Good girl goes bad: Understanding how gut commensals cause disease.

This review examines the complex connection between commensal microbiota and the development of opportunistic infections. Several underlying conditions, such as metabolic diseases and weakened immune systems, increase the vulnerability of patients to opportunistic infections. The increasing antibiotic resistance adds significant complexity to the management of infectious diseases. Although commensals have long been considered beneficial, recent research contradicts this notion by uncovering chronic illnesses linked to atypical pathogens or commensal bacteria. This review examines conditions in which commensal bacteria, which are usually beneficial, contribute to developing diseases. Commensals' support for opportunistic infections can be categorized based on factors such as colonization fitness, pathoadaptive mutation, and evasion of host immune response. Individuals with weakened immune systems are especially susceptible, highlighting the importance of mucosal host-microbiota interaction in promoting infection when conditions are inappropriate. Dysregulation of gut microbial homeostasis, immunological modulation, and microbial interactions are caused by several factors that contribute to the development of chronic illnesses. Knowledge about these mechanisms is essential for developing preventive measures, particularly for susceptible populations, and emphasizes the importance of maintaining a balanced gut microbiota in reducing the impact of opportunistic infections.

The opportunistic nature of gut commensal microbiota.

The abundance of gut commensals has historically been associated with health-promoting effects despite the fact that the definition of good or bad microbiota remains condition-specific. The beneficial or pathogenic nature of microbiota is generally dictated by the dimensions of host-microbiota and microbe-microbe interactions. With the increasing popularity of gut microbiota in human health and disease, emerging evidence suggests opportunistic infections promoted by those gut bacteria that are generally considered beneficial. Therefore, the current review deals with the opportunistic nature of the gut commensals and aims to summarise the concepts behind the occasional commensal-to-pathogenic transformation of the gut microbes. Specifically, relevant clinical and experimental studies have been discussed on the overgrowth and bacteraemia caused by commensals. Three key processes and their underlying mechanisms have been summarised to be responsible for the opportunistic nature of commensals, viz. improved colonisation fitness that is dictated by commensal-pathogen interactions and availability of preferred nutrients; pathoadaptive mutations that can trigger the commensal-to-pathogen transformation; and evasion of host immune response as a survival and proliferation strategy of the microbes. Collectively, this review provides an updated concept summary on the underlying mechanisms of disease causative events driven by gut commensal bacteria.

Antiinflammatory phytochemicals against virus-induced hyperinflammatory responses: Scope, rationale, application, and limitations.

Uncontrolled inflammatory responses or cytokine storm associated with viral infections results in deleterious consequences such as vascular leakage, severe hemorrhage, shock, immune paralysis, multi-organ failure, and even death. With the emerging new viral infections and lack of effective prophylactic vaccines, evidence-based complementary strategies that limit viral infection-mediated hyperinflammatory responses could be a promising approach to limit host tissue injury. The present review emphasizes the potentials of antiinflammatory phytochemicals in limiting hyperinflammatory injury caused by viral infections. The predominant phytochemicals along with their mechanism in limiting hyperimmune and pro-inflammatory responses under viral infection have been reviewed comprehensively. How certain phytochemicals can be effective in limiting hyper-inflammatory response indirectly by favorably modulating gut microbiota and maintaining a functional intestinal barrier has also been presented. Finally, we have discussed improved systemic bioavailability of phytochemicals, efficient delivery strategies, and safety measures for effective antiinflammatory phytotherapies, in addition to emphasizing the requirement of tightly controlled clinical studies to establish the antiinflammatory efficacy of the phytochemicals. Collectively, the review provides a scooping overview on the potentials of bioactive phytochemicals to mitigate pro-inflammatory injury associated with viral infections.

Controlled Feeding of an 8-d, High-Dairy Cheese Diet Prevents Sodium-Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy, Older Adults through Reductions in Superoxide.

BACKGROUND: While excess dietary sodium impairs vascular function by increasing oxidative stress, the dietary incorporation of dairy foods improves vascular health. We demonstrated that single-meal cheese consumption ameliorates acute, sodium-induced endothelial dysfunction. However, controlled feeding studies examining the inclusion of cheese, a dairy product that contains both bioactive constituents and sodium, are lacking. OBJECTIVES: We tested the hypothesis that microcirculatory endothelium-dependent dilation (EDD) would be impaired by a high-sodium diet, but a sodium-matched diet high in dairy cheese would preserve EDD through oxidant stress mechanisms. METHODS: We gave 11 adults without salt-sensitive blood pressure (<10 mmHg Δ mean arterial pressure; 64 ± 2 y) 4 separate 8-d controlled dietary interventions in a randomized, crossover design: a low-sodium, no-dairy intervention (LNa; 1500 mg/d sodium); a low-sodium, high-cheese intervention (LNaC; 1500 mg/d sodium, 170 g/d cheese); a high-sodium, no-dairy intervention (HNa; 5500 mg/d sodium); and a high-sodium, high-cheese intervention (HNaC; 5500 mg/d sodium, 170 g/d cheese). On Day 8 of each diet, EDD was assessed through a localized infusion (intradermal microdialysis) of acetylcholine (ACh), both alone and during coinfusion of NG-nitro-L-arginine methyl ester (NO synthase inhibitor), L-ascorbate (nonspecific antioxidant), apocynin [NAD(P)H oxidase inhibitor], or tempol (superoxide scavenger). RESULTS: Compared with LNa, microvascular responsiveness to ACh was attenuated during HNa (LNa: -4.82 ± 0.20 versus HNa: -3.21 ± 0.55 M logEC50; P = 0.03) but not LNaC (-5.44 ± 0.20 M logEC50) or HNaC (-4.46 ± 0.50 M logEC50). Further, ascorbate, apocynin, and tempol administration each increased ACh-induced vasodilation during HNa only (Ringer's: 38.9 ± 2.4; ascorbate: 48.0 ± 2.5; tempol: 45.3 ± 2.7; apocynin: 48.5 ± 2.6% maximum cutaneous vascular conductance; all P values < 0.01). CONCLUSIONS: These results demonstrate that incorporating dairy cheese into a high-sodium diet preserves EDD by decreasing the concentration of superoxide radicals. Consuming sodium in cheese, rather than in nondairy sources of sodium, may be an effective strategy to reduce cardiovascular disease risk in salt-insensitive, older adults. This trial was registered at clinicaltrials.gov as NCT03376555.

Infant Rhesus Macaque Brain α-Tocopherol Stereoisomer Profile Is Differentially Impacted by the Source of α-Tocopherol in Infant Formula.

BACKGROUND: α-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown. OBJECTIVE: We sought to compare αT and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-αT or all rac-αT) with a reference group fed a mixed diet of breast milk and maternal diet. METHODS: From 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at ∼2 mo (MF; n = 8). Formulas contained either 21 µmol RRR-αT/L (NAT-F; n = 8) or 30 µmol all rac-αT/L (SYN-F; n = 7). Total αT and αT stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. α-Tocopherol transfer protein (α-TTP), lipoprotein αT, and urinary α-carboxyethyl-hydroxychroman (α-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis. RESULTS: At study termination, plasma, liver, lipoprotein, and brain total αT did not differ between groups. However, the NAT-F-fed group had higher RRR-αT than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic αT 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-αT (r = -0.99, P < 0.0001). Brain αT profiles were not explained by α-TTP mRNA or protein expression. Urine α-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01). CONCLUSIONS: Consumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) αT differentially impacted brain αT stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of αT stereoisomer profiles on brain health.

Targeting gut barrier dysfunction with phytotherapies: Effective strategy against chronic diseases.

The intestinal epithelial layer serves as a physical and functional barrier between the microbe-rich lumen and immunologically active submucosa; it prevents systemic translocation of microbial pyrogenic products (e.g. endotoxin) that elicits immune activation upon translocation to the systemic circulation. Loss of barrier function has been associated with chronic 'low-grade' systemic inflammation which underlies pathogenesis of numerous no-communicable chronic inflammatory disease. Thus, targeting gut barrier dysfunction is an effective strategy for the prevention and/or treatment of chronic disease. This review intends to emphasize on the beneficial effects of herbal formulations, phytochemicals and traditional phytomedicines in attenuating intestinal barrier dysfunction. It also aims to provide a comprehensive understanding of intestinal-level events leading to a 'leaky-gut' and systemic complications mediated by endotoxemia. Additionally, a variety of detectable markers and diagnostic criteria utilized to evaluate barrier improving capacities of experimental therapeutics has been discussed. Collectively, this review provides rationale for targeting gut barrier dysfunction by phytotherapies for treating chronic diseases that are associated with endotoxemia-induced systemic inflammation.

Gut microbiota in phytopharmacology: A comprehensive overview of concepts, reciprocal interactions, biotransformations and mode of actions.

The dynamic and delicate interactions amongst intestinal microbiota, metabolome and metabolism dictates human health and disease. In recent years, our understanding of gut microbial regulation of intestinal immunometabolic and redox homeostasis have evolved mainly out of in vivo studies associated with high-fat feeding induced metabolic diseases. Techniques utilizing fecal transplantation and germ-free mice have been instrumental in reproducibly demonstrating how the gut microbiota affects disease pathogenesis. However, the pillars of modern drug discovery i.e. evidence-based pharmacological studies critically lack focus on intestinal microflora. This is primarily due to targeted in vitro molecular-approaches at cellular-level that largely overlook the etiology of disease pathogenesis from the physiological perspective. Thus, this review aims to provide a comprehensive understanding of the key notions of intestinal microbiota and dysbiosis, and highlight the microbiota-phytochemical bidirectional interactions that affects bioavailability and bioactivity of parent phytochemicals and their metabolites. Potentially by focusing on the three major aspects of gut microbiota i.e. microbial abundance, diversity, and functions, I will discuss phytochemical-microbiota reciprocal interactions, biotransformation of phytochemicals and plant-derived drugs, and pre-clinical and clinical efficacies of herbal medicine on dysbiosis. Additionally, in relation to phytochemical pharmacology, I will briefly discuss the role of dietary-patterns associated with changes in microbial profiles and review pharmacological study models considering possible microbial effects. This review therefore, emphasize on the timely and critically needed evidence-based phytochemical studies focusing on gut microbiota and will provide newer insights for future pre-clinical and clinical phytopharmacological interventions.

Effects of prior aerobic exercise on sitting-induced vascular dysfunction in healthy men.

INTRODUCTION: Acute aerobic exercise prevents sitting-induced impairment of flow-mediated dilation (FMD). Further, evidence suggests that sitting-induced impairment of FMD occurs via an oxidative stress-dependent mechanism that disrupts endothelial function. PURPOSE: We hypothesized that acute aerobic exercise would prevent impairment of femoral artery FMD by limiting oxidative stress responses that increase endothelin-1 (ET-1) levels and disrupt nitric oxide (NO) status. METHODS: In a randomized, cross-over study, healthy men (n = 11; 21.2 ± 1.9 years) completed two 3 h sitting trials that were preceded by 45 min of either quiet rest (REST) or a single bout of continuous treadmill exercise (65% maximal oxygen consumption) (EX). Superficial femoral artery FMD, plasma glucose, malondialdehyde (MDA), ET-1, arginine (ARG) and its related metabolites [homoarginine (HA), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)] were assessed at baseline, 1 h following EX (or REST) (0 h), and at 1 h intervals during 3 h of uninterrupted sitting. Data were analyzed using repeated measures ANOVA. RESULTS: During REST, femoral artery FMD declined from baseline (2.6 ± 1.8%) at 1, 2, and 3 h of sitting and resting shear rate decreased at 3 h. In contrast, when sitting was preceded by EX, femoral artery FMD (2.7 ± 2.0%) and resting shear rate responses were unaffected. No between trial differences were detected for plasma glucose, MDA, ET-1, ARG, HA, ADMA, or SDMA. CONCLUSION: Prior aerobic exercise prevented the decline in femoral artery FMD that is otherwise induced by prolonged sitting independent of changes in oxidative stress, ET-1, and NO status.

Radical Scavenging Activities of Lagerstroemia speciosa (L.) Pers. Petal Extracts and its hepato-protection in CCl4-intoxicated mice.

BACKGROUND: Lagerstroemia speciosa (L.) Pers. has medicinal importance. Bioactive phytochemicals isolated from different parts of L. speciosa, have revealed hypoglycemic, antibacterial, anti-inflammatory, antioxidant and hepato protective properties. Despite one report from Philippines detailing the use of L. speciosa as curative for fever and as well as diuretic, there is no experimental evidence about the hepatoprotective activity of the flower extracts. METHODS: Several spectroscopic methods, including GC-MS, were used to characterize phytochemicals present in the petal extract of L. speciosa. Ethanol extract of petals was evaluated for anti-oxidant and free radical scavenging properties by using methods related to hydrogen atom transfer, single electron transfer, reducing power, and metal chelation. This study has also revealed the in vitro antioxidant and in vivo hepatoprotective properties of petal extract against carbon tetra chloride (CCl4)-induced liver toxicity in Swiss albino mice. Hepatoprotection in CCl4 -intoxicated mice was studied with the aid of histology and different enzymatic and non-enzymatic markers of liver damage. Cytotoxicity tests were done using murein spleenocytes and cancareous cell lines, MCF7 and HepG2. RESULT: GCMS of the extract has revealed the presence of several potential antioxidant compounds, of them γ-Sitosterol and 1,2,3-Benzenetriol (Pyrogallol) were the predominant ones. The antioxidants activities of the flower-extract were significantly higher than curcumin (in terms of Nitric oxide scavenging activity; p = 0.0028) or ascorbic acid (in terms of 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay; p = 0.0022). The damage control by the flower extract can be attributed to the reduction in lipid peroxidation and restoration of catalase activity. In vitro cytotoxicity tests have shown that the flower extract did not affect growth and survivability of the cell lines. It left beyond doubt that a flower of L. speciosa is a reservoir of antioxidant and hepatoprotective agents capable of reversing the damage inflicted by CCl4-intoxication. CONCLUSION: Results from the present study may be used in developing a potential hepato-protective health drink enriched with antioxidants from Lagerstroemia speciosa (L.) Pers.

Haloalkane induced hepatic insult in murine model: amelioration by Oleander through antioxidant and anti-inflammatory activities, an in vitro and in vivo study.

BACKGROUND: Nerium oleander L. (syn. Nerium indicum Mill, Nerium odorum Aiton) belongs to the family Apocynaceae. It is used for its anti-inflammatory, anti-diabetic, anti-cancer and hepatoprotective activities in traditional medicine. Previous pharmacognostic studies suggested that 70 % hydro-methanolic extracts of oleander possess potent free radical scavenging and anti-inflammatory activities, both of which are helpful against hepatotoxicity. METHODS: Hydro-methanolic extracts of oleander stem and root were evaluated for their hepatoprotective activities in acute CCl4 intoxicated mouse through in vitro and in vivo studies. Silymarin was used as positive reference. Antioxidant enzymes, pro-inflammatory markers and liver enzymatic and biochemical parameters were studied. The extracts were further chemically characterized using Fourier Transform Infrared (FTIR) spectroscopy and Gas chromatography-mass spectrometry (GC-MS). RESULTS: CCl4 toxicity caused fatty liver formation by increase of relative liver weight (32.53 g) compared to control group (16.08 g). The elevated liver enzymatic and biochemical parameters due to CCl4 toxicity were considerably normalized by the extracts treatment under both in vivo and in vitro models. Oleander stem (NOSE) and root (NORE) extracts increased the reduced hepatic catalase activity 27.37 and 25.25 %, whereas peroxidase activity was increased 18.19 and 22.78 %, respectively. The extent of lipid peroxidation was significantly (p < 0.01) lowered 20.76 % (NOSE) and 21.12 % (NORE) compared to CCl4 group. The levels of pro-inflammatory tumor necrosis factor-α (TNF-α) was lowered 71.33 % (NOSE) and 61.60 % (NORE). Histopathological study demonstrated substantial reduction of hepatocellular necrosis, fatty infiltration, sinusoidal dilation, bile duct proliferation, vascular congestion, leukocyte infiltration in the silymarin and extract treated groups. Furthermore, various bioactive compounds were identified in the extracts such as apocynin, tocopherol, squalene, vanillin, isoeugenol, amyrin, lupeol etc. CONCLUSION: The present study provided convincing evidence that oleander extracts possess potent hepatoprotective capacity which was primarily governed by its antioxidant and anti-inflammatory activities. The collegial bioactivities of the phytochemicals may be accredited behind the hepatoprotective activity of oleander.

Assessment of haemolytic, cytotoxic and free radical scavenging activities of an underutilized fruit, Baccaurea ramiflora Lour. (Roxb.) Muell. Arg.

Baccaurea ramiflora Lour. (Roxb.) Muell. Arg. is an underutilized juicy fruit bearing plant found in sub-Himalayan area, South China, Indo-Burma region, etc. The fruit is considered to be nutritive, and in this study, we evaluated its antioxidant, haemolytic and cytotoxic properties. The juice was examined for the quenching activity of hydroxyl radical, nitric oxide, singlet oxygen, peroxynitrite, total antioxidant activity (TAA), erythrocyte membrane stabilizing activity (EMSA) along with quantification of phenolic and flavonoid contents and also tested for its potential activity as iron chelator, inhibitor of lipid peroxidation and total reducing power. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were also performed to correlate antioxidant capacities with the phenolic and flavonoid content. Haemolytic activity on murine erythrocyte and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cytotoxic test was performed on murine splenocytes, thymocytes, hepatocytes and peritoneal exudates macrophage to examine the cytotoxic effect of its juice. The result exhibited its potent free radical scavenging activity. In case of TAA, DPPH (2, 2-diphenyl-1-picrylhydrazyl), EMSA and lipid peroxidation, the fruit juice was found to have significant (P < 0.001) antioxidant capacity, which is evident from low IC50 (half maximal inhibitory concentration) value. Results obtained from haemolytic inhibition assay and MTT cytotoxic test confirms that the juice does not contain any cytotoxic effect and the fruit is safe for consumption. Fourier transform infrared (FTIR) spectra analysis exhibited high possibility of presence of flavonoid compounds in the juice.

Evaluation of anti-inflammatory activity and standardisation of hydro-methanol extract of underground tuber of Dioscorea alata.

Context The underground edible tuber of Dioscorea alata L. (Dioscoreaceae) is a functional food with high nutritive value and therapeutic potential. The tuber is known to possess anti-inflammatory properties in traditional medicine. Objective The present study explores the anti-inflammatory activity and standardisation of D. alata tuber hydromethanol extract. Materials and methods Hydromethanol extract (70%) of D. alata tuber was chemically characterised using HPLC and GC-MS techniques. Murine lymphocytes were cultured for 48 h with six different concentrations (0-80 µg/mL) of the extract. The expression of nitric oxide (NO), TNF-α, COX-1, COX-2, and PGE2 were evaluated using colorimetric and ELISA methods. Results Dioscorea alata extract inhibited the expression of NO and TNF-α with an IC50 value of 134.51 ± 6.75 and 113.30 ± 7.44 µg/mL, respectively. The IC50 values for inhibition of total COX, COX-1, COX-2 activities and PGE2 level were 41.96 ± 3.07, 141.41 ± 8.99, 32.50 ± 1.69, and 186.34 ± 15.36 µg/mL, respectively. Inhibition of PGE2 level and COX-2 activity was positively correlated (R(2) = 0.9393). Gallic acid (GA), 4-hydroxy benzoic acid (4HBA), syringic acid (SYA), p-coumaric acid (PCA), and myricetin (MY) were identified and quantified using HPLC. GC-MS analysis revealed the presence of 13 different phytocompounds such as hexadecanoic acid, methyl stearate, cinnamyl cinnamate, and squalene. Conclusion The D. alata extract significantly down-regulated the pro-inflammatory signals in a gradual manner compared with control (0 µg/mL). Different bioactive phytocompounds individually possessing anti-inflammatory activities contributed to the overall bioactivity of the D. alata tuber extract.

Chemical characterization and assessment of antioxidant potentiality of Streptocaulon sylvestre Wight, an endangered plant of sub-Himalayan plains of West Bengal and Sikkim.

BACKGROUND: S. sylvestre Wright is an extremely rare plant, found only in the sub-Himalayan Terai region of West Bengal and neighboring Sikkim foot-hills. The plant has never been evaluated for any pharmaceutical properties. The phytochemical status of the plant is still unknown. Therefore, the aim of the study was to explore the antioxidant and free radical scavenging activities and analysis of bioactive compounds present in S. sylvestre. METHODS: S. sylvestre methanolic extract (SSME) was evaluated for different free radical scavenging activities such as hydroxyl radical, nitric oxide, singlet oxygen, hypochlorous acid, peroxynitrite, superoxide radical and hydrogen peroxide scavenging etc. Iron chelating capacity and inhibition of lipid peroxidation were studied in addition to the assessment of haemolytic activity and erythrocyte membrane stabilizing activity (EMSA). Chemical characterization of SSME were performed by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). RESULTS: The results indicate that SSME possess potent antioxidant activity with IC50 value of 113.06 ± 5.67 µg/ml, 63.93 ± 4.16 µg/ml and 142.14 ± 6.13 µg/ml for hydroxyl radical, superoxide radical and hypochlorous acid, respectively. HPLC analysis revealed presence of different phenolic secondary metabolites such as gallic acid, ferulic acid, p-coumaric acid, syringic acid, myricetin, quercetin etc. GC-MS analysis displayed the predominance of γ-sitosterol, vitamin E and squalene in SSME. CONCLUSION: The present study provides a convincing evidence that S. sylvestre not only possess potent antioxidant activity but also can be used as a source of natural bioactive phytochemicals in the future.

Navigating commensal dysbiosis: Gastrointestinal host-pathogen interplay orchestrating opportunistic infections.

The gut commensals, which are usually symbiotic or non-harmful bacteria that live in the gastrointestinal tract, have a positive impact on the health of the host. This review, however, specifically discuss distinct conditions where commensals aid in the development of pathogenic opportunistic infections. We discuss that the categorization of gut bacteria as either pathogens or non-pathogens depends on certain circumstances, which are significantly affected by the tissue microenvironment and the dynamic host-microbe interaction. Under favorable circumstances, commensals have the ability to transform into opportunistic pathobionts by undergoing overgrowth. These conditions include changes in the host's physiology, simultaneous infection with other pathogens, effective utilization of nutrients, interactions between different species of bacteria, the formation of protective biofilms, genetic mutations that enhance pathogenicity, acquisition of genes associated with virulence, and the ability to avoid the host's immune response. These processes allow commensals to both initiate infections themselves and aid other pathogens in populating the host. This review highlights the need of having a detailed and sophisticated knowledge of the two-sided nature of gut commensals. Although commensals mostly promote health, they may also become harmful in certain changes in the environment or the body's functioning. This highlights the need of acknowledging the intricate equilibrium in interactions between hosts and microbes, which is crucial for preserving intestinal homeostasis and averting diseases. Finally, we also emphasize the further need of research to better understand and anticipate the behavior of gut commensals in different situations, since they play a crucial and varied role in human health and disease.

The intestinal-level metabolic benefits of green tea catechins: Mechanistic insights from pre-clinical and clinical studies.

BACKGROUND: The intestinal-level host-microbiota interaction has been implicated in the pathogenesis of chronic diseases. The current review is intended to provide a comprehensive insight into deciphering whether intestinal-level bioactivities mediate the overall metabolic health benefits of green tea catechins. PURPOSE: We have comprehensively discussed pre-clinical and clinical evidences of intestinal-level changes in metabolism, microbiota, and metabolome due to catechin-rich green tea treatments, ultimately limiting metabolic diseases. Exclusive emphasis has been given to purified catechins and green tea, and discussions on extraintestinal mechanisms of metabolic health benefits were avoided. METHODS: A literature search for relevant pre-clinical and clinical studies was performed in various online databases (e.g., PubMed) using specific keywords (e.g., catechin, intestine, microbiota). Out of all the referred literature, ∼15% belonged to 2021-2023, ∼51% were from 2011-2020, and ∼32% from 2000-2010. RESULT: The metabolic health benefits of green tea catechins are indeed influenced by the intestinal-level bioactivities, including reduction of mucosal inflammation and oxidative stress, attenuation of gut barrier dysfunction, decrease in intestinal lipid absorption and metabolism, favorable modulation of mucosal nuclear receptor signaling, alterations of the luminal global metabolome, and mitigation of the gut dysbiosis. The results from the recent clinical studies support the pre-clinical evidences. The challenges and pitfalls of the currently available knowledge on catechin bioactivities have been discussed, and constructive directions to harness the translational benefits of green tea through future interventions have been provided. CONCLUSION: The metabolism, metabolome, and microbiota at the intestinal epithelia play critical roles in catechin metabolism, pharmacokinetics, bioavailability, and bioactivities. Especially the reciprocal interaction between the catechins and the gut microbiota dictates the metabolic benefits of catechins.

Prebiotics Plus Probiotics May Favorably Impact on Gut Permeability, Endocannabinoid Receptors, and Inflammatory Biomarkers in Patients with Coronary Artery Diseases: A Clinical Trial.

While gut-to-systemic translocation of pyrogenic endotoxin due to a leaky gut elicits systemic inflammation, at the intestine, the endocannabinoid system (eCB) also plays a major role in modulating the impact of gut dysbiosis on the host system. Therefore, we hypothesized that coadministration of prebiotic inulin with probiotics would improve the eCB system, gut microbial composition, and inflammatory parameters associated with coronary artery diseases (CAD). We designed a randomized, double-blind trial with 92 CAD patients. Patients were randomly allocated to receive inulin (15 mg/day), LGG capsules 1.9 × 109 colony-forming unit (CFU) or inulin plus probiotic (synbiotics) supplements, for a duration of 60 days. We assessed gut microbiota composition, expression of cannabinoid receptors (i.e., CB1 and CB2), serum levels of interleukin-6 (IL-6), toll-like receptor 4 (TLR-4), lipopolysaccharides (LPS), total antioxidant capacity (TAC), and malondialdehyde (MDA) before and after the supplementation. Probiotic-inulin cosupplementation significantly decreased IL6, LPS, and TLR-4 and increased serum TAC concentrations compared with the placebo. While CB1 receptor expression had no difference, significant differences were observed for the CB2 receptor expression among the four treatments. CB2 receptor mRNA expression significantly (p < .05) correlated with serum levels of LPS (r = -.10) and F/B ratio (r = -.407, p = .047). Our data collectively provide preliminary evidence that gut microbiota determines gut permeability through the LPS-eCB system. We also have found that synbiotics improved the eCB receptors, and inflammatory biomarkers more than either of the two supplementations given alone.

Oleander attenuates hepatic inflammation in a TLR4-independent manner and by favorable modulation of hepatocellular global metabolome that supports cytoprotection.

ETHNOPHARMACOLOGICAL RELEVANCE: Nerium oleander is used to treat liver-associated chronic metabolic diseases in traditional medicinal systems across the globe. The hepatoprotective effects of oleander are mentioned in Indian and Chinese traditional medicinal literature. AIM OF THE STUDY: The present study aimed to investigate the cellular mechanisms behind the hepatoprotective effects of a non-toxic dose of oleander (NO). MATERIALS AND METHODS: The hepatoprotective effects of NO were tested against lipopolysaccharide (LPS)-treated HepG2 cells. Oxidative stress response was studied using cellular enzymatic assays, and gene expression was analyzed using qRT-PCR. HepG2 cells were pretreated with TAK-242 (pharmacological inhibitor of TLR4) to decipher the anti-inflammatory mechanisms of NO. Cell-free metabolites were analyzed using GCMS and were subjected to pathway enrichment analysis. RESULTS: NO reduced systemic inflammation, serum lipid peroxidation byproducts, and glucose without affecting serum transaminase levels and hepatic histopathological features. NO attenuated the inflammation-induced loss of antioxidant enzyme activities and mRNA expressions of toll-like receptor-4 (TLR4)/nuclear factor κß (NFκß)-dependent inflammatory genes. In TAK-242 pretreated cells, LPS was unable to induce inflammatory and oxidative responses. However, NO treatment in TAK-242 pretreated cells with LPS stimulation further reduced the signs of inflammation and improved hepatoprotective activities. A comparative analysis of the intracellular global metabolome from HepG2 cells with and without NO treatment indicated NO-mediated favorable modulation of intracellular metabolic pathways that support cytoprotective activities. CONCLUSION: NO protects HepG2 cells from LPS-induced oxidative and inflammatory injury. The hepatoprotective effects of NO are mediated by a TLR4-independent process and through a favorable modulation of the intracellular global metabolome that supports cytoprotection.

Spinal cord injury-induced metabolic impairment and steatohepatitis develops in non-obese rats and is exacerbated by premorbid obesity.

Impaired sensorimotor functions are prominent complications of spinal cord injury (SCI). A clinically important but less obvious consequence is development of metabolic syndrome (MetS), including increased adiposity, hyperglycemia/insulin resistance, and hyperlipidemia. MetS predisposes SCI individuals to earlier and more severe diabetes and cardiovascular disease compared to the general population, which trigger life-threatening complications (e.g., stroke, myocardial infarcts). Although each comorbidity is known to be a risk factor for diabetes and other health problems in obese individuals, their relative contribution or perceived importance in propagating systemic pathology after SCI has received less attention. This could be explained by an incomplete understanding of MetS promoted by SCI compared with that from the canonical trigger diet-induced obesity (DIO). Thus, here we compared metabolic-related outcomes after SCI in lean rats to those of uninjured rats with DIO. Surprisingly, SCI-induced MetS features were equal to or greater than those in obese uninjured rats, including insulin resistance, endotoxemia, hyperlipidemia, liver inflammation and steatosis. Considering the endemic nature of obesity, we also evaluated the effect of premorbid obesity in rats receiving SCI; the combination of DIO + SCI exacerbated MetS and liver pathology compared to either alone, suggesting that obese individuals that sustain a SCI are especially vulnerable to metabolic dysfunction. Notably, premorbid obesity also exacerbated intraspinal lesion pathology and worsened locomotor recovery after SCI. Overall, these results highlight that normal metabolic function requires intact spinal circuitry and that SCI is not just a sensory-motor disorder, but also has significant metabolic consequences.