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Roles of Diet-Associated Gut Microbial Metabolites on Brain Health: Cell-to-Cell Interactions between Gut Bacteria and the Central Nervous System.
Kim, CS
Advances in nutrition (Bethesda, Md.). 2024;(1):100136
Abstract
Gut microbiota have crucial effects on brain function via the gut-brain axis. Growing evidence suggests that this interaction is mediated by signaling molecules derived from dietary components metabolized by the intestinal microbiota. Although recent studies have provided a substantial understanding of the cell-specific effects of gut microbial molecules in gut microbiome-brain research, further validation is needed. This review presents recent findings on gut microbiota-derived dietary metabolites that enter the systemic circulation and influence the cell-to-cell interactions between gut microbes and cells in the central nervous system (CNS), particularly microglia, astrocytes, and neuronal cells, ultimately affecting cognitive function, mood, and behavior. Specifically, this review highlights the roles of metabolites produced by the gut microbiota via dietary component transformation, including short-chain fatty acids, tryptophan metabolites, and bile acid metabolites, in promoting the function and maturation of brain cells and suppressing inflammatory signals in the CNS. We also discuss future directions for gut microbiome-brain research, focusing on diet-induced microbial metabolite-based therapies as possible novel approaches to mental health treatment.
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Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.
Lee, SA, Hong, SJ, Sung, JH, Kim, KS, Kim, SH, Cho, JM, Chun, SW, Lee, SR, Kim, CS, Kim, TN, et al
Medicine. 2023;(47):e36122
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Abstract
BACKGROUND We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters. RESULTS Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline. CONCLUSIONS The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.
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Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study.
Kim, KS, Han, KA, Kim, TN, Park, CY, Park, JH, Kim, SY, Kim, YH, Song, KH, Kang, ES, Kim, CS, et al
Diabetes & metabolism. 2023;(4):101440
Abstract
AIMS: This study evaluated the efficacy and safety of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor, versus dapagliflozin in Korean patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and gemigliptin. METHODS In this multicenter, double-blind, randomized study, patients with inadequate response to metformin (≥ 1000 mg/day) plus gemigliptin (50 mg/day) were randomized to receive enavogliflozin 0.3 mg/day (n = 134) or dapagliflozin 10 mg/day (n = 136) in addition to the metformin plus gemigliptin therapy. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS Both treatments significantly reduced HbA1c at week 24 (-0.92% in enavogliflozin group, -0.86% in dapagliflozin group). The enavogliflozin and dapagliflozin groups did not differ in terms of changes in HbA1c (between-group difference: -0.06%, 95% confidence interval [CI]: -0.19, 0.06) and fasting plasma glucose (between-group difference: -3.49 mg/dl [-8.08;1.10]). An increase in urine glucose-creatinine ratio was significantly greater in the enavogliflozin group than in the dapagliflozin group (60.2 g/g versus 43.5 g/g, P < 0.0001). The incidence of treatment-emergent adverse events was similar between the groups (21.64% versus 23.53%). CONCLUSIONS Enavogliflozin, added to metformin plus gemigliptin, was well tolerated and as effective as dapagliflozin in the treatment of patients with T2DM.
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Probiotic supplementation has sex-dependent effects on immune responses in association with the gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial.
Kim, CS, Jung, MH, Choi, EY, Shin, DM
Nutrition research and practice. 2023;(5):883-898
Abstract
BACKGROUND/OBJECTIVES Probiotics have been suggested as potent modulators of age-related disorders in immunological functions, yet little is known about sex-dependent effects of probiotic supplements. Therefore, we aimed to investigate sex-dependent effects of probiotics on profiles of the gut microbiota and peripheral immune cells in healthy older adults. SUBJECTS/METHODS In a randomized, double-blind, placebo-controlled, multicenter trial, healthy elderly individuals ≥ 65 yrs old were administered probiotic capsules (or placebo) for 12 wk. Gut microbiota was analyzed using 16S rRNA gene sequencing and bioinformatic analyses. Peripheral immune cells were profiled using flow cytometry for lymphocytes (natural killer, B, CD4+ T, and CD8+ T cells), dendritic cells, monocytes, and their subpopulations. RESULTS Compared with placebo, phylum Firmicutes was significantly reduced in the probiotic group in women, but not in men. At the genus level, sex-specific responses included reductions in the relative abundances of pro-inflammatory gut microbes, including Catabacter and unclassified_Coriobacteriales, and Burkholderia and unclassified Enterobacteriaceae, in men and women, respectively. Peripheral immune cell profiling analysis revealed that in men, probiotics significantly reduced the proportions of dendritic cells and CD14+ CD16- monocytes; however, these effects were not observed in women. In contrast, the proportion of total CD4+ T cells was significantly reduced in women in the probiotic group. Additionally, serum lipopolysaccharide-binding protein levels showed a decreasing tendency that were positively associated with changes in gut bacteria, including Catabacter (ρ = 0.678, P < 0.05) and Burkholderia (ρ = 0.673, P < 0.05) in men and women, respectively. CONCLUSIONS These results suggest that probiotic supplementation may reduce the incidence of inflammation-related diseases by regulating the profiles of the gut microbiota and peripheral immune cells in healthy elders in a sex-specific manner.
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Vitamin C and catheter-related bladder discomfort after transurethral resection of bladder tumor: A double-blind, randomized, placebo-controlled study.
Park, JY, Baek, JW, Yu, J, Kim, CS, Bae, J, Kim, YK
Journal of clinical anesthesia. 2023;:111191
Abstract
STUDY OBJECTIVE We evaluated the effect of vitamin C administration on postoperative catheter-related bladder discomfort (CRBD). DESIGN A double-blind, randomized controlled trial. SETTING University tertiary hospital. PATIENTS The participants were patients undergoing transurethral resection of bladder tumor. INTERVENTION Patients were randomly assigned to either vitamin C (n = 59) or control (n = 59). The vitamin C group received 1 g of vitamin C intravenously and the control group received normal saline, administered after the induction of anesthesia. MEASUREMENTS The primary endpoint was moderate or greater CRBD immediately postoperatively. Secondary outcomes included the incidence of moderate or greater CRBD at 1, 2, and 6 h postoperatively. The symptom of CRBD is either a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate CRBD was defined as spontaneously reported by the patient without any behavioral responses, such as attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. Severe CRBD was spontaneously reported by the patient with behavioral responses. Patient satisfaction scores were also evaluated. MAIN RESULTS The group that received vitamin C exhibited a significantly lower incidence of moderate or greater CRBD immediately postoperatively compared with the control group (17 [28.8%] vs. 40 [67.8%], p < 0.001, relative risk [95% confidence interval] = 0.426 [0.274-0.656]). The vitamin C group also showed a significantly lower incidence of moderate or greater CRBD at 1 and 2 h postoperatively compared with the control group (10 [16.9%] vs. 25 [42.4%], p = 0.003; and 5 [8.5%] vs. 16 [27.1%], p = 0.008, respectively). However, there was no significant difference in the incidence of moderate or greater CRBD 6 h postoperatively. Patient satisfaction scores were significantly higher in the vitamin C group than in the control group (5.0 ± 1.3 vs. 4.4 ± 1.4, p = 0.009). CONCLUSIONS Patients who received vitamin C had decreased CRBD and improved patient satisfaction following transurethral resection of bladder tumor.
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Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: A randomized, double-blind, placebo-controlled, multicenter trial and in vitro study.
Kim, CS, Jung, S, Hwang, GS, Shin, DM
Clinical nutrition (Edinburgh, Scotland). 2023;(6):1025-1033
Abstract
BACKGROUND & AIMS The beneficial effects of probiotic consumption on age-related decline in cerebral function have been previously reported in the literature; however, the mechanistic link between gut and brain interactions has not yet been fully elucidated. Therefore, this study aimed to identify the role of gut microbiota-derived metabolites in gut-brain interactions via blood metabolomic profiling analysis in clinical trials and in vitro mechanistic studies. METHODS A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 63 healthy elderly individuals (≥65 years of age). Participants were administered either placebo (placebo group, N = 31) or probiotic capsules (Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI; probiotics group, N = 32) for 12 weeks. Global and targeted metabolomic profiling analyses of their blood samples were then performed using 1H nuclear magnetic resonance and liquid chromatography-mass spectrometry methods, both at baseline and at the end of the trial. Gut microbial analysis was conducted using the 16S ribosomal ribonucleic acid gene sequencing method. Subsequently, microglial BV2 cells were treated in vitro with indole-3-propionic acid (IPA) following lipopolysaccharide stimulation, and neuronal SH-SY5Y cells were treated with conditioned media from the BV2 cells. Finally, the levels of pro-inflammatory cytokines in BV2 cells and neurotrophins in SH-SY5Y cells were quantified using a real-time polymerase chain reaction or enzyme-linked immunosorbent assay. RESULTS The metabolomic profiling analyses showed that probiotic consumption significantly altered the levels of metabolites involved in tryptophan metabolism (P < 0.01). Among these metabolites, gut microbiota-produced IPA had a 1.91-fold increase in the probiotics group (P < 0.05) and showed a significant relation to gut bacterial profiles (P < 0.01). Elevated IPA levels were also positively associated with the level of serum brain-derived neurotropic factor (BDNF) in the probiotics group (r = 0.28, P < 0.05), showing an inverse trend compared to the placebo group. In addition, in vitro treatment with IPA (5 μM) significantly reduced the concentration of proinflammatory TNF-α in activated microglia (P < 0.05), and neuronal cells cultured with conditioned media from IPA-treated microglia showed a significant increase in BDNF and nerve growth factor production (P < 0.05). CONCLUSIONS These results show that gut microbiota-produced IPA plays a role in protecting the microglia from inflammation, thus promoting neuronal function. Therefore, this suggests that IPA is a significant mediator linking the interaction between the gut and the brain in the elderly with probiotic supplementation.
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Effect of chewing gum on anxiety in women undergoing elective cesarean section: a randomized controlled study.
Bang, YJ, Lee, EK, Kang, R, Kim, AH, Kim, CS, Sim, WS, Choi, SJ, Oh, SY, Roh, CR, Ko, JS
Annals of palliative medicine. 2023;(3):529-537
Abstract
BACKGROUND Preoperative anxiety is a common problem in pregnant women undergoing elective cesarean section. We aimed to determine the anxiolytic effects of chewing gum in pregnant women undergoing elective cesarean section under regional anesthesia. METHODS This was a single-center, prospective, randomized controlled trial. Sixty-six women were randomly assigned to either the control group (n=33) or gum group (n=33) in a 1:1 ratio. In the gum group, the participants chewed xylitol gum for at least 10 min/h, regardless of fasting. Gum chewing was started at 5 pm a day before surgery and continued till the participant entered the operation room. In the control group, participants were requested to follow fasting guidelines without further instruction. The primary outcome was preoperative anxiety measured using the Amsterdam Preoperative Anxiety and Information Scale (APAIS) immediately before surgery. RESULTS The APAIS score immediately before surgery showed no significant difference between the control and the gum group (19.2±5.8 vs. 19.1±4.1, P>0.99). There were no statistically significant differences in the eight items related to anxiety: unfitness, concentration difficulty, hunger, thirst, dry mouth, fatigue, headache, and nausea. However, the pain score during the procedure of combined spinal epidural anesthesia was significantly lower in the chewing gum group [4 (IQR, 3-5.5)] than in the control group [5 (IQR, 3-7), P=0.045]. CONCLUSIONS Preoperative gum chewing did not reduce anxiety levels measured immediately before entering the operating room in the participants undergoing elective cesarean section. TRIAL REGISTRATION Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/index.jsp and identifier: KCT0006602; date of registration: September 27, 2021; principal investigator's name: RyungA Kang.
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Marine Biological Macromolecules and Chemically Modified Macromolecules; Potential Anticoagulants.
Chandika, P, Tennakoon, P, Kim, TH, Kim, SC, Je, JY, Kim, JI, Lee, B, Ryu, B, Kang, HW, Kim, HW, et al
Marine drugs. 2022;(10)
Abstract
Coagulation is a potential defense mechanism that involves activating a series of zymogens to convert soluble fibrinogen to insoluble fibrin clots to prevent bleeding and hemorrhagic complications. To prevent the extra formation and diffusion of clots, the counterbalance inhibitory mechanism is activated at levels of the coagulation pathway. Contrariwise, this system can evade normal control due to either inherited or acquired defects or aging which leads to unusual clots formation. The abnormal formations and deposition of excess fibrin trigger serious arterial and cardiovascular diseases. Although heparin and heparin-based anticoagulants are a widely prescribed class of anticoagulants, the clinical use of heparin has limitations due to the unpredictable anticoagulation, risk of bleeding, and other complications. Hence, significant interest has been established over the years to investigate alternative therapeutic anticoagulants from natural sources, especially from marine sources with good safety and potency due to their unique chemical structure and biological activity. This review summarizes the coagulation cascade and potential macromolecular anticoagulants derived from marine flora and fauna.
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Escherichia coli small molecule metabolism at the host-microorganism interface.
Gatsios, A, Kim, CS, Crawford, JM
Nature chemical biology. 2021;(10):1016-1026
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Escherichia coli are a common component of the human microbiota, and isolates exhibit probiotic, commensal and pathogenic roles in the host. E. coli members often use diverse small molecule chemistry to regulate intrabacterial, intermicrobial and host-bacterial interactions. While E. coli are considered to be a well-studied model organism in biology, much of their chemical arsenal has only more recently been defined, and much remains to be explored. Here we describe chemical signaling systems in E. coli in the context of the broader field of metabolism at the host-bacteria interface and the role of this signaling in disease modulation.
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Effectiveness of liraglutide 3 mg for the treatment of obesity in a real-world setting without intensive lifestyle intervention.
Park, JH, Kim, JY, Choi, JH, Park, HS, Shin, HY, Lee, JM, Kim, JW, Ko, HJ, Chon, S, Kim, BK, et al
International journal of obesity (2005). 2021;(4):776-786
Abstract
OBJECTIVE We investigated the efficacy and safety of liraglutide 3 mg daily in combination with diet and exercise 2, 4, and 6 months after initiation in real-world settings in Korea. METHODS People first using liraglutide starting in 2018 were recruited from ten sites in Korea. Body weight and body mass index (BMI) were measured after 2, 4, and 6 months and compared with baseline values. RESULTS The full cohort comprised 769 participants: 672 in the 2-month group, 427 in the 4-month group, and 219 in the 6-month group. The baseline mean ± standard deviation of BMI and body weight were 32.2 ± 5.1 kg/m2, and 87.5 ± 18.8 kg, respectively. Body weight and BMI decreased after initiation of liraglutide treatment: -2.94 kg and -1.08 kg/m2 at 2 months; -4.23 kg and -1.55 kg/m2 at 4 months, and -5.14 kg and -1.89 kg/m2 at 6 months (all P < 0.001). In the 6-month cohort, 52.5% and 18.3% of subjects lost ≥5% and ≥10% of body weight, respectively. After 6 months, systolic and diastolic blood pressure decreased significantly by 3.90 and 1.93 mmHg, respectively. In those with diabetes mellitus, HbA1c and fasting glucose levels decreased significantly by 1.14% and 27.8 mg/dl, respectively. Among all participants, 27.6% experienced adverse effects, including nausea (20.8%), vomiting (5.2%), diarrhoea (2.5%), and skin rash (3.6%). Documented reasons for discontinuation of treatment were lack of effect (4.4%), adverse events (4.3%), and high cost (3.1%). CONCLUSIONS In real-world settings in Korea, daily treatment with liraglutide 3 mg was associated with clinically meaningful weight loss without serious adverse events.