A comprehensive review of synbiotics: an emerging paradigm in health promotion and disease management.

Synbiotics are complex preparations of prebiotics that can be selectively utilized by live microorganisms to improve host health. Synbiotics are divided into complementary synbiotics, which consist of probiotics and prebiotics with independent functions, and synergistic synbiotics, which consist of prebiotics that are selectively used by gut microorganisms. Complementary synbiotics used in human clinical trials include Lactobacillus spp. and Bifidobacterium spp. as probiotics, and fructooligosaccharides, galactooligosaccharides, and inulin as prebiotics. Over the past five years, synbiotics have been most commonly used in patients with metabolic disorders, including obesity, and immune and gastrointestinal disorders. Several studies have observed alterations in the microbial community; however, these changes did not lead to significant improvements in disease outcomes or biochemical and hematological markers. The same synbiotics have been applied to individuals with different gut environments. As a result, even with the same synbiotics, there are non-responders who do not respond to the applied synbiotics due to the different intestinal environment for each individual. Therefore, to obtain meaningful results, applying different synbiotics depending on the individual is necessary. Synergistic synbiotics are one solution to circumvent this problem, as they combine elements that can effectively improve health, even in non-responders. This review aims to explain the concept of synbiotics, highlight recent human clinical trials, and explore the current state of research on synergistic synbiotics.

Complete genome sequence of probiotic Lactobacillus johnsonii 7409N31 isolated from a healthy Hanwoo calf.

Lactobacillus johnsonii 7409N31 was isolated from the feces of a healthy 11-day-old Hanwoo calf from a farm in Geochang-gun, Gyeongsangnam-do, Korea. The genome of the strain was completely sequenced using the PacBio RSII sequencing system, and it was confirmed that it was composed of one circular chromosome. The size of the entire genome was 2,198,442 bp, and it had 35.01 mol% guanine + cytosine (G + C) content and 2,222 protein-coding sequences, 24 rRNA, 3 ncRNA, and 112 tRNA genes. Strain 7409N31 possessed genes encoding enzymes involved in the hydrolysis of both fibrous and non-fibrous carbohydrates. These data provide a comprehensive theoretical understanding for developing industrial probiotic feed additives that improve nutrient digestibility.

The Radical Scavenging Activities and Anti-Wrinkle Effects of Soymilk Fractions Fermented with Lacticaseibacillus paracasei MK1 and Their Derived Peptides.

Soybean-derived peptides exert several beneficial effects in various experimental models. However, only a few studies have focused on the radical scavenging and anti-wrinkle effects of soymilk-derived peptides produced via different processes, such as fermentation, enzymatic treatment, and ultrafiltration. Therefore, in this study, we investigated the radical scavenging and antiwrinkle effects of soymilk fractions produced using these processes. We found that 50SFMKUF5, a 5 kDa ultrafiltration fraction fermented with Lacticaseibacillus paracasei MK1 after flavourzyme treatment, exhibited the highest radical scavenging activity using the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay as well as potent anti-wrinkle effects assessed by type 1 procollagen production and tumor necrosis factor-α production in ultraviolet B (UVB)-treated human dermal fibroblasts and HaCaT keratinocytes. To identify potential bioactive peptides, candidate peptides were synthesized, and their anti-wrinkle effects were assessed. APEFLKEAFGVN (APE), palmitoyl-APE, and QIVTVEGGLSVISPK peptides were synthesized and used to treat UVB-irradiated fibroblasts, HaCaT keratinocytes, and α-melanocyte-stimulating hormone-induced B16F1 melanoma cells. Among these peptides, Pal-APE exerted the strongest effect. Our results highlight the potential of soymilk peptides as anti-aging substances.

Monitoring mRNA Expression Patterns in Macrophages in Response to Two Different Strains of Probiotics.

As an initial study to elucidate the molecular mechanism of how probiotics modulate macrophage activity, we monitored mRNA expression patterns in peritoneal macrophages (PMs) treated with two different strains of probiotics. After treatment with either Weissella cibaria WIKIM28 or Latilactobacillus sakei WIKIM50, total RNAs from PMs were isolated and subjected into gene chip analyses. As controls, mRNAs from vehicle (phosphate-buffered saline, PBS)-treated PMs were also subjected to gene chip analysis. Compared to vehicle (PBS)-treated PMs, WIKIM28-treated and WIKIM50-treated PMs exhibited a total of 889 and 432 differentially expressed genes with expression differences of at least 4 folds, respectively. Compared to WIKIM28-treated PMs, WIKIM50-treated PMs showed 25 up-regulated genes and 21 down-regulated genes with expression differences of more than 2 folds. Interestingly, mRNA transcripts of M2 macrophage polarization marker such as anxa1, mafb, and sepp1 were increased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. Reversely, mRNA transcripts of M1 macrophage polarization marker such as hdac9, ptgs2, and socs3 were decreased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. In agreement with these observations, mRNA expression levels of tumor necrosis factor-α and interleukin-1α were significantly reduced in WIKIM50-treated macrophages compared to those in WIKIM28-treated macrophages. These results may indicate that probiotics can be classified as two different types depending on their ability to convert macrophages into M1 or M2 polarization.

Kimchi intake alleviates obesity-induced neuroinflammation by modulating the gut-brain axis.

A high-fat diet (HFD) induces low-grade, chronic inflammation throughout the body including the hypothalamus, a key brain region involved in the control of satiety and energy expenditure in central nervous system (CNS). Kimchi is a traditional fermented Korean food, which is recognized as a healthy food. In this study, we evaluated its ability to suppress the obesity-induced inflammation in mice fed an HFD. Male C57BL/6 mice were fed an HFD or HFD with kimchi (pH 5.2 âˆ¼ 5.8). Oral administration of kimchi significantly reduced the body weight, fat mass gain, and levels of pro-inflammatory cytokines in serum. Furthermore, kimchi diminished the HFD-induced activation of astrocyte and microglial cells (reactive gliosis, a hallmark of CNS injury and inflammation) in hypothalamus region. IgG accumulation assay showed that kimchi ingestion suppressed HFD-induced breakage of the blood brain barrier (BBB) via upregulating the expression of tight junction molecules in cerebrovascular endothelial cells. In addition, kimchi modulated gut microbiome profiles, which showed an increase in the abundance of Akkermansia muciniphila. Moreover, kimchi enhanced acetate level and BBB integrity in A. muciniphila-colonized gnotobiotic mice. These results suggest that kimchi may exert beneficial effects to prevent and ameliorate obesity and associated neuroinflammation by changing gut microbiota composition and short-chain fatty acids production.

Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression.

The timely mobilization of hematopoietic stem and progenitor cells (HSPCs) is essential for maintaining hematopoietic and tissue leukocyte homeostasis. Understanding how HSPCs migrate between bone marrow (BM) and peripheral tissues is of great significance in the clinical setting, where therapeutic strategies for modulating their migration capacity determine the clinical outcome. Here, we identify an epigenetic regulator, Phc2, as a critical modulator of HSPC trafficking. The genetic ablation of Phc2 in mice causes a severe defect in HSPC mobilization through the derepression of Vcam1 in bone marrow stromal cells (BMSCs), ultimately leading to a systemic immunodeficiency. Moreover, the pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses the symptoms. We further determine that Phc2-dependent Vcam1 repression in BMSCs is mediated by the epigenetic regulation of H3K27me3 and H2AK119ub. Together, our data demonstrate a cell-extrinsic role for Phc2 in controlling the mobilization of HSPCs by finely tuning their bone marrow niche.

Monitoring mRNA transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells of pregnant pigs with different parity.

The reproductive success of mammals is largely dependent on the interaction between maternal and foetal interfaces during early pregnancy. Particularly, immune cells which reside at the maternal endometrium can modulate the conception and placental vascularization. In this study, we analysed the transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells (PBMCs) of pregnant pigs with different parity. Briefly, three groups of female pigs were divided based on parity (0, 2 and 5) and each group was artificially inseminated. Within 30 days of gestation, the total RNA was isolated from the endometrium and PBMCs of sacrificed experimental pigs and the expression patterns of genes involved in early pregnancy were monitored by quantitative real-time RT-PCR. Results indicated absence of correlation between increased parity and the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) mRNA in endometrium among the groups of pigs analysed. Yet, the mRNA levels of Fas, Fas ligand (FasL) and tumour necrosis factor-α (TNF-α) in the endometrium of parity 5 sows were much higher than those of pregnant gilts (parity 0), and the mRNA ratios of both TNF-α:interleukin-4 (IL-4) and IFN-γ (interferon-γ):interleukin-10 (IL-10) in PBMCs of pregnant pigs were augmented with increasing parity. Furthermore, the mRNA levels of TNF-α and IFN-γ in PBMCs of pregnant pigs were inversely correlated with litter size. These combined results may demonstrate that increased parity of pregnant pigs leads to enhance Th1-prone immunity within the maternal-foetal interface during early pregnancy.

Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice.

Severe hepatic inflammation is a common cause of acute or chronic liver disease. Macrophages are one of the key mediators which regulate the progress of hepatic inflammation. Increasing evidence shows that the TAM (TYRO3, AXL and MERTK) family of RTKs (receptor tyrosine kinases), which is expressed in macrophages, alleviates inflammatory responses through a negative feedback loop. However, the functional contribution of each TAM family member to the progression of hepatic inflammation remains elusive. In this study, we explore the role of individual TAM family proteins during autophagy induction and evaluate their contribution to hepatic inflammation. Among the TAM family of RTKs, AXL (AXL receptor tyrosine kinase) only induces autophagy in macrophages after interaction with its ligand, GAS6 (growth arrest specific 6). Based on our results, autophosphorylation of 2 tyrosine residues (Tyr815 and Tyr860) in the cytoplasmic domain of AXL in mice is required for autophagy induction and AXL-mediated autophagy induction is dependent on MAPK (mitogen-activated protein kinase)14 activity. Furthermore, induction of AXL-mediated autophagy prevents CASP1 (caspase 1)-dependent IL1B (interleukin 1, ß) and IL18 (interleukin 18) maturation by inhibiting NLRP3 (NLR family, pyrin domain containing 3) inflammasome activation. In agreement with these observations, axl-/- mice show more severe symptoms than do wild-type (Axl+/+) mice following acute hepatic injury induced by administration of lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). Hence, GAS6-AXL signaling-mediated autophagy induction in murine macrophages ameliorates hepatic inflammatory responses by inhibiting NLRP3 inflammasome activation.

Glabretal-type triterpenoid from the root bark of Dictamnus dasycarpus ameliorates collagen-induced arthritis by inhibiting Erk-dependent lymphocyte proliferation.

ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of Dictamnus dasycarpus Turcz. (Rutaceae) has been used as a traditional herbal medicine to treat various inflammatory diseases in East Asia. We have showed previously that a glabretal type triterpenoid (dictabretol A) from D. dasycarpus root bark has immunosuppressive activity. AIM OF THE STUDY: This study was conducted to define the molecular mechanism of how dictabretol A inhibits lymphocyte proliferation and to evaluate the therapeutic efficacy of dictabretol A in an animal model of rheumatoid arthritis. MATERIALS AND METHODS: Various murine immune cells (T cells, B cells, and macrophages) and splenocytes were used to study the anti-proliferative effect of dictabretol A in vitro. A collagen-induced arthritis model was also used to examine the therapeutic effect of dictabretol A in vivo. RESULTS: Dictabretol A specifically inhibited lymphocyte proliferation by blocking the cell cycle transition from the G1 to the S phase. This effect was achieved by blocking Erk1/2, nuclear factor kappa B, and the C-myc axis of cell cycle progression. Further dictabretol A treatment alleviated the severity of collagen-induced arthritis. CONCLUSION: Our results reveal the molecular mechanism for the anti-lymphoproliferative effect of dictabretol A and show the therapeutic efficacy of dictabretol A for rheumatoid arthritis.

Saponins from soy bean and mung bean inhibit the antigen specific activation of helper T cells by blocking cell cycle progression.

Treatment of helper T (Th) cells with saponins from soy bean and mung bean prevented their activation by inhibiting cell proliferation and cytokine secretion. However, the saponins did not affect the expression of major histocompatibility complex class II (A(b)) and co-stimulatory molecule (CD86) on professional antigen-presenting cells. Instead, the saponins directly inhibited Th cell proliferation by blocking the G(1) to S phase cell cycle transition. Moreover, blocking of the cell cycle by the saponins was achieved by decreased expression of cyclin D1 and cyclin E, and constitutive expression of p27(KIP1). Saponins also increased stability of p27(KIP1) in Th cells after antigenic stimulation.

Generation and evaluation of the efficacy of rhesus monkey soluble cytotoxic T lymphocyte-associated antigen-4 in the allogeneic mixed lymphocyte reaction.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a transmembrane protein that is structurally similar to CD28. As CTLA-4 has a much higher binding affinity to B7 than CD28, several approaches using soluble CTLA-4 have been tried to down-regulate T cell activity by blocking the interaction between CD28 and B7. We constructed soluble rhesus monkey CTLA-4 immunoglobulin (CTLA-4Ig) containing a critical binding site to B7 combined with a constant Ig heavy chain region in a mammalian system. Flow cytometry analyses indicated that soluble rhesus monkey CTLA-4Ig bound to rhesus monkey CD86 (B7.2). Moreover, soluble rhesus monkey CTLA-4Ig more effectively blocked the rhesus monkey-rhesus monkey allogeneic mixed lymphocyte reaction compared with that of humans. These results indicate that soluble rhesus monkey CTLA-4Ig may be useful in preclinical trials in a rhesus monkey model.