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Abstract Gut microbiota is an intricate microbial community containing bacteria, fungi, viruses, archaea, and protozoa, and each of them contributes to diverse aspects of host health. Nevertheless, the influence of interaction among gut microbiota on host health remains uncovered. Here, we showed that the interaction between intestinal fungi and bacteria shaped lung inflammation during infection. Specifically, antifungal drug‐induced dysbiosis of gut mycobiota enhanced lung inflammation during infection. Dysbiosis of gut mycobiota led to gut Escherichia coli (E. coli) overgrowth and translocation to the lung during infection, which induced lung accumulation of the CD45+F4/80+Ly6G−Ly6C−CD11b+CD11c+ macrophages. Clearance of macrophages or deletion of TLR4 (Toll‐like receptor 4, recognition of LPS) rather than Dectin‐1 (recognition of beta‐1,3/1,6 glucans on fungi) blocked the antifungal drug‐induced aggravation of lung inflammation during infection. These findings suggest that the interaction between intestinal mycobiota and commensal bacteria affects host health through the gut–lung axis, offering a potential therapeutic target for ameliorating lung inflammation during infection.

ABSTRACTMelatonin has various physiological effects, such as the maintenance of circadian rhythms, anti-inflammatory functions, and regulation of intestinal barriers. The regulatory functions of melatonin in gut microbiota remodeling have also been well clarified; however, the role of gut microbiota in regulating host melatonin production remains poorly understood. To address this, we studied the contribution of gut microbiota to host melatonin production using gut microbiota-perturbed models. We demonstrated that antibiotic-treated and germ-free mice possessed diminished melatonin levels in the serum and elevated melatonin levels in the colon. The influence of the intestinal microbiota on host melatonin production was further confirmed by fecal microbiota transplantation. Notably, Lactobacillus reuteri (L. R) and Escherichia coli (E. coli) recapitulated the effects of gut microbiota on host melatonin production. Mechanistically, L. R and E. coli activated the TLR2/4/MyD88/NF-κB signaling pathway to promote expression of arylalkylamine N-acetyltransferase (AANAT, a rate-limiting enzyme for melatonin production), and MyD88 deficiency in colonic epithelial cells abolished the influence of intestinal microbiota on colonic melatonin production. Collectively, we revealed a specific underlying mechanism of gut microbiota to modulate host melatonin production, which might provide novel therapeutic ideas for melatonin-related diseases.

The prevalence of food allergies is increasing dramatically and causing serious public health concerns. Notably, melatonin metabolism imbalance in patients with food allergies; however, the role of melatonin in food allergies remains unclear. Here, we demonstrated that melatonin suppresses food allergy responses and reprograms the gut microbiota of food-allergic mice, while melatonin aggravates food allergy during gut microbiota depletion. Mechanistically, melatonin boosts the degranulation of mast cells by up-regulating the expression of membrane high-affinity immunoglobulin E (IgE) receptor (FcεRI). Melatonin increases the mRNA expression of Rabenosyn-5 (a component of factors for endosome recycling and Rab interactions) through melatonin receptor 2 (MT2)–extracellular signal-regulated kinase (ERK) signaling, thereby driving the recycling of FcεRI and elevating the abundance of membrane FcεRI. Likewise, the inhibition of MT2 attenuates melatonin-induced food allergy in mice with gut microbiota depletion. Collectively, our finding provides insights into the pathogenesis of food allergies and provides a potential therapeutic target for the prevention and treatment of food allergies.

Intestinal microbes are closely associated with host health, depending on metabolic crosstalk between the microbiota and host. Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host; however, our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited. Thus, we established germ-free (GF) pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism. Five GF pigs were kept in GF conditions throughout the experiment (GF group). Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs. Compared with control pigs, the GF pigs had remarkable alterations in tryptophan metabolism. The differential metabolites (P

Objective This is the first study to explore the risk factors for nephropathy caused by gadolinium-based contrast agents and establish a prediction model to identify high-risk patients.Methods A total of 1404 patients who received gadolinium-based contrast agents in our hospital were included. The participants were randomly assigned in a 7:3 ratio to the modeling and validation groups. The modeling group was divided into a contrast-induced nephropathy group and a non-contrast-induced nephropathy group. The clinical characteristics before the use of contrast agents were compared between the two groups. The risk factors for contrast-induced nephropathy were analyzed by logistic regression. A nomogram that could predict the incidence of contrast-induced nephropathy was plotted. The validation group was used to verify the predictive model.Results The incidence of contrast-induced nephropathy caused by gadolinium-based contrast agents was 3.92% (55/1404). The logistic stepwise regression analysis showed that sex, systolic pressure (SBP), absolute neutrophil count, albumin, fasting blood glucose level, and furosemide use were significant predictors of contrast-induced nephropathy caused by gadolinium-based contrast agents. The above predictors were then included in the nomogram construction. The area under the receiver operating characteristic (ROC) curve was 0.82 (p

Abstract. Intestinal infectious diseases refer to the inflammatory changes in the intestinal tract caused by pathogens (including bacteria, viruses, fungi, protozoa, or parasites) or their toxic products. A large number of microorganisms colonize the intestinal tract of healthy people, which together with the intestinal epithelium constitute the biological barrier of the intestinal tract to resist infectious diseases. As an “invisible organ,” the intestinal flora is closely related to human nutrition metabolism and intestinal infections. A variety of intestinal flora participates in the nutritional metabolism of amino acids, and the small molecular substances produced by the amino acid metabolism through the intestinal flora can enhance intestinal immunity and resist bacterial infections. In turn, amino acids can also regulate the composition of the intestinal flora, maintain the steady-state of the intestinal flora, protect the intestinal barrier, and inhibit colonization by pathogenic bacteria. As a model animal with a clear microbial background, germ-free (GF) animals can clarify the mechanisms of interactions between intestinal microbes and amino acid metabolism in intestinal infections by combining genetic engineering technology and multi-omics studies. This article reviews related researches on the involvement of intestinal microbes in host amino acid metabolism and resistance to intestinal infections and discusses the advantages of GF animal models for studying the underlying mechanisms. The GF animal model is helpful to further study the intervention effects of amino acid metabolism of targeted intestinal flora on intestinal infections.

Recent discoveries have underscored the cross-talk between intestinal microbes and their hosts. Notably, intestinal microbiota impacts the development, physiological function and social behavior of hosts. This influence usually revolves around the microbiota-gut-brain axis (MGBA). In this review, we firstly outline the impacts of the host on colonization of intestinal microorganisms, and then highlight the influence of intestinal microbiota on hosts focusing on short-chain fatty acid (SCFA) and tryptophan metabolite-mediated MGBA. We also discuss the intervention of intestinal microbial metabolism by dietary supplements, which may provide new strategies for improving the welfare and production of pigs. Overall, we summarize a state-of-the-art theory that gut microbiome affects brain functions via metabolites from dietary macronutrients.

Abstract Bacteria, viruses, protozoa, and fungi establish a complex ecosystem in the gut. Like other microbiota, gut mycobiota plays an indispensable role in modulating intestinal physiology. Notably, the most striking characteristics of intestinal fungi are their extraintestinal functions. Here, we provide a comprehensive review of the importance of gut fungi in the regulation of intestinal, pulmonary, hepatic, renal, pancreatic, and brain functions, and we present possible opportunities for the application of gut mycobiota to alleviate/treat human diseases. Video Abstract.

Introduction Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. Methods In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. Results The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. Conclusions The CKD5 patients’ baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.

Background: Heart rate variability (HRV), reflecting circadian rhythm of heart rate, is reported to be associated with clinical outcomes in stage 5 chronic kidney disease (CKD5) patients. Whether CKD related factors combined with HRV can improve the predictive ability for their death remains uncertain. Here we evaluated the prognosis value of nomogram model based on HRV and clinical risk factors for all-cause mortality in CKD5 patients.Methods: CKD5 patients were enrolled from multicenter between 2011 and 2019 in China. HRV parameters based on 24-h Holter and clinical risk factors associated with all-cause mortality were analyzed by multivariate Cox regression. The relationships between HRV and all-cause mortality were displayed by restricted cubic spline graphs. The predictive ability of nomogram model based on clinical risk factors and HRV were evaluated for survival rate.Results: CKD5 patients included survival subgroup (n = 155) and all-cause mortality subgroup (n = 45), with the median follow-up time of 48 months. Logarithm of standard deviation of all sinus R-R intervals (lnSDNN) (4.40 ± 0.39 vs. 4.32 ± 0.42; p = 0.007) and logarithm of standard deviation of average NN intervals for each 5 min (lnSDANN) (4.27 ± 0.41 vs. 4.17 ± 0.41; p = 0.008) were significantly higher in survival subgroup than all-cause mortality subgroup. On the basis of multivariate Cox regression analysis, the lnSDNN (HR = 0.35, 95%CI: 0.17–0.73, p = 0.01) and lnSDANN (HR = 0.36, 95% CI: 0.17–0.77, p = 0.01) were associated with all-cause mortality, their relationships were negative linear. Spearman’s correlation analysis showed that lnSDNN and lnSDANN were highly correlated, so we chose lnSDNN, sex, age, BMI, diabetic mellitus (DM), β-receptor blocker, blood glucose, phosphorus and ln intact parathyroid hormone (iPTH) levels to build the nomogram model. The area under the curve (AUC) values based on lnSDNN nomogram model for predicting 3-year and 5-year survival rates were 79.44% and 81.27%, respectively.Conclusion: In CKD5 patients decreased SDNN and SDANN measured by HRV were related with their all-cause mortality, meanwhile, SDNN and SDANN were highly correlated. Nomogram model integrated SDNN and clinical risk factors are promising for evaluating their prognosis.

Purpose Microwave ablation (MWA) is feasible for severe renal secondary hyperparathyroidism (SHPT) and primary hyperparathyroidism (PHPT) patients ineligible for parathyroidectomy (PTX). Here we compared the clinical manifestations and characteristics of parathyroid glands in these two groups, and summarized the techniques, safety and efficacy of MWA. Methods Baseline clinical characteristics, ablation-related techniques, adverse events/complications, and efficacy were recorded. Results In SHPT group, malnutrition, cardiovascular/pulmonary complications, and abnormal bone metabolism were severe. SHPT patients had more hyperplastic parathyroid glands. The volume of each gland was smaller, and the time of ablation for a single parathyroid was shorter in the SHPT group, although there were no significant differences compared with patients in the PHPT group. Three patients in both groups had recurrent laryngeal nerve injuries and all recovered, except for one SHPT patient. By the end of follow-up, serum iPTH levels had decreased from 2400.26 ± 844.26 pg/mL to 429.39 ± 407.93 pg/mL (p

Abstract Background Immunotransmitters (e.g., neurotransmitters and neuromodulators) could orchestrate diverse immune responses; however, the elaborated mechanism by which melatonergic activation governs inflammation remains less defined. Methods Primary macrophages, various cell lines, and Pasteurella multocida (PmCQ2)‐infected mice were respectively used to illustrate the influence of melatonergic signalling on inflammation in vitro and in vivo. A series of methods (e.g., RNA‐seq, metabolomics, and genetic manipulation) were conducted to reveal the mechanism whereby melatonergic signalling reduces macrophage inflammation. Results Here, we demonstrate that melatonergic activation substantially lessens interleukin (IL)‐1β‐dependent inflammation. Treatment of macrophages with melatonin rewires metabolic program, as well as remodels signalling pathways which depends on interferon regulatory factor (IRF) 7. Mechanistically, melatonin acts via membrane receptor (MT) 1 to increase heat shock factor (Hsf) 1 expression through lowering the inactive glycogen synthase kinase (GSK3) β, thereby transcriptionally inhibiting interferon (IFN)‐γ receptor (IFNGR) 2 and ultimately causing defective canonical signalling events [Janus kinase (JAK) 1/2‐signal transducer and activator of transcription (STAT) 1‐IRF7] and lower IL‐1β production in macrophages. Moreover, we find that melatonin amplifies host protective responses to PmCQ2 infection‐induced pneumonia. Conclusions Our conceptual framework provides potential therapeutic targets to prevent and/or treat inflammatory diseases associating with excessive IL‐1β production.

Increasing evidence support that cellular amino acid metabolism shapes the fate of immune cells; however, whether aspartate metabolism dictates macrophage function is still enigmatic. Here, we found that the metabolites in aspartate metabolism are depleted in lipopolysaccharide (LPS) plus interferon gamma (IFN-γ)-stimulated macrophages. Aspartate promotes interleukin-1β (IL-1β) secretion in M1 macrophages. Mechanistically, aspartate boosts the activation of hypoxia-inducible factor-1α (HIF-1α) and inflammasome and increases the levels of metabolites in aspartate metabolism, such as asparagine. Interestingly, asparagine also accelerates the activation of cellular signaling pathways and promotes the production of inflammatory cytokines from macrophages. Moreover, aspartate supplementation augments the macrophage-mediated inflammatory responses in mice and piglets. These results uncover a previously uncharacterized role for aspartate metabolism in directing M1 macrophage polarization.

Abstract Background Ochratoxin A (OTA) is a widespread mycotoxin and induces liver inflammation to human and various species of animals. The intestinal microbiota has critical importance in liver inflammation; however, it remains to know whether intestinal microbiota mediates the liver inflammation induced by OTA. Here, we treated ducklings with oral gavage of OTA (235 μg/kg body weight) for 2 weeks. Then, the microbiota in the cecum and liver were analyzed with 16S rRNA sequencing, and the inflammation in the liver was analyzed. To explore the role of intestinal microbiota in OTA-induced liver inflammation, intestinal microbiota was cleared with antibiotics and fecal microbiota transplantation was conducted. Results Here, we find that OTA treatment in ducks altered the intestinal microbiota composition and structure [e.g., increasing the relative abundance of lipopolysaccharides (LPS)-producing Bacteroides], and induced the accumulation of LPS and inflammation in the liver. Intriguingly, in antibiotic-treated ducks, OTA failed to induce these alterations in the liver. Notably, with the fecal microbiota transplantation (FMT) program, in which ducks were colonized with intestinal microbiota from control or OTA-treated ducks, we elucidated the involvement of intestinal microbiota, especially Bacteroides, in liver inflammation induced by OTA. Conclusions These results highlight the role of gut microbiota in OTA-induced liver inflammation and open a new window for novel preventative or therapeutic intervention for mycotoxicosis.

Intracellular metabolic programs tightly regulate the functions of macrophages, and previous studies have shown that serine mainly shapes the macrophage function via one-carbon metabolism. However, it is unknown whether serine modulates the macrophage function independent of one-carbon metabolism. Here, we find that serine deprivation lowers interleukin (IL)-1β production and inflammasome activation, as well as reprograms the transcriptomic and metabolic profile in M1 macrophages. Intriguingly, supplementation of formate, glycine, dNTPs, and glucose cannot rescue the production of IL-1β from serine-deprived macrophages. Mechanistically, serine deprivation inhibits macrophage IL-1β production through inhibition of mechanistic target of rapamycin (mTOR) signaling. Of note, the macrophages from mice feeding serine-free diet have lower IL-1β production, and these mice also show less inflammation after LPS challenge. Collectively, our data highlight a new regulatory mechanism for serine to modulate the macrophage function.

ABSTRACT Melatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming the gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of the administration of exogenous melatonin on the diurnal variation in the gut microbiota in mice fed a high-fat diet (HFD) is unclear. Here, we further confirmed the antiobesogenic effect of melatonin on mice fed an HFD for 2 weeks. Samples were collected every 4 h within a 24-h period, and diurnal rhythms of clock gene expression (Clock, Cry1, Cry2, Per1, and Per2) and serum lipid indexes varied with diurnal time. Notably, Clock and triglycerides (TG) showed a marked rhythm in the control in melatonin-treated mice but not in the HFD-fed mice. The rhythmicity of these parameters was similar between the control and melatonin-treated HFD-fed mice compared with that in the HFD group, indicating an improvement caused by melatonin in the diurnal clock of host metabolism in HFD-fed mice. Moreover, 16S rRNA gene sequencing showed that most microbes exhibited daily rhythmicity, and the trends were different for different groups and at different time points. We also identified several specific microbes that correlated with the circadian clock genes and serum lipid indexes, which might indicate the potential mechanism of action of melatonin in HFD-fed mice. In addition, effects of melatonin exposure during daytime or nighttime were compared, but a nonsignificant difference was noticed in response to HFD-induced lipid dysmetabolism. Interestingly, the responses of microbiota-transplanted mice to HFD feeding also varied at different transplantation times (8:00 and 16:00) and with different microbiota donors. In summary, the daily oscillations in the expression of circadian clock genes, serum lipid indexes, and the gut microbiota appeared to be driven by short-term feeding of an HFD, while administration of exogenous melatonin improved the composition and diurnal rhythmicity of some specific gut microbiota in HFD-fed mice. IMPORTANCE The gut microbiota is strongly shaped by a high-fat diet, and obese humans and animals are characterized by low gut microbial diversity and impaired gut microbiota compositions. Comprehensive data on mammalian gut metagenomes shows gut microbiota exhibit circadian rhythms, which is disturbed by a high-fat diet. On the other hand, melatonin is a natural and ubiquitous molecule showing multiple mechanisms of regulating the circadian clock and lipid metabolism, while the role of melatonin in the regulation of the diurnal patterns of gut microbial structure and function in obese animals is not yet known. This study delineates an intricate picture of melatonin-gut microbiota circadian rhythms and may provide insight for obesity intervention.

Abstract Sow milk contains necessary nutrients for piglets; however, the relationship between the levels of metabolites in sow milk and lactation performance has not been thoroughly elucidated to date. In this study, we analysed the metabolites in sow milk from Yorkshire sows with high lactation (HL) or low lactation (LL) performance; these categories were assigned based on the weight gain of piglets during the entire lactation period (D1 to D21). The concentration of milk fat in the colostrum tended to be higher in the HL group (P = 0.05), the level of mannitol was significantly lower in the HL group (P

Background/Aims: Our previous reports suggested that dietary supplementation with lysine influenced intestinal absorption and metabolism of amino acids. In this study, we further investigated the effect of lysine restriction (30%) on feed intake and we also tested the hypothesis that gut microbiome contributed to the potential mechanism of lysine restriction-mediated feeding behavior. Here, we profiled gut microbial communities by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from gut samples as well as growth performance, serum hormones, and intestinal lysine transport in a piglet model. Results: Piglets preferred to the lysine restricted diet when giving three diets and the feed intake was markedly higher in the lysine-restricted group than that in the control group. Altered hormones (leptin, CCK, and ghrelin) might contribute to the feeding behavior caused by lysine restriction. Meanwhile, lysine transporting ability (SLC7A1 and SLC7A2 expression, intestinal electrophysiological changes, and amino acid pool in mesenteric vein) was decreased in response to lysine restriction. Through deep sequencing of bacterial rRNA markers, we observed that bacterial diversity was enhanced in the lysine-restricted group (Shannon H, PD, and Chao1). At the phylum level, lysine restriction enhanced gut Actinobacteria, Saccharibacteria, and Synergistetes abundances. At the family level, Moraxellaceae, Halomonadaceae, Shewanellaceae, Corynebacteriaceae, Bacillaceae, Comamonadaceae, Microbacteriaceae, Caulobacteraceae, and Synergistaceae abundances were increased in response to lysine restriction. Predictive functional profiling of microbial communities by PICRUSt also confirmed that dietary lysine restriction affected gut microbiome, which might further mediate amino acid metabolism, membrane transport, and endocrine system. Conclusion: Our results indicated that lysine restriction inhibited intestinal lysine transport and promoted feed intake, which might be associated with gut microbiome.

Polyamines such as putrescine, spermidine, spermine and agmatine are aliphatic polycationic compounds present in all living cells, and are derived from amino acids, intestinal bacteria, exfoliated enterocytes and supported from diet. Polyamines as the key compounds play essential role in cell proliferation, growth and differentiation. They also exert significant effects on embryonic development, implantation, embryonic diapause, placentation, angiogensis and fetal development. This review paper summarizes the functions of polyamines and embryo/fetus development and its regulatory mechanism which should help to provide some evidences for clinic.

Taurine may alleviate the inflammatory injury induced by Streptococcus uberis (S. uberis) infection by regulating intracellular Ca2+ levels. However, the underlying mechanisms remain unclear. Infection leads to subversion of phosphoinositides (PIs) which are closely related to Ca2+ signaling. In order to investigate whether taurine regulates inflammation by means of PIs/ Ca2+ systems, competitive inhibitors of taurine (β-alanine) siTauT, siPAT1, siPLC, siCaN, siPKC, and inhibitors of PLC (U73122), PKC (RO31-8220), and CaN (FK 506) were used. The results indicate that taurine transfers the extracellular nutrient signal for intercellular innate immunity to phosphoinositides without a need to enter the cytoplasm while regulating intracellular Ca2+ levels during inflammation. Both the Ca2+-PKCα-NF-κB, and Ca2+-CaM-CaN-NFAT signaling pathways of S. uberis infection and the regulatory roles of taurine follow activation of PIs/Ca2+ systems. These data increase our understanding on the mechanisms of multifunctional nutrient, taurine attenuated inflammatory responses caused by S. uberis infection, and provide theoretical support for the prevention of this disease.

The present study is undertaken to assess the alleviating effects of antimicrobial peptide cecropin A on inflammatory bowel disease (IBD) in C57BL/6 mice and changes in the gut microbiota, compared to an antibiotic gentamicin. Different doses of cecropin A were intraperitoneally injected into C57BL/6 mice for 5 days to determine the safe doses. The injection doses at ≤ 15 mg/kg showed no negative impact on the liver, heart, spleen, and kidney. The severe and moderate IBD mice model was successfully established via supplementation of 4 or 2.5% dextran sulfate sodium (DSS) in drinking water for 5 days. The severe IBD model was used to ensure the optimal therapeutic dose of cecropin A. Survival rate, body weight and disease activity index (DAI) scores were measured. Administration of 15 mg/kg, not 5 mg/kg cecropin A, for 5 days increased survival rate and decreased body weight loss of mice. The moderate IBD model was applied to investigate the mechanisms for cecropin A to alleviate inflammation in comparison to gentamicin. The mice were treated with 15 mg/kg cecropin A or 5 mg/kg gentamicin for 3 days. The levels of cytokines and related proteins in the colon were detected by ELISA and Western blotting. The microbiota in cecum contents were analyzed using 16S rRNA gene sequencing. The results showed that cecropin A and gentamicin relieved body weight loss, DAI, and gut mucosa disruption, while decreasing tumor necrosis factor-α (TNF-α), interlukin-1β (IL-1β), and interlukin-6 (IL-6) induced by DSS. In addition, cecropin A and gentamicin showed different effects on the gut microbiota structure. Both cecropin A and gentamicin decreased DSS-induced enrichment of Bacteroidaceae and Enterobacteriaceae. However, cecropin A showed a selective enrichment of Lactobacillus in contrast to gentamicin, which demonstrated a selective effect on Desulfovibrionaceae and Ruminococcaceae. Cecropin A alleviates IBD through decreasing harmful gut microflora and specifically enhancing beneficial gut microflora. The mechanism of this effect is different from gentamicin.

This study was conducted to explore the effect of chitosan supplementation on mouse intestinal microbiota and interleukin-17 (IL-17) expression. Chitosan supplementation reduced mouse body weight, associating with change of intestinal microbiota (i.e. lowering the ratio of Firmicutes: Bacteroidetes). In antibiotics treated mice, chitosan supplementation had little effect on mouse body weight. Chitosan supplementation decreased expression of IL-17 in mouse jejunum and inhibited the mTOR pathway. In antibiotics treated mice, chitosan also reduced expression of IL-17 in the jejunum. Activation of mTOR signalling in mouse increased expression of IL-17 in the jejunum in the context of chitosan supplementation. We conclude that chitosan supplementation reduces mouse body weight through the intestinal microbiota, and inhibits intestinal IL-17 expression through the mTOR signalling. The discovery of this study suggests the potentials of chitosan as a functional supplement in intestinal health.

Betaine is a critical nutrient for mammal health, and has been found to alleviate inflammation by lowering interleukin (IL)-1β secretion; however, the underlying mechanisms by which betaine inhibits IL-1β secretion remain to be uncovered. In this review, we summarize the current understanding about the mechanisms of betaine in IL-1β production and release. For IL-1β production, betaine affects canonical and non-canonical inflammasome-mediated processing of IL-1β through signaling pathways, such as NF-κB, NLRP3 and caspase-8/11. For IL-1β release, betaine inhibits IL-1β release through blocking the exocytosis of IL-1β-containing secretory lysosomes, reducing the shedding of IL-1β-containing plasma membrane microvesicles, suppressing the exocytosis of IL-1β-containing exosomes, and attenuating the passive efflux of IL-1β across hyperpermeable plasma membrane during pyroptotic cell death, which are associated with ERK1/2/PLA2 and caspase-8/A-SMase signaling pathways. Collectively, this review highlights the anti-inflammatory property of betaine by inhibiting the production and release of IL-1β, and indicates the potential application of betaine supplementation as an adjuvant therapy in various inflammatory diseases associating with IL-1β secretion.

Intestinal metabolites participate in various physiological processes, including energy metabolism, cell-to-cell communication, and host immunity. These metabolites mainly originate from gut microbiota and hosts. Although many host metabolites are dominant in intestines, such as free fatty acids, amino acids and vitamins, the metabolites derived from gut microbiota are also essential for intestinal homeostasis. In addition, some metabolites are only generated and released by gut microbiota, such as bacteriocins, short-chain fatty acids, and quorum-sensing autoinducers. In this review, we summarize recent studies regarding the crosstalk between pathogens and metabolites from different sources, including the influence on bacterial development and the activation/inhibition of immune responses of hosts. All of these functions would affect the colonization of and infection by pathogens. This review provides clear ideas and directions for further exploring the regulatory mechanisms and effects of metabolites on pathogens.

It has been suggested that gut microbiota play a critical role in maternal metabolic oxidative stress responses and offspring growth. However, whether the gut microbiota and oxidative stress status of the sows affect the litter performance during lactation is unclear. A total of 66 Yorkshire sows were identified as high (H) or low (L) litter performance sows based on litter weight at day 21 of lactation. Ten sows per group with similar parity, backfat thickness, and litter weight after cross-foster from the H or L group were collected randomly to analyze the oxidative stress and gut microbiota during lactation. The result showed that the serum total antioxidant capacity was higher in the H group, while 8-hydroxy-deoxyguanosine and thiobarbituric acid reactive substances were lower in the H group at farrowing. Four distinct clusters of bacteria were related to litter performance and reproductive periods of sows. Twelve differentially abundant taxa during gestation and 13 taxa during lactation were identified as potential biomarkers between the H group and the L group. Moreover, the litter performance and the antioxidant capacity of sows were positively correlated with Bacteroides_f__Bacteroidaceae but negatively with Phascolarctobacterium and Streptococcus. In conclusion, this study found that gut microbiota and oxidative stress were significantly correlated with the litter performance of sows during lactation.

Unrestricted cell proliferation is a hallmark of cancer. Purines are basic components of nucleotides in cell proliferation, thus impaired purine metabolism is associated with the progression of cancer. The de novo biosynthesis of purine depends on six enzymes to catalyze the conversion of phosphoribosylpyrophosphate to inosine 5′-monophosphate. These enzymes cluster around mitochondria and microtubules to form purinosome, which is a multi-enzyme complex involved in de novo purine biosynthesis and purine nucleotides requirement. In this review, we highlighted the purine metabolism and purinosome biology with emphasis on the therapeutic potential of manipulating of purine metabolism or purinosome in cancers. We also reviewed current advances in our understanding of mammalian target of rapamycin for regulating purinosome formation or purine metabolism in cancers and discussed the future prospects for targeting purinosome to treat cancers.

Short chain fatty acids (SCFAs, e.g., acetate, propionate, and butyrate) are a subset of fatty acids that are produced by gut microbiota during the fermentation of dietary fiber. They modulate different processes in the gastrointestinal tract and play various positive roles in mediating the intestinal health. Most beneficial roles of SCFAs in the gastrointestinal tract are mediated by directly activating its receptor, G protein-coupled receptor 43 (GPR43, also known as FFAR2). Various recent studies have demonstrated the role of GPR43 in intestinal inflammatory diseases, such as inflammatory bowel diseases. These SCFAs-mediated regulations of intestinal health are associated with neutrophil chemotaxis, T cell differentiation, activation, and subsequent cytokines production. Therefore, GPR43 could potentially be a drug target for intestinal inflammatory diseases. In this review, we review the current knowledge on the regulatory mechanisms associated with GPR43 in intestinal inflammation. The role of GPR43-mediated regulation of antibody responses is also discussed.

Betaine is known as trimethylglycine and is widely distributed in animals, plants, and microorganisms. Betaine is known to function physiologically as an important osmoprotectant and methyl group donor. Accumulating evidence has shown that betaine has anti-inflammatory functions in numerous diseases. Mechanistically, betaine ameliorates sulfur amino acid metabolism against oxidative stress, inhibits nuclear factor-κB activity and NLRP3 inflammasome activation, regulates energy metabolism, and mitigates endoplasmic reticulum stress and apoptosis. Consequently, betaine has beneficial actions in several human diseases, such as obesity, diabetes, cancer, and Alzheimer’s disease.

The interaction between host and pathogen decidedly shapes the outcome of an infection, thus understanding this interaction is critical to the treatment of a pathogen-induced infection. Although research in this area of cell biology has yielded surprising findings regarding interactions between host and pathogen, understanding of the metabolic cross talk between host and pathogen is limited. At the site of infection, host and pathogen share similar or identical nutritional substrates and generate common metabolic products, thus metabolic cross talk between host and pathogen could profoundly affect the pathogenesis of an infection. In this review, we present results of a recent discovery of a metabolic interaction between host and pathogen from an amino acid (AA) metabolism-centric point of view. The host depends on AA metabolism to support defensive responses against pathogens, while the pathogens modulate AA metabolism for its own advantage. Some AA, such as arginine, asparagine, and tryptophan, are central points of competition between the host and pathogen. Thus, a better understanding of AA-mediated metabolic cross talk between host and pathogen will provide insight into fruitful therapeutic approaches to manipulate and prevent progression of an infection.

This study was conducted to determine the positive effects of dietary supplementation with l-arginine (Arg) on piglets fed a deoxynivalenol (DON)-contaminated diet. A total of eighteen, 28-day-old healthy weanling pigs were randomly assigned into one of three groups: uncontaminated basal diet (control group), 6 mg/kg DON-contaminated diet (DON group) and 6 mg/kg DON + 1% l-arginine (DON + ARG group). After 21 days of Arg supplementation, piglets in the DON and DON + ARG groups were challenged by feeding 6 mg/kg DON-contaminated diet for seven days. The results showed that DON resulted in damage to piglets. However, clinical parameters, including jejunal morphology, amino acid concentrations in the serum, jejunum and ileum, were improved by Arg (p < 0.05). Furthermore, the mRNA levels for sodium-glucose transporter-1 (SGLT-1), glucose transporter type-2 (GLUT-2) and y+l-type amino acid transporter-1 (y+LAT-1) were downregulated in the DON group, but the values were increased in the DON + ARG group (p < 0.05). Collectively, these results indicate that dietary supplementation with Arg exerts a protective role in pigs fed DON-contaminated diets.

Pasteurella multocida infection in cattle causes serious epidemic diseases and leads to great economic losses in livestock industry; however, little is known about the interaction between host and P. multocida in the lungs. To explore a fully insight into the host responses in the lungs during P. multocida infection, a mouse model of Pasteurella pneumonia was established by intraperitoneal infection, and then transcriptomic analysis of infected lungs was performed. P. multocida localized and grew in murine lungs, and induced inflammation in the lungs, as well as mice death. With transcriptomic analysis, approximately 107 clean reads were acquired. 4236 differently expressed genes (DEGs) were detected during P. multocida infection, of which 1924 DEGs were up-regulated. By gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichments, 5,303 GO enrichments and 116 KEGG pathways were significantly enriched in the context of P. multocida infection. Interestingly, genes related to immune responses, such as pattern recognition receptors (PRRs), chemokines and inflammatory cytokines, were significantly up-regulated, suggesting the key roles of these genes in P. multocida infection. Transcriptomic data showed that IFN-γ/IL-17-related genes were increased, which were validated by qRT-PCR, ELISA, and immunoblotting. Our study characterized the transcriptomic profile of the lungs in mice upon Pasteurella infection, and our findings could provide valuable information with respect to better understanding the responses in mice during P. multocida infection.

Secretory IgA (SIgA) is one important line of defense in intestinal mucosal surface to protect the intestinal epithelium from enteric toxins and pathogenic microorganisms. Multiple factors, such as intestinal microbiota, intestinal cytokines and nutrients, are highly involved in intestinal production of SIgA. Recently, glutamine has been shown to affect intestinal SIgA production, however, the underlying mechanism by which glutamine promotes intestinal SIgA secretion remains to know. Here, we review the current knowledge regarding glutamine in intestinal immunity, and show that glutamine enhances intestinal SIgA production may through intestinal microbiota, intestinal antigen sampling and presentation, induction pathways for SIgA production by plasma cells (both T-dependent and T-independent pathway), and even SIgA transportation. Altogether, the glutamine-intestinal SIgA axis has broad therapeutic implications for intestinal SIgA -associated diseases, such as celiac disease, allergy, and inflammatory bowel disease.

This study was conducted to explore the effects of interferon tau (IFNT) on the intestinal microbiota and expression of interleukin 17 (IL-17) in the intestine of mice. IFNT supplementation increased microbial diversity in the jejunum and ileum but decreased microbial diversity in the feces. IFNT supplementation influenced the composition of the intestinal microbiota as follows: (1) decreasing the percentage of Firmicutes and increasing Bacteroidetes in the jejunum and ileum; (2) enhancing the percentage of Firmicutes but decreasing Bacteroidetes in the colon and feces; (3) decreasing Lactobacillus in the jejunum and ileum; (4) increasing the percentage of Blautia, Bacteroides, Alloprevotella, and Lactobacillus in the colon; and (5) increasing the percentage of Lactobacillus, Bacteroides, and Allobaculum, while decreasing Blautia in the feces. Also, IFNT supplementation decreased the expression of IL-17 in the intestines of normal mice and of an intestinal pathogen infected mice. In conclusion, IFNT supplementation modulates the intestinal microbiota and intestinal IL-17 expression, indicating the applicability of IFNT to treat the intestinal diseases involving IL-17 expression and microbiota.

Inflammatory bowel disease (IBD) in humans and animals is associated with bacterial infection and intestinal barrier dysfunction. Cecropin A, an antimicrobial peptide, has antibacterial activity against pathogenic bacteria. However, the effect of cecropin A on intestinal barrier function and its related mechanisms is still unclear. Here, we used porcine jejunum epithelial cells (IPEC-J2) as a model to investigate the effect and mechanism of cecropin A on intestinal barrier function. We found that cecropin A reduced Escherichia coli (E. coli) adherence to IPEC-J2 cells and downregulated mRNA expression of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). Furthermore, cecropin A elevated the transepithelial electrical resistance (TER) value while reducing the paracellular permeability of the IPEC-J2 cell monolayer barrier. Finally, by using Western blotting, immunofluorescence and pathway-specific antagonists, we demonstrated that cecropin A increased ZO-1, claudin-1 and occludin protein expression and regulated membrane distribution and F-actin polymerization by increasing CDX2 expression. We conclude that cecropin A enhances porcine intestinal epithelial cell barrier function by downregulating the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We suggest that cecropin A has the potential to replace antibiotics in the treatment of IBD due to its antibacterial activity on gram-negative bacteria and its enhancement effect on intestinal barrier function.

This study aimed to investigate the protective effects of dietary glutamate and aspartate supplementations on diquat-induced oxidative stress in piglets. Diquat injection significantly reduced growth performance, including body weight, average daily weight gain, and feed intake (P

The present study was performed to determine the protective role of dietary selenium (Se) yeast supplementation in porcine circovirus type 2 (PCV2) infected mice. Forty-eight Kun Ming female mice were randomly assigned to Se yeast group (0.3%Se +basal diet, n = 24) and control group (basal diet, n = 24). After 3 days of adaptive feeding and 15 days treatment with the experimental feed, mice were challenged by intraperitioneal injection of PCV2 at the dosage of 2000 TCID50 (50% tissue culture infection dose, TCID50). Serum total superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) and interleukin-1 beta (IL-1β) levels were measured at 5, 10, 15, 20 days post infection (dpi). The PCV2 virus load in the liver, spleen and lung, and the microscopic lesions in the liver, spleen and lung also were determined on 5, 10, 15, and 20 dpi. Dietary Se yeast supplementation decreased (Pμ0.05) the serum levels of TNF-α, but had no significant effect on the activity of SOD and the levels of MDA, CRP and IL-1β between experimental and control groups. Dietary Se yeast supplementation had little effect on the PCV2 virus load in the liver, spleen and lung. However, mice in the selenium yeast group showed a significant decrease in microscopic lesion scores in the lung and spleen compared with those in the control group (Pμ0.05). These data indicate Se yeast attenuated the PCV2 infection through altering the systemic inflammation and maintaining the normal organ morphology.

The mycotoxin deoxynivalenol (DON), one of the most common food contaminants, primarily targets the gastrointestinal tract to affect animal and human health. This study was conducted to examine the protective function of glutamic acid on intestinal injury and oxidative stress caused by DON in piglets. Twenty-eight piglets were assigned randomly into 4 dietary treatments (7 pigs/treatment): 1) uncontaminated control diet (NC), 2) NC+DON at 4 mg/kg (DON), 3) NC+2% glutamic acid (GLU), and 4) NC+2% glutamic acid + DON at 4 mg/kg (DG). At day 15, 30 and 37, blood samples were collected to determine serum concentrations of CAT (catalase), T-AOC (total antioxidant capacity), H2O2 (hydrogen peroxide), NO (nitric oxide), MDA (maleic dialdehyde), DAO (diamine oxidase) and D-lactate. Intestinal morphology, and the activation of Akt/mTOR/4EBP1 signal pathway, as well as the concentrations of H2O2, MDA, and DAO in kidney, liver and small intestine, were analyzed at day 37. Results showed that DON significantly (P

This study was conducted to investigate serum amino acids profile in dextran sulfate sodium (DSS)-induced colitis, and impacts of graded dose of arginine or glutamine supplementation on the colitis. Using DSS-induced colitis model, which is similar to human ulcerative colitis, we determined serum profile of amino acids at day 3, 7, 10 and 12 (5 days post DSS treatment). Meanwhile, effects of graded dose of arginine (0.4%, 0.8%, and 1.5%) or glutamine (0.5%, 1.0% and 2.0%) supplementation on clinical parameters, serum amino acids, colonic tight junction proteins, colonic anti-oxidative indicators [catalase, total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px)], colonic pro-inflammatory cytokines [interleukin-1 beta (IL-1β), IL-6, IL-17 and tumor necrosis factor alpha (TNF-α)] in DSS-induced colitis were fully analyzed at day 7 and 12. Additionally, the activation of signal transduction pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), phosphoinositide-3-kinases (PI3K)/PI3K-protein kinase B (Akt), and myosin light chain kinase (MLCK)-myosin light chain (MLC20), were analyzed using immunoblotting. Serum amino acids analysis showed that DSS treatment changed the serum contents of amino acids, such as Trp, Glu, and Gln (P

Deoxynivalenol (DON) has various toxicological effects in humans and pigs that result from the ingestion of contaminated cereal products. This study was conducted to investigate the protective effects of dietary supplementation with glutamic acid on piglets challenged with DON. A total of 20 piglets weaned at 28 d of age were randomly assigned to receive 1 of 4 treatments (5 piglets/treatment): 1) basal diet, negative control (NC); 2) basal diet +4 mg/kg DON (DON); 3) basal diet +2% (g/g) glutamic acid (GLU); 4) basal diet +4 mg/kg DON +2% glutamic acid (DG). A 7-d adaptation period was followed by 30 days of treatment. A metabolite analysis using nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomic technology and the determination of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities for plasma, as well as the activity of Caspase-3 and the proliferation of epithelial cells were conducted. The results showed that contents of low-density lipoprotein, alanine, arginine, acetate, glycoprotein, trimethylamine-N-oxide (TMAO), glycine, lactate, and urea, as well as the glutamate/creatinine ratio were higher but high-density lipoprotein, proline, citrate, choline, unsaturated lipids and fumarate were lower in piglets of DON treatment than that of NC treatment (P

The purpose of this study was to investigate the hypothesis that dietary supplementation with glutamic acid has beneficial effects on growth performance, antioxidant system, intestinal morphology, serum amino acid profile and the gene expression of intestinal amino acid transporters in growing swine fed mold-contaminated feed. Fifteen pigs (Landrace×Large White) with a mean body weight (BW) of 55 kg were randomly divided into control group (basal feed), mycotoxin group (contaminated feed) and glutamate group (2% glutamate+contaminated feed). Compared with control group, mold-contaminated feed decreased average daily gain (ADG) and increased feed conversion rate (FCR). Meanwhile, fed mold-contaminated feed impaired anti-oxidative system and intestinal morphology, as well as modified the serum amino acid profile in growing pigs. However, supplementation with glutamate exhibited potential positive effects on growth performance of pigs fed mold-contaminated feed, ameliorated the imbalance antioxidant system and abnormalities of intestinal structure caused by mycotoxins. In addition, dietary glutamate supplementation to some extent restored changed serum amino acid profile caused by mold-contaminated feed. In conclusion, glutamic acid may be act as a nutritional regulating factor to ameliorate the adverse effects induced by mycotoxins.

Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases. [ABSTRACT FROM AUTHOR]