Regulation of human enteric α-defensins by NOD2 in the Paneth cell lineage.
Tan Gao,Zeng Bin,Zhi Fa-Chao
European journal of cell biology
Human enteric α-defensins (HD5 and HD6), major antimicrobial peptides produced by Paneth cells in the intestine, play important roles in intestinal innate immunity. Since their expression is decreased in Crohn's disease (CD), with decreased expression being more pronounced in the presence of NOD2 mutations, it would be extremely interesting to investigate the mechanism by which NOD2 may regulate expression of human enteric α-defensins. Here we show that although NOD2 by itself can slightly up-regulate expression of enteric α-defensins mainly through activation of the NF-κB pathway, it can strongly down-regulates their expression during differentiation of the Paneth cell lineage mainly by inhibiting activation of the MAPK pathway. Since NOD2 is over-expressed in CD and mutant NOD2 cannot result in NF-κB activity, our finding can provide an explanation of the previous observation showing decreased expression of human enteric α-defensin in CD and even more so in the presence of NOD2 mutations. In addition, this finding provides a new view on the function of NOD2 in regulating intestinal innate immunity.
10.1016/j.ejcb.2014.10.007
Positive and negative regulatory effects of transcription factor activator protein 1 (AP1) on the expression of antimicrobial peptides in Macrobrachium nipponense.
Zhang Chao,Cao Xueying,Wang Kaiqiang,Dai Xiaoling,Zhang Ruidong,Zhang Zhuoxing,Huang Xin,Ren Qian
Fish & shellfish immunology
Transcription factor activator protein 1 (AP1) plays an irreplaceable role in the response to a variety of external stimulants, such as cellar stress, bacterial and viral infections, and inflammatory cytokines. In this study, we identified a novel AP1 gene from Macrobrachium nipponense and named it MnAP1, which has a full length of 1747 bp contains an 882 bp open reading frame, and encodes a protein with 293 amino acids. The MnAP1 protein contains Pfam and bZIP domains. MnAP1 is widely distributed in hemocytes, heart, hepatopancreas, gill, stomach, and intestinal tissues. The expression levels of MnAP1 in the gills and stomach were significantly upregulated after Vibrio parahaemolyticus and Staphylococcus aureus attacks. We studied the relationship between MnAP1 and the transcripts of antimicrobial peptides (AMPs) in gills through RNA interference. Interestingly, the regulatory effects of MnAP1 on the expression of different AMPs were different. We found that the expression levels of crustins, including Cru1, Cru3, and Cru4 in the gills were evidently decreased, whereas the synthesis of Cru5 and anti-lipopolysaccharide factors (ALF3 and ALF4) were obviously increased. We further explored the effect of MnAP1 on the expression of transcription factor relish from M. nipponense. The result showed that the knockdown of MnAP1 can remarkably upregulate the expression of MnRelish. Relish as a member of the nuclear factor κB family that regulates the expression of AMPs in the innate immunity of crustacean. Hence, we also detected the expression levels of Cru5, ALF3, and ALF4 in the gills of MnRelish-silenced prawns. The Data showed that the expression levels of these three AMPs were evidently reduced after MnRelish silencing. Our results indicated that MnAP1 plays a positive role in regulating the expression of AMPs, promotes the JNK/AP1 signaling pathway, and exerts a negative regulatory effect on the synthesis of AMPs by inhibiting the transcription of NF-κB factor in the innate immunity of M. nipponense.
10.1016/j.fsi.2020.01.002
L-Threonine upregulates the expression of β-defensins by activating the NF-κB signaling pathway and suppressing SIRT1 expression in porcine intestinal epithelial cells.
Wang Chenxi,Yang Yang,Gao Nan,Lan Jing,Dou Xiujing,Li Jianping,Shan Anshan
Food & function
The use of antimicrobial peptide (AMP), found in all forms of life and playing a pivotal role in the innate immune system, has been developed as a new strategy for maintaining intestinal health and reducing antibiotic usage due to its ability to resist pathogens and commensal microbes. The current study investigated the effects of l-threonine on β-defensin expression, the intestinal mucosal barrier and inflammatory cytokine expression in porcine intestinal epithelial cell lines (IPEC-J2). The results revealed that in IPEC-J2 cells, l-threonine significantly increased the expression of β-defensin (including pBD-1, pBD-2, and pBD-3) in a dose- and time-dependent manner (P < 0.05). By using different concentrations and treatment times of l-threonine, the results showed that the expression of β-defensin was upregulated to the greatest extent in IPEC-J2 cells cultured with 1 mM l-threonine for 24 h. Although the mRNA expression levels of β-defensins were markedly increased (P < 0.05), there was relatively little inducible pBD-1, pBD-2 and pBD-3 mRNA expression at the sub-confluent and confluent densities in comparison with post-confluent densities. Furthermore, we found that l-threonine enhanced the β-defensin expression by suppressing the expression of SIRT1, which increased acetylated p65 expression, and activating the NF-κB signaling pathway, which induced the translocation of p65 from the cytoplasm to the nucleus. In addition, l-threonine significantly prevented LPS-induced intestinal mucosal barrier damage by attenuating the decreasing tendency of the mRNA expression of Mucin1 and Mucin2 (P < 0.05). Simultaneously, l-threonine enhanced the expression of β-defensins upon LPS challenge in IPEC-J2 cells (P < 0.05). l-Threonine obviously decreased the mRNA expression of inflammatory cytokines compared to that in untreated cells (P < 0.05). In conclusion, l-threonine can upregulate β-defensin expression and reduce inflammatory cytokine expression in IPEC-J2 cells; meanwhile, l-threonine alleviates LPS-induced intestinal mucosal barrier damage in porcine intestinal epithelial cells. The l-threonine-mediated modulation of endogenous defensin expression may be a promising approach to reduce antibiotic use, enhance disease resistance and intestinal health in animals.
10.1039/d1fo00269d
Colonic MUC2 mucin regulates the expression and antimicrobial activity of β-defensin 2.
Mucosal immunology
In this study we identified mechanisms at the colonic mucosa by which MUC2 mucin regulated the production of β-defensin in a proinflammatory milieu but functionally protected susceptible bacteria from its antimicrobial effects. The regulator role of MUC2 on production of β-defensin 2 in combination with the proinflammatory cytokine interleukin-1β (IL-1β) was confirmed using purified human colonic MUC2 mucin and colonic goblet cells short hairpin RNA (shRNA) silenced for MUC2. In vivo, Muc2(-/-) mice showed impaired β-defensin mRNA expression and peptide localization in the colon as compared with Muc2(+/-) and Muc2(+/+) littermates. Importantly, purified MUC2 mucin abrogated the antimicrobial activity of β-defensin 2 against nonpathogenic and enteropathogenic Escherichia coli. Sodium metaperiodate oxidation of MUC2 removed the capacity of MUC2 to stimulate β-defensin production and MUC2's inhibition of defensin antimicrobial activity. This study highlights that a defective MUC2 mucin barrier, typical in inflammatory bowel diseases, may lead to deficient stimulation of β-defensin 2 and an unbalanced microbiota that favor the growth of β-defensin-resistant microbes such as Clostridium difficile.
10.1038/mi.2015.27
The protective roles of NLRP6 in intestinal epithelial cells.
Yin Jiuheng,Sheng Baifa,Yang Kunqiu,Sun Lihua,Xiao Weidong,Yang Hua
Cell proliferation
The evolution of chronic inflammatory diseases is thought to be due to a combination of host genetic variations and environmental factors that include the alteration of intestinal flora, termed "dysbiosis." The intestinal mucosal barrier includes a chemical barrier and physical barrier that have important roles in protecting the intestine against inflammatory injury. The chemical barrier includes antimicrobial peptides (AMPs), and the physical barrier includes a mucous layer, a monolayer of intestinal epithelial cells and cell junctions. The intestinal mucosal barrier is not a static barrier, but rather, it strongly interacts with the gut microbiome and cells of the immune system. Correct expression of AMPs, together with mucus and balanced epithelial cell proliferation, prevents the occurrence of disease. NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, participates in the progression of intestinal inflammation and enteric pathogen infections. It has become apparent in recent years that NLRP6 is important in disease pathogenesis, as it responds to internal ligands that lead to the release of AMPs and mucus, thus regulating the regeneration of intestinal epithelial cells. This review summarizes the activation of NLRP6 and its protective role in the intestinal epithelial cell.
10.1111/cpr.12555
Down-regulation of human enteric antimicrobial peptides by NOD2 during differentiation of the paneth cell lineage.
Tan Gao,Li Run-hua,Li Chen,Wu Fang,Zhao Xin-mei,Ma Jia-yi,Lei Shan,Zhang Wen-di,Zhi Fa-chao
Scientific reports
Ileal Crohn's disease (CD) arising from the alteration of intestinal homeostasis is characterized by two features, namely a decrease in Paneth cell-produced antimicrobial peptides that play a key role in maintaining this balance and an increase in NOD2, an intracellular sensor. Although mutations in NOD2 are highly correlated with the incidence of CD, the physiological role of NOD2 in intestinal immunity remains elusive. Here, we show that NOD2 can down-regulate the expression of human enteric antimicrobial peptides during differentiation of the Paneth cell lineage. This finding, which links the decrease of human enteric antimicrobial peptides to increased NOD2 in ileal CD patients, provides a new view into the pathogenesis of ileal CD.
10.1038/srep08383
FOXO inhibition rescues α-defensin expression in human intestinal organoids.
Proceedings of the National Academy of Sciences of the United States of America
To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring and to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.
10.1073/pnas.2312453120
Natural molecules induce and synergize to boost expression of the human antimicrobial peptide β-defensin-3.
Sechet Emmanuel,Telford Erica,Bonamy Clément,Sansonetti Philippe J,Sperandio Brice
Proceedings of the National Academy of Sciences of the United States of America
Antimicrobial peptides (AMPs) are mucosal defense effectors of the human innate immune response. In the intestine, AMPs are produced and secreted by epithelial cells to protect the host against pathogens and to support homeostasis with commensals. The inducible nature of AMPs suggests that potent inducers could be used to increase their endogenous expression for the prevention or treatment of diseases. Here we aimed at identifying molecules from the natural pharmacopoeia that induce expression of human β-defensin-3 (HBD3), one of the most efficient AMPs, without modifying the production of proinflammatory cytokines. By screening, we identified three molecules isolated from medicinal plants, andrographolide, oridonin, and isoliquiritigenin, which induced HBD3 production in human colonic epithelial cells. This effect was observed without activation of the NF-κB pathway or the expression of associated proinflammatory cytokines. We identified the EGF receptor as the target of these compounds and characterized the downstream-activated MAPK pathways. At the chromatin level, molecules increased phosphorylation of histone H3 on serine S10 and recruitment of the c-Fos, c-Jun, and Elk1 or c-Myc transcription factors at the HBD3 promoter. Interestingly, stimulating cells with a combination of andrographolide and isoliquiritigenin synergistically enhanced HBD3 induction 10-fold more than observed with each molecule alone. Finally, we investigated the molecular basis governing the synergistic effect, confirmed our findings in human colonic primary cells, and demonstrated that synergism increased cellular antimicrobial activity. This work shows the capability of small molecules to achieve induction of epithelial antimicrobial defenses while simultaneously avoiding the deleterious risks of an inflammatory response.
10.1073/pnas.1805298115
Expression of the human antimicrobial peptide β-defensin-1 is repressed by the EGFR-ERK-MYC axis in colonic epithelial cells.
Bonamy Clément,Sechet Emmanuel,Amiot Aurélien,Alam Antoine,Mourez Michael,Fraisse Laurent,Sansonetti Philippe J,Sperandio Brice
Scientific reports
The human β-defensin-1 (HBD1) is an antimicrobial peptide constitutively expressed by epithelial cells at mucosal surfaces. In addition to its microbicidal properties, the loss of HBD1 expression in several cancers suggests that it may also have an anti-tumor activity. Here, we investigated the link between HBD1 expression and cancer signaling pathways in the human colon cancer cell lines TC7 and HT-29, and in normal human colonic primary cells, using a mini-gut organoid model. Using available datasets from patient cohorts, we found that HBD1 transcription is decreased in colorectal cancer. We demonstrated that inhibiting the Epidermal Growth Factor Receptor (EGFR) increased HBD1 expression, whereas activating EGFR repressed HBD1 expression, through the MEKK1/2-ERK1/2 pathway that ultimately regulates MYC. We finally present evidences supporting a role of MYC, together with the MIZ1 coregulator, in HBD1 regulation. Our work uncovers the role and deciphers the function of the EGFR-ERK-MYC axis as a repressor of HBD1 expression and contributes to the understanding of HBD1 suppression observed in colorectal cancer.
10.1038/s41598-018-36387-z
Expression and regulation of antimicrobial peptides in the gastrointestinal tract.
Cunliffe R N,Mahida Y R
Journal of leukocyte biology
The gastrointestinal (GI) tract is exposed to a wide range of microorganisms. The expression of antimicrobial peptides has been demonstrated in different regions of the GI tract, predominantly in epithelial cells, which represent the first host cells with which the microorganisms have to interact for invasion. The intestinal epithelial monolayer is complex, consisting of different cell types, and most have a limited lifespan. Of the GI antimicrobial peptides, alpha- and beta-defensins have been studied the most and are expressed by distinct types of epithelial cells. Enteric alpha-defensin expression is normally restricted to Paneth and intermediate cells in the small intestine. However, there are important differences between mice and humans in the processing of the precursor forms of enteric alpha-defensins. Parasite infection induces an increase in the number of enteric alpha-defensin-expressing Paneth and intermediate cells in the murine small intestine. In the chronically inflamed colonic mucosa, metaplastic Paneth cells (which are absent in the normal colon) also express enteric alpha-defensins. Epithelial expression of beta-defensins may be constitutive or inducible by infectious and inflammatory stimuli. The production of some members of the beta-defensin family appears to be restricted to distinct parts of the GI tract. Recent studies using genetically manipulated rodents have demonstrated the likely in vivo importance of enteric antimicrobial peptides in innate host defense against microorganisms. The ability of these peptides to act as chemoattractants for cells of the innate- and adaptive-immune system may also play an important role in perpetuating chronic inflammation in the GI tract.
10.1189/jlb.0503249
Regulation of expression of beta-defensins: endogenous enteric peptide antibiotics.
O'Neil Deborah A
Molecular immunology
Evidence for the central role that intestinal beta-defensins play in maintaining gut health continues to accumulate within the literature. Two epithelially-derived enteric beta-defensins, hBD1 and hBD2, have been identified thus far and the following chapter reviews our current understanding of how the expression and secretion of these endogenous antimicrobial, chemotactic and adjuvant peptides is regulated within the context of the most microbe-rich of mucosal environments, the gastrointestinal tract. The agonists and microbial moieties identified as being responsible for the direct receptor-mediated induction of enteric epithelial beta-defensins, the signaling and nuclear events that are triggered as a consequence and which drive defensin gene transcription, the potential antimicrobial and immunomodulatory consequences of beta-defensin release within the luminal and mucosal aspects of the alimentary tract thereafter and the validity of animal models for the study of these key immune effector molecules in vivo are discussed. These significant and recent discoveries have provided much in the way of momentum for the pace with which this exciting and dynamic area of mucosal immunology research continues to move forward.
Paneth cell alpha-defensin synthesis and function.
Ouellette A J
Current topics in microbiology and immunology
Endogenous antimicrobial peptides (AMPs) mediate innate immunity in every species in which they have been investigated. Cathelicidins and defensins are the two major AMP families in mammals, and they are abundant components of phagocytic leukocytes and are released by epithelial cells at mucosal surfaces. In the small intestine, Paneth cells at the base of the crypts of Lieberkühn secrete alpha-defensins and additional AMPs at high levels in response to cholinergic stimulation and when exposed to bacterial antigens. Paneth cell alpha-defensins evolved to function in the extracellular environment with broad-spectrum antimicrobial activities, and they constitute the majority of bactericidal peptide activity secreted by Paneth cells. The release of Paneth cell products into the crypt lumen is inferred to protect mitotically active crypt cells from colonization by potential pathogens and confers protection from enteric infection, as is evident from the immunity of mice expressing a human Paneth cell alpha-defensin transgene to oral infection by Salmonella enterica serovar Typhimurium. alpha-Defensins in Paneth cell secretions also may interact with bacteria in the intestinal lumen above the crypt-villus boundary and influence the composition of the enteric microbial flora. Mutations that cause defects in the activation, secretion, dissolution, and bactericidal effects of Paneth cell AMPs may alter crypt innate immunity and contribute to immunopathology.
Defensins.
Ganz T,Lehrer R I
Current opinion in immunology
Defensins are widely distributed and abundant 3-4 kDa antimicrobial peptides that are variable cationic and contain six disulfide-paired cysteines. Three structurally distinct peptide families have been identified: 'classical' defensins, beta-defensins and insect defensins. In many animal species, defensin genes are found in clusters with substantial sequence variability outside the core disulfide-linked cysteines. Defensin peptides have been found in the granules of phagocytes and intestinal Paneth cells, on epithelial surfaces of the intestine and the trachea, and in the hemolymph of insects. They are produced from larger precursors by stepwise, tissue-specific, proteolytic processing, a production resembling that of peptide hormones. Microbes in the phagocytic vacuoles of granulocytes and certain macrophages encounter high concentrations of defensins. Increased transcription of defensin genes and stimulus-dependent release of pre-synthesized defensin-containing cytoplasmic granules contribute to the local antimicrobial response.
Transcriptional Regulation of Antimicrobial Host Defense Peptides.
Lyu Wentao,Curtis Amanda R,Sunkara Lakshmi T,Zhang Guolong
Current protein & peptide science
Host defense peptides (HDPs) are of either myeloid or epithelial origin with antimicrobial and immunomodulatory functions. Due to HDP's ability to physically disrupt bacterial cell membranes and profoundly regulate host innate and adaptive immunity, microbial resistance to these peptides is rare. As an important first line of defense, HDPs are mostly present in epithelial cells of the digestive, respiratory or urogenital tracts as well as in the granules of neutrophils, macrophages or intestinal secretory Paneth cells. HDPs are either directly released or inducibly expressed upon exposure to microbes or microbial products, although certain pathogens such as Shigella have evolved an ability to down-regulate HDP synthesis as an immune invasion strategy. Even if a majority of HDPs are induced by infection and inflammation, it is undesirable to augment HDP synthesis and host immunity using pathogen-associated molecular patterns because of an excessive inflammation that is usually accompanied. Recently, several different classes of small-molecule compounds have been identified with the capacity to specifically induce HDP synthesis without triggering extensive inflammatory response. A few HDPinducing compounds even synergize with each other in HDP induction. In this review, we summarized the recent progresses on transcriptional regulation of HDPs by infection and inflammation and by small-molecule compounds. We suggested the potential of dietary regulation of HDPs as a novel antibiotic-alternative strategy to antimicrobial therapy, as oral supplementation of HDP-inducing compounds has shown promise of preventing and controlling infections in humans and several animal species.
10.2174/1389203716666150630133432
ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides.
Hu Xiaoming,Deng Jiali,Yu Tianming,Chen Shanghai,Ge Yadong,Zhou Ziheng,Guo Yajie,Ying Hao,Zhai Qiwei,Chen Yan,Yuan Feixiang,Niu Yuguo,Shu Weigang,Chen Huimin,Ma Caiyun,Liu Zhanju,Guo Feifan
Gastroenterology
BACKGROUND & AIMS:Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBDs) and mice with enterocolitis. METHODS:We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of the colon from 21 patients with active Crohn's disease (CD), 22 patients with active ulcerative colitis (UC), and 38 control individuals without IBD and of the ileum from 19 patients with active CD and 8 individuals without IBD in China. Mice with disruption of Atf4 specifically in intestinal epithelial cells (Atf4ΔIEC mice) and Atf4-floxed mice (controls) were given dextran sodium sulfate (DSS) to induce colitis. Some mice were given injections of recombinant defensin α1 (DEFA1) and supplementation of l-alanyl-glutamine or glutamine in drinking water. Human and mouse ileal and colon tissues were analyzed by quantitative real-time polymerase chain reaction, immunoblots, and immunohistochemistry. Serum and intestinal epithelial cell (IEC) amino acids were measured by high-performance liquid chromatography-tandem mass spectrometry. Levels of ATF4 were knocked down in IEC-18 cells with small interfering RNAs. Microbiomes were analyzed in ileal feces from mice by using 16S ribosomal DNA sequencing. RESULTS:Levels of ATF4 were significantly decreased in inflamed intestinal mucosa from patients with active CD or active UC compared with those from uninflamed regions or intestinal mucosa from control individuals. ATF4 was also decreased in colonic epithelia from mice with colitis vs mice without colitis. Atf4ΔIEC mice developed spontaneous enterocolitis and colitis of greater severity than control mice after administration of DSS. Atf4ΔIEC mice had decreased serum levels of glutamine and reduced levels of antimicrobial peptides, such as Defa1, Defa4, Defa5, Camp, and Lyz1, in ileal Paneth cells. Atf4ΔIEC mice had alterations in ileal microbiomes compared with control mice; these changes were reversed by administration of glutamine. Injections of DEFA1 reduced the severity of spontaneous enteritis and DSS-induced colitis in Atf4ΔIEC mice. We found that expression of solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, was directly regulated by ATF4 in cell lines. Overexpression of SLC1A5 in IEC-18 or primary IEC cells increased glutamine uptake and expression of antimicrobial peptides. Knockdown of ATF4 in IEC-18 cells increased expression of inflammatory cytokines, whereas overexpression of SLC1A5 in the knockdown cells reduced cytokine expression. Levels of SLC1A5 were decreased in inflamed intestinal mucosa of patients with CD and UC and correlated with levels of ATF4. CONCLUSIONS:Levels of ATF4 are decreased in inflamed intestinal mucosa from patients with active CD or UC. In mice, ATF4 deficiency reduces glutamine uptake by intestinal epithelial cells and expression of antimicrobial peptides by decreasing transcription of Slc1a5. ATF4 might therefore be a target for the treatment of IBD.
10.1053/j.gastro.2018.11.033
Paneth cell α-defensin 6 (HD-6) is an antimicrobial peptide.
Mucosal immunology
Defensins protect human barriers from commensal and pathogenic microorganisms. Human α-defensin 6 (HD-6) is produced exclusively by small intestinal Paneth cells but, in contrast to other antimicrobial peptides (AMPs) for HD-6, no direct antibacterial killing activity has been detected so far. Herein, we systematically tested how environmental factors, like pH and reducing conditions, affect antimicrobial activity of different defensins against anaerobic bacteria of the human intestinal microbiota. Remarkably, by mimicking the intestinal milieu we detected for the first time antibacterial activity of HD-6. Activity was observed against anaerobic gut commensals but not against some pathogenic strains. Antibiotic activity was attributable to the reduced peptide and independent of free cysteines or a conserved histidine residue. Furthermore, the oxidoreductase thioredoxin, which is also expressed in Paneth cells, is able to reduce a truncated physiological variant of HD-6. Ultrastructural analyses revealed that reduced HD-6 causes disintegration of cytoplasmic structures and alterations in the bacterial cell envelope, while maintaining extracellular net-like structures. We conclude that HD-6 is an antimicrobial peptide. Our data suggest two distinct antimicrobial mechanisms by one peptide: HD-6 kills specific microbes depending on the local environmental conditions, whereas known microbial trapping by extracellular net structures is independent of the reducing milieu.
10.1038/mi.2014.100
Current understanding of the gut microbiota shaping mechanisms.
Chang Cherng-Shyang,Kao Cheng-Yuan
Journal of biomedical science
Increasing evidences have shown strong associations between gut microbiota and many human diseases, and understanding the dynamic crosstalks of host-microbe interaction in the gut has become necessary for the detection, prevention, or therapy of diseases. Many reports have showed that diet, nutrient, pharmacologic factors and many other stimuli play dominant roles in the modulation of gut microbial compositions. However, it is inappropriate to neglect the impact of host factors on shaping the gut microbiota. In this review, we highlighted the current findings of the host factors that could modulate the gut microbiota. Particularly the epithelium-associated factors, including the innate immune sensors, anti-microbial peptides, mucus barrier, secretory IgAs, epithelial microvilli, epithelial tight junctions, epithelium metabolism, oxygen barrier, and even the microRNAs are discussed in the context of the microbiota shaping. With these shaping factors, the gut epithelial cells could select the residing microbes and affect the microbial composition. This knowledge not only could provide the opportunities to better control many diseases, but may also be used for predicting the success of fecal microbiota transplantation clinically.
10.1186/s12929-019-0554-5
Shorter sleep time relates to lower human defensin 5 secretion and compositional disturbance of the intestinal microbiota accompanied by decreased short-chain fatty acid production.
Gut microbes
Sleep is essential for our health. Short sleep is known to increase disease risks via imbalance of intestinal microbiota, dysbiosis. However, mechanisms by which short sleep induces dysbiosis remain unknown. Small intestinal Paneth cell regulates the intestinal microbiota by secreting antimicrobial peptides including α-defensin, human defensin 5 (HD5). Disruption of circadian rhythm mediating sleep-wake cycle induces Paneth cell failure. We aim to clarify effects of short sleep on HD5 secretion and the intestinal microbiota. Fecal samples and self-reported sleep time were obtained from 35 healthy middle-aged Japanese (41 to 60-year-old). Shorter sleep time was associated with lower fecal HD5 concentration ( = 0.354, = 0.037), lower centered log ratio (CLR)-transformed abundance of short-chain fatty acid (SCFA) producers in the intestinal microbiota such as ( = 0.504, = 0.002) and ( = 0.484, = 0.003), and lower fecal SCFA concentration. Furthermore, fecal HD5 positively correlated with the abundance of these genera and SCFA concentration. These findings suggest that short sleep relates to disturbance of the intestinal microbiota via decreased HD5 secretion.
10.1080/19490976.2023.2190306
Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.
bioRxiv : the preprint server for biology
Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical host-derived regulators of the microbiota. However, mechanisms that support homeostasis of the microbiota in response to inflammatory stimuli such as supraphysiologic oxygen remain unclear. Here, we show that neonatal mice breathing supraphysiologic oxygen or direct exposure of intestinal organoids to supraphysiologic oxygen suppress the intestinal expression of AMPs and alters the composition of the intestinal microbiota. Oral supplementation of the prototypical AMP lysozyme to hyperoxia exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury. Together, these data support that intestinal AMPs modulate lung injury and repair. In Brief:Using a combination of murine models and organoids, Abdelgawad and Nicola et al. find that suppression of antimicrobial peptide release by the neonatal intestine in response to supra-physiological oxygen influences the progression of lung injury likely via modulation of the ileal microbiota. Highlights:Supraphysiologic oxygen exposure alters intestinal antimicrobial peptides (AMPs).Intestinal AMP expression has an inverse relationship with the severity of lung injury.AMP-driven alterations in the intestinal microbiota form a gut-lung axis that modulates lung injury.AMPs may mediate a gut-lung axis that modulates lung injury.
10.1101/2023.03.14.529700
Dietary Nutrients Mediate Intestinal Host Defense Peptide Expression.
Advances in nutrition (Bethesda, Md.)
The intestinal tract is the shared locus of intestinal epithelial cells, immune cells, nutrient digestion and absorption, and microbial survival. The gut in animals faces continuous challenges in communicating with the external environment. Threats from endogenous imbalance and exogenous feeds, especially pathogens, could trigger a disorder of homeostasis, leading to intestinal disease and even systematic disease risk. As a part of the intestinal protective barrier, endogenous host defense peptides (HDPs) play multiple beneficial physiological roles in the gut mucosa. Moreover, enhancing endogenous HDPs is being developed as a new strategy for resisting pathogens and commensal microbes, and to maintain intestinal health and reduce antibiotic use. In recent years, multiple nutrients such as branched-chain amino acids, SCFAs, lactose, zinc, and cholecalciferol (vitamin D3) have been reported to significantly increase HDP expression. Nutritional intervention has received more attention and is viewed as a promising means to defend against pathogenic infections and intestinal inflammation. The present review focuses on current discoveries surrounding HDP expression and nutritional regulation of mechanisms in the gut. Our aim is to provide a comprehensive overview, referable tactics, and novel opinions.
10.1093/advances/nmz057
Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.
Microbiome
BACKGROUND:Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical, host-derived regulators of the microbiota. However, mechanisms that support microbiota homeostasis in response to inflammatory stimuli, such as supraphysiologic oxygen, remain unclear. RESULTS:We show that supraphysiologic oxygen exposure to neonatal mice, or direct exposure of intestinal organoids to supraphysiologic oxygen, suppresses the intestinal expression of AMPs and alters intestinal microbiota composition. Oral supplementation of the prototypical AMP lysozyme to hyperoxia-exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. CONCLUSIONS:Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury in newborns. Together, these data support that intestinal AMPs modulate lung injury and repair. Video Abstract.
10.1186/s40168-023-01673-0
Mechanisms and regulation of defensins in host defense.
Signal transduction and targeted therapy
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
10.1038/s41392-023-01553-x
Regulation of microbiota by antimicrobial peptides in the gut.
Masuda Koji,Nakamura Kiminori,Yoshioka Sawako,Fukaya Rie,Sakai Naoki,Ayabe Tokiyoshi
Advances in oto-rhino-laryngology
The antimicrobial peptide is one of major effectors of the innate immunity, and is common in the entire multicellular organisms. In mammals, one family of antibacterial peptide named defensins plays a central role in host defense, especially in the epithelial surface such as oral cavity, skin and the intestine. Recently, the importance of the antimicrobial peptides has been widely recognized. The epithelium of the gut is a largest surface that is exposed to various pathogens in the environment. It is the Paneth cells that produce antimicrobial peptides, α-defensins in the small intestine. Paneth cells contribute to mucosal innate immunity by sensing bacteria and releasing microbicidal activities mostly from activated α-defensins. In mice, α-defensins, named cryptdins, consisted of six major isoforms (cryptdin-1 to cryptdin-6), and among those cryptdin-4 is the most microbicidal, suggesting that cryptdin-4 has a pivotal role in innate immunity. Paneth cell α-defensins have selective activities against commensal bacteria which may be associated with compositions of intestinal microbiota in vivo and homeostasis of the entire intestine. In addition, Paneth cell α-defensins appeared to be regulated topographically to control intestinal integrity.
10.1159/000324625
Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis.
Bevins Charles L,Salzman Nita H
Nature reviews. Microbiology
Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host-microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.
10.1038/nrmicro2546
Developmental switch of intestinal antimicrobial peptide expression.
The Journal of experimental medicine
Paneth cell-derived enteric antimicrobial peptides provide protection from intestinal infection and maintenance of enteric homeostasis. Paneth cells, however, evolve only after the neonatal period, and the antimicrobial mechanisms that protect the newborn intestine are ill defined. Using quantitative reverse transcription-polymerase chain reaction, immunohistology, reverse-phase high-performance liquid chromatography, and mass spectrometry, we analyzed the antimicrobial repertoire in intestinal epithelial cells during postnatal development. Surprisingly, constitutive expression of the cathelin-related antimicrobial peptide (CRAMP) was observed, and the processed, antimicrobially active form was identified in neonatal epithelium. Peptide synthesis was limited to the first two weeks after birth and gradually disappeared with the onset of increased stem cell proliferation and epithelial cell migration along the crypt-villus axis. CRAMP conferred significant protection from intestinal bacterial growth of the newborn enteric pathogen Listeria monocytogenes. Thus, we describe the first example of a complete developmental switch in innate immune effector expression and anatomical distribution. Epithelial CRAMP expression might contribute to bacterial colonization and the establishment of gut homeostasis, and provide protection from enteric infection during the postnatal period.
10.1084/jem.20071022
Antimicrobial defense of the intestine.
Mukherjee Sohini,Hooper Lora V
Immunity
The mammalian gastrointestinal tract is home to a dense community of resident bacteria and is also exposed to microorganisms from the external environment. The epithelial surface of the intestine plays a critical role in host protection by producing a diverse repertoire of antimicrobial proteins that directly kill or hinder the growth of microorganisms. Here we discuss the general principles that govern the mechanisms of action of epithelial antimicrobial proteins, regulation of antimicrobial protein expression and activity, and in vivo functions of intestinal antimicrobial proteins. We also consider how altered antimicrobial protein expression and function can contribute to disease and how these endogenous antibiotics might be harnessed for the benefit of human health.
10.1016/j.immuni.2014.12.028
Multi-layered regulation of intestinal antimicrobial defense.
Cellular and molecular life sciences : CMLS
The gastrointestinal tract of mammals is heavily colonized with a complex and dynamic microbial community. To cope with this complex microbial challenge, multiple epithelial lineages, such as enterocytes and Paneth cells, elaborate a diverse repertoire of protein antibiotics. The gut antimicrobial arsenal encompasses multiple protein families, including defensins, cathelicidins, and C-type lectins. These antimicrobial peptides and proteins play a key role in protecting the host against pathogen challenge, and likely also function to limit invasion of indigenous microbes. It is becoming increasingly apparent that expression of mucosal antimicrobial defenses is tightly controlled. This occurs at multiple levels, including transcriptional regulation in response to bacterial cues, post-translational proteolytic processing, and bacterial regulation of Paneth cell degranulation. Impaired antimicrobial peptide expression has also been implicated in inflammatory bowel disease, underscoring the essential role of antimicrobial defenses in maintaining intestinal homeostasis.
10.1007/s00018-008-8182-3
Porcine-derived antimicrobial peptide PR39 alleviates DSS-induced colitis via the NF-κB/MAPK pathway.
International immunopharmacology
PR39 is an antimicrobial peptide (AMP) with a variety of biological functions, including antimicrobial, wound healing, leukocyte chemotaxis, angiogenesis, and immunomodulation; however, its therapeutic efficacy in colitis (IBD) has rarely been reported. For this reason, the present study aimed to investigate the therapeutic effect of PR39 on IBD and its underlying mechanisms. In this experiment, a mouse model of ulcerative colitis (UC) was induced with 3 % dextran sulfate (DSS) and administered by rectal injection of PR39. The results of the study showed that 5 mg/kg of PR39 was able to ameliorate the clinical manifestations of DSS-induced UC mice by improving the clinical symptoms, colonic tissue damage, up-regulating the expression of tight junction proteins, and alleviating the systemic inflammation in mice in various ways. The mechanism of action may involve inhibition of the phosphorylation level of proteins related to the NF-κB/MAPK signaling pathway and modulation of the relative abundance of potentially pathogenic (Bacteroides, Pseudoflavonifractor, Barnesiella, and Oscillibacter) and potentially beneficial bacteria (Candidatus_Saccharibacteria, Desulfovibrio, Saccharibacteria) in the intestinal flora. The results enriched the biological functions of PR-39 and also suggested that PR-39 may be able to be used as a novel drug for the treatment of IBD.
10.1016/j.intimp.2023.111385
Peptide YY: A Paneth cell antimicrobial peptide that maintains gut commensalism.
Science (New York, N.Y.)
The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have found that peptide YY (PYY), but not endocrine PYY, acts as an antimicrobial peptide (AMP) expressed by gut epithelial paneth cells (PC). PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Although PC-PYY shows some antibacterial activity, it displays selective antifungal activity against virulent hyphae-but not the yeast form. PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming that selects for the yeast phenotype. Hence, PC-PYY is an antifungal AMP that contributes to the maintenance of gut fungal commensalism.
10.1126/science.abq3178