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Antibiotic-resistant strains of Streptococcus uberis ( S. uberis ) frequently cause clinical mastitis in dairy cows resulting in enormous economic losses. The regulation of immunometabolism is a promising strategy for controlling this bacterial infection. To investigate whether taurine alleviates S. uberis infection by the regulation of host glycolysis via HIF1α, the murine mammary epithelial cell line (EpH4-Ev) and C57BL/6J mice were challenged with S. uberis. Our data indicate that HIF1α-driven glycolysis promotes inflammation and damage in response to the S. uberis challenge. The activation of HIF1α is dependent on mTOR-mediated ROS production. These results were confirmed in vivo . Taurine, an intracellular metabolite present in most animal tissues, has been shown to effectively modulate HIF1α-triggered metabolic reprogramming and contributes to a reduction of inflammation, which reduces mammary tissue damage and prevents mammary gland dysfunction in S. uberis -induced mastitis. These data provide a novel putative prophylactic and therapeutic strategy for amelioration of dairy cow mastitis and bacterial inflammation.

Streptococcus uberis (S. uberis) is an important causative agent of mastitis, leading to significant economic losses to dairy industry. This research used a mouse mastitis model to investigate the protective effects of taurine on mammary inflammatory response and blood-milk barrier integrity in S. uberis challenge. The results showed that taurine attenuated S. uberis-induced mammary histopathological changes, especially neutrophil infiltration. The S. uberis-induced expression of pro-inflammatory mediators were decreased significantly by taurine. Further, we demonstrated that taurine limited the S. uberis-induced inflammatory responses via inhibiting the activation of NF-κB and MAPK signaling pathways. Inflammation usually disrupts the mammary barrier system. The recovery of claudin-3 and occludin expressions indicated that attenuation of inflammatory response by taurine can protect the integrity of blood-milk barrier in S. uberis infection. Taken together, our results reveal that the development of taurine as an effective prevention and control strategy for S. uberis-induced mastitis., (Copyright © 2021. Published by Elsevier B.V.)

Streptococcus uberis ( S. uberis ) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis -induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK-mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lan, Wan, Xu, Wang, Fu, Zhou, Lin, Han, Luo, Miao and Yin.)

Metabolic alterations occur in pathogenic infections, but the role of lipid metabolism in the progression of bacterial mastitis is unclear. Cross talk between lipid droplets (LDs) and invading bacteria occurs, and targeting of de novo lipogenesis inhibits pathogen reproduction. In this study, we investigate the role(s) of lipid metabolism in mammary cells during Streptococcus uberis infection. Our results indicate that S. uberis induces the synthesis of fatty acids and production of LDs. Importantly, taurine reduces fatty acid synthesis, the abundance of LDs and the in vitro bacterial load of S. uberis These changes are mediated, at least partly, by the E3 ubiquitin ligase IDOL, which is associated with the degradation of low-density lipoprotein receptors (LDLRs). We have identified a critical role for IDOL-mediated fatty acid synthesis in bacterial infection, and we suggest that taurine may be an effective prophylactic or therapeutic strategy for preventing S. uberis mastitis., (Copyright © 2021 American Society for Microbiology.)

Streptococcus uberis infection can cause serious inflammation and damage to mammary epithelial cells and tissues that can be significantly alleviated by taurine. Autophagy plays an important role in regulating immunity and clearing invasive pathogens and may be regulated by taurine. However, the relationships between taurine, autophagy, and S. uberis infection remain unclear. Herein, we demonstrate that taurine augments PTEN activity and inhibits Akt/mTOR signaling, which decreases phosphorylation of ULK1 and ATG13 by mTOR and activates autophagy. Activating autophagy accelerates the degradation of intracellular S. uberis , reduces intracellular bacterial load, inhibits over-activation of the NF-κB pathway, and alleviates the inflammation and damage caused by S. uberis infection. This study increases our understanding of the mechanism through which taurine regulates autophagy and is the first to demonstrate the role of autophagy in S. uberis infected MAC-T cells. Our study also provides a theoretical basis for employing nutritional elements (taurine) to regulate innate immunity and control S. uberis infection. It also provides theoretical support for the development of prophylactic strategies for this important pathogen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Lan, Xu, Zuo, Han, Phouthapane, Luo and Miao.)

Taurine may alleviate the inflammatory injury induced by Streptococcus uberis ( S. uberis ) infection by regulating intracellular Ca 2+ levels. However, the underlying mechanisms remain unclear. Infection leads to subversion of phosphoinositides (PIs) which are closely related to Ca 2+ signaling. In order to investigate whether taurine regulates inflammation by means of PIs/ Ca 2+ 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 Ca 2+ levels during inflammation. Both the Ca 2+ -PKCα-NF-κB, and Ca 2+ -CaM-CaN-NFAT signaling pathways of S. uberis infection and the regulatory roles of taurine follow activation of PIs/Ca 2+ 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.

To provide insight into the mechanisms of taurine attenuation of pro-inflammatory response in mouse mammary epithelial cell line (EpH4-Ev, purchased by ATCC, USA) after Streptococcus uberis (S. uberis, 0140J) challenge, we infected MECs with S. uberis (2.5×10(7)cfumL(-1), MOI=10) for 3h and quantified changes in TLR-2 and calcium (Ca(2+)) mediated signaling pathways. The results indicate that S. uberis infection significantly increases the expression of TLR-2, intracellular Ca(2+) levels, PLC-γ1 and PKC-α, the activities of transcription factors NF-κB and NFAT, and related cytokines (TNF-α, IL-1β, IL-6, G-CSF, IL-2, KC, IL-15, FasL, MCP-1, and LIX) in culture supernatants. Taurine administration downregulated all these indices, the activities of NF-κB and NFAT. Cytokine secretions were similar using special PKC inhibitor Go 6983 and NFAT inhibitor VIVIT. Our data indicate that S. uberis infection induces pro-inflammatory response of MECs through a TLR-2 mediated signaling pathway. In addition, taurine can prevent MEC damage by affecting both PLC-γ1-Ca(2+)-PKC-α-NF-κB and PLC-γ1-Ca(2+)-NFATs signaling pathways. This is the first report to demonstrate the mechanisms of taurine attenuated pro-inflammatory response in MECs after S. uberis challenge., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) are important pathogens causing subclinical and clinical bovine mastitis, respectively. Taurine, an organic acid found in animal tissues, has been used for the treatment of various superficial infections and chronic inflammations. We challenged a bovine mammary epithelial cell (MEC) line (MAC-T) or a mouse mammary epithelial cell line (EpH4-Ev) with either E. coli or S. aureus and compared the responses of MECs to these 2 pathogens. We also examined the regulatory effects of taurine on these responses. Receptor analyses showed that both TLR2 and TLR4 are upregulated upon exposure to either E. coli or S. aureus. Taurine pre-treatment dampened upregulation to some extent. E. coli and S. aureus stimulated comparable levels of ROS, which could be inhibited by taurine pre-treatment. E. coli infection elicited a dramatic change in iNOS expression. Taurine significantly decreased iNOS expression in the S. aureus challenged group. Protein microarray demonstrated that 32/40 and 8/40 inflammatory molecules/mediators were increased after E. coli or S. aureus challenge, respectively. The fold changes of most molecules were higher in the E. coli infection group than that in the S. aureus infection group. Taurine negatively regulated the inflammatory profile in both bacterial infections. Pro-inflammatory cytokines (such as TNF-α) connected with TLR activation were down-regulated by taurine pre-treatment. The influence of TAK-242 and OxPAPC on cytokine/molecule expression profiles to E. coli challenge are different than to S. aureus. Some important factors (MyD88, TNF-α, IL-1β, iNOS and IL-6) mediated by TLR activation were suppressed either in protein microarray or special assay (PCR/kits) or both. TAK-242 restrained ROS production and NAGase activity similar to the effect of taurine in E. coli challenge groups. The detection of 3 indices (T-AOC, SOD and MDA) reflecting oxidative stress in vivo, showed that taurine improved the antioxidant ability of cells. We conclude that taurine can regulate the inflammatory response during infection with E. coli and prevent cell damage by affecting the signaling pathways mediated by TLRs and by improving the antioxidant ability of cells. In S. aureus infections, taurine's antioxidant ability may be the primary means of resistance to inflammation. This study provides a better understanding of the inflammatory mechanisms of E. coli and S. aureus mastitis, and it provides a putative strategy for the prevention of this disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To investigate the influence of dietary taurine and reduced housing density on hepatic functions in laying hens, green-shell laying hens were randomly assigned to 3 groups: a free-range group, a caged group with low-density, and a caged group with high-density. Each group was further divided into the control (C) and taurine-treatment (T) groups. All the test birds were fed the same basic diet, except that the T groups were supplemented with 0.1% taurine. After 15 d, sera and liver were aseptically collected. The results show that dietary taurine supplementation and reduced housing density significantly attenuated physiopathological changes in the liver. When compared with the free-range group, serum alanine aminotransterase and aspartate aminotransterase in the caged hens were significantly higher and were deceased by taurine (P < 0.05). Serum inducible nitric oxide synthase activity in caged hens was higher than that in free-range hens, and taurine reduced serum inducible nitric oxide synthase activities in the low-density group (P < 0.05). Nuclear factor-κB DNA-binding activity increased significantly in the high-density housing group when compared with the other 2 housing patterns and was decreased by taurine (P < 0.05). Taurine reduced the expression of tumor necrosis factor-α mRNA in all 3 rearing patterns, IL-4 mRNA expression in the high-density group, and IL-10 in the low-density group (P < 0.05). Malondialdehyde levels decreased in serum and liver from T groups and serum total antioxidation capability levels increased significantly (P < 0.05) in the low-density group. Dietary taurine supplementation decreased acetyl-CoA and sterol regulatory element-binding protein-1c mRNA expression in the high-density groups (P < 0.05). Taurine significantly increased lipoprotein lipase mRNA expression in the high-density group and peroxisome proliferator receptor mRNA expression both in the low- and high-density groups (P < 0.05). Taurine supplementation reduced total cholesterol levels in the low- and high-density groups, decreased triglyceride and low-density lipoprotein cholesterol levels in high-density groups, and increased high-density lipoprotein cholesterol levels in all 3 rearing patterns (P < 0.05). Our data demonstrate that dietary taurine and reduced housing density offer significant protection from hepatic damage in laying hens., (© 2014 Poultry Science Association Inc.)

In order to evaluate the role of taurine on the oxidative stress mediated by NADPH oxidase in Streptococcus uberis-induced (S. uberis) mastitis, rats were administered daily (per os) 100mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) from gestation day 14 until parturition. Seventy-two hours after parturition, approximately 100cfu of S. uberis was infused into each of 2 mammary glands. Pretreatment with taurine significantly decreased mRNA and protein expression of p47phox and p22phox in mammary tissues. The total anti-oxidation capability (T-AOC) levels and superoxide dismutase (SOD) activities decreased, while malondialdehyde (MDA) levels increased both in mammary tissues and serum of rats with intramammary S. uberis infusion. Gavage administration of taurine moderated this change. Concentrations of interleukin-1β (IL-1β) and IL-6 in mammary glands decreased as a result of taurine administration. Significant differences (P<0.05) were present at 48 and 72 h post S. uberis-infusion (PI) for IL-1β and 72 h PI for IL-6. Our data indicate that, in S. uberis-induced mastitis, taurine has the ability of regulating redox conditions which leads to the suppression of oxidative stress and secretion of proinflammatory cytokines. This phenomenon may be ascribed to taurines's ability to inhibit the expression of NADPH oxidase., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The intent of this study was to evaluate the active defense reaction of mouse mammary epithelial cells and the cytoprotective and anti-inflammatory properties of taurine to lipopolysaccharide (LPS)-induced disfunction in mouse mammary epithelial cells. (1) Primary cultured mouse mammary epithelial cells were stimulated with LPS for 24 h (final concentration=0, 5, 10, 20 μg/mL). Western blotting demonstrated a significant decrease in the secretion of β-casein in the 20 μg/mL LPS treatment group (P<0.05), while nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), lactoferrin (LF) and N-acetyl-β-D-glucosaminidase (NAGase) were all significantly increased following LPS treatment (P<0.01). Furthermore, cell survival was significantly inhibited after treatment with 20 μg/mL LPS; however, neither 5 μg/mL nor 10 μg/mL LPS had any effect on cell survival. Therefore, a level of 10 μg/mL LPS was selected to test the protective effect of taurine on mouse mammary epithelial cells. (2) Primary cultured mouse mammary epithelial cells were treated with 0, 5, 15 or 45 mmol/L taurine for 3 h, followed by 10 μg/mL LPS for 24 h. Taurine significantly attenuated the LPS-induced increase in NAGase activity, NO concentrations and the level of TNF-α, IL-1β, IL-6 and LF. Taurine at 45 mmol/L markedly increased β-casein secretion in response to LPS-induced disfunction. This study demonstrated that the addition of taurine to a culture medium significantly inhibited the LPS-induced release of inflammatory factors and increased β-casein secretion from mammary epithelial cells, thereby providing a possible explanation for the protective effect proposed for taurine in the prevention of LPS-induced disfunction in mammary epithelial cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Taurine (Tau) is reported to have a key role in the regulation of the innate immune response and thus reduce tissue damage induced by bacterial infection. In this study, the effects of Tau on a rat model of mastitis induced by Streptococcus uberis (S. uberis) and the changes of T regulatory cells (Tregs) were assessed. Starting on gestation day 14 and continuing until parturition, 100 mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) was administered daily, per os. Seventy-two hours after parturition, rats were infused with approximately 100 cfu of S. uberis into each of two mammary glands. The results showed that the resultant inflammation, evidenced by swelling, secretory epithelial cell degeneration, increased adipose tissue and neutrophil (PMN) infiltration were evident in mammary tissue following injection with S. uberis. Pre-treatment with Tau attenuated these morphologic changes, the expression of interleukin (IL)-2, interferon (INF)-γ mRNA, myeloperoxidase (MPO) activity and N-acetyl-β-D-glucosaminidase (NAGase) in mammary tissue. The percentages of Foxp3+CD25+CD4+/lymphocytes (Tregs) were dramatically increased after the S. uberis challenge. Significant differences (P<0.05) were observed at 24, and 72 h post S. uberis-injection (PI) in CS. Pre-treatment further increased the percentage of Tregs and a significant difference between CS and TS (P<0.05) was apparent at 24 h PI. Our data indicate that in rats, Tau can be used to regulate the immune response following infection by S. uberis and consequently prevent mammary tissue damage by increasing Tregs.

To investigate whether taurine ameliorates mammary damage in a rat model of S. uberis mastitis by suppressing inflammation related to the toll-like receptors/nuclear factor kappa B (TLRs/NF-κB) signaling pathway. Starting on gestation day 14 and continuing until parturition, 100 mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) was administered daily to rats. Seventy-two hours after parturition, rats were infused with 100 cfu of S. uberis into each of 2 mammary glands. The resultant inflammation, evidenced by swelling, degeneration of secretory epithelium, increased tissue loss and neutrophil (PMN) infiltration was observed. Pretreatment with taurine attenuated inflammatory changes and significantly decreased mRNA expression of TLR-2 (8 h post S. uberis-injection, PI), NF-κB p65 (16 h and 24 h PI), and NF-κB DNA binding activity (16 h PI). Tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) levels were also decreased. Significant differences (P<0.05) were present at 24 h and 48 h PI for TNF-α and at 16 h PI for iNOS. TLR-4 mRNA expression was increased by taurine administration and significant differences were observed at 8h, 16 h and 24 h PI. These results suggest that the in vivo relationship of immunomodulatory reagents with TLRs is complex. Taurine may modulate inflammatory injury induced by S. uberis in mammary glands though TLR-2 and TLR-4. Suppression of inflammation may be related to TLRs/NF-κB and may be one mechanism of taurine action in controlling S. uberis mastitis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

To evaluate the effects of taurine on the laying performance and health status in laying hens,4 000 green-shell laying hens, randomly assigned into control group, and treatments 1,2,3, respectively,were fed with the basal diet and the diet added 0.01 %, 0.1% and 1% taurine. The survival rate, laying rate, daily feed consumption and weight gain of each group were recorded every day. Seven weeks later,10 hens were selected randomly from each group and serum, livers and kidneys were aseptically collected. The results showed that taurine supplementation with different dosage in the diet improved the survival rate and laying rate of hens, among which 0.1% taurine supplementation had the most significant effect on it. Histologic examination showed that taurine could ameliorate hepatic and renal structure. Compared with the control,the activity of serum alanine aminotransferase( ALT), and the levels of creatinine (SCr), blood uric acid(UA), malondialdehyde (MDA), low density lipoprotein cholesterol(LDL-C)of treatments 2 and 3 in serum were significantly lower,and the aspartate aminotransferase( AST) activity, serum triglyceride( TG) and total cholesterol( TC) content in treatment 2 also decreased significantly. Taurine could significantly enhance the high density lipoprotein cholesterol(HDL-C) content (P<0.05). Tumor necrosis factor alpha(TNF-α),interleukin-1 beta(IL-1β) in kidneys and livers decreased with taurine supplied. Interleukin-4(IL-4)and interferon-γ(IFN-γ)significantly decreased with 0. 1% and 1% taurine supplimention. TNF-αIL-1β,IL-10 levels of treatment 2,3 and IFN-γ,IL-4 levels of treatment 3 reduced significantly in livers. Total antioxidative capacity( T-AOC) activity of all three treatment groups increased in livers with taurine supplied(P<0.05). These results showed that dietary taurine could improve the survival rate and the laying rate of hens, enhance the antioxidant levels, facilitate lipid metabolism and decrease the level of inflammatory mediators. 0.1% taurine supplied in the diet appears to be optimum for laying hens. [ABSTRACT FROM AUTHOR]

• Taurine protects blood-milk barrier from neutrophils infiltration. • Taurine reduces neutrophil recruitment by inhibiting CXCL2 expression. • Taurine inhibits S.uberis -induced TAK1/MAPK/NF-κB signaling activation in RAW264.7. • AMPK/Nrf2 signaling activation by taurine enhances the antioxidant capacity. Mastitis is a common disease of dairy cows characterized by infiltration of leukocytes, especially neutrophils, resulting in increased permeability of the blood-milk barrier (BMB). Taurine, a functional nutrient, has been shown to have anti-inflammatory and antioxidant effects. Here, we investigated the regulatory effects and mechanisms of taurine on the complex immune network of the mammary gland in Streptococcus uberis (S. uberis) infection. We found that taurine had no direct effect on CXCL2-mediated neutrophil chemotaxis. However, it inhibited MAPK and NF-κB signalings by modulating the activity of TAK1 downstream of TLR2, thereby reducing CXCL2 expression in macrophages to reduce neutrophil recruitment in S. uberis infection. Further, the AMPK/Nrf2 signaling pathway was activated by taurine to help mitigate oxidative damage, apoptosis and disruption of tight junctions in mammary epithelial cells caused by hypochlorous acid, a strong oxidant produced by neutrophils, thus protecting the integrity of the mammary epithelial barrier. Taurine protects the BMB from damage caused by neutrophils via blocking the macrophage-CXCL2-neutrophil signaling axis and increasing the antioxidant capacity of mammary epithelial cells. [ABSTRACT FROM AUTHOR]