥␦ T cells and intestinal microbiota that promotes beneficial host-microbial relationships in the intestine.
During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.