Chronic lead poisoning-induced budgerigar liver damage, gut microbiota dysbiosis, and metabolic disorder.

Birds are sensitive to heavy metal pollution, and lead (Pb) contamination can negatively affect their liver and gut. Therefore, we used budgerigars to examine liver and gut toxicosis caused by Pb exposure in bird, and the possible toxic mechanisms. The findings showed Pb exposure increased liver weight and decreased body weight. Moreover, histopathological and immunofluorescence assay results demonstrated obvious liver damage and cell apoptosis increased in Pb- treated budgerigars. Quantitative polymerase chain reaction (qPCR) results also showed Pb caused an increase in apoptosis by inhibiting the PPAR-γ/PI3K/Akt pathway. The gut microbe analyses indicated Firmicutes, Proteobacteria, and Bacteroidetes were dominant microbial phyla, and Network analysis results shown Arthrobacter, Bradyrhizobium and Alloprevotella as the hubs of Modules I, II, and III, respectively. Phenylpropanoids and polyketides, Organoheterocyclic compounds, Organic oxygen compounds, and Organic nitrogen compounds were dominant metabolite superclasses. Tauroursodeoxycholic acid, taurochenodeoxycholic acid (sodium salt), and 2-[2-(5-bromo-2-pyridyl)diaz-1-enyl]-5-(diethylamino)phenol were significantly enriched in the Pb-treated group. It showed that 41 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues and 183 pathways differed between the Pb-treated and control budgerigars using microbial and metabolomic data. Moreover, orthogonal partial least-squares discrimination analysis (OPLS-DA) based on microbial and metabolite indicated distinct clusters in the Pb-treated and control groups. Additionally, the correlation analysis results indicated that a positive correlation for the Pb-treated and control groups between gut microbiota and metabolomic data, respectively. Furthermore, the microenvironment of the gut and liver were found to affect each other, and this study demonstrated heavy metal especially Pb may pose serious health risks to birds through the "gut-liver axis" too.

The impact of a western diet on gut microbiota and circadian rhythm: A comprehensive systematic review of in vivo preclinical evidence.

AIMS: Here, we present a systematic review that compiles in vivo experimental data regarding the effect of the WD on the gut microbiota and its impact on the circadian rhythm. Additionally, we reviewed studies evaluating the combined effects of WD and circadian cycle disruption on gut microbiota and circadian cycle markers. MATERIALS AND METHODS: The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. KEY FINDINGS: Preclinical studies revealed that WD triggers circadian rhythmicity disruption, reduces the alpha-diversity of the microbiota and favors the growth of bacterial groups that are detrimental to intestinal homeostasis, such as Clostridaceae, Enterococcus, Parasutterella and Proteobacteria. When the WD is combined with circadian clock disruption, gut dysbiosis become more pronounced. Reduced cycling of Per3, Rev-erb and CLOCK in the intestine, which are related to dysregulation of lipid metabolism and potential metabolic disease, was observed. SIGNIFICANCE: In conclusion, current evidence supports the potential of WD to trigger microbiota dysregulation, disrupt the biological clock, and increase susceptibility to metabolic disorders and potentially chronic diseases.

Gut-bacteria derived membrane vesicles and host metabolic health: a narrative review.

The intestinal microbiota, consisting of an estimated 10^10-10^11 organisms, regulate physiological processes involved in digestion, metabolism, and immunity. Surprisingly, these intestinal microorganisms have been found to influence tissues that are not directly in contact with the gut, such as adipose tissue, the liver, skeletal muscle, and the brain. This interaction takes place even when intestinal barrier function is uncompromised. An increasing body of evidence suggests that bacterial membrane vesicles (bMVs), in addition to bacterial metabolites such as short-chain fatty acids, are able to mediate effects of the microbiota on these host tissues. The ability of bMVs to dissipate from the intestinal lumen into systemic circulation hereby facilitates the transport and presentation of bacterial components and metabolites to host organs. Importantly, there are indications that the interaction between bMVs and tissues or immune cells may play a role in the etiology of (chronic metabolic) disease. For example, the gut-derived bMV-mediated induction of insulin resistance in skeletal muscle cells and pro-inflammatory signaling by adipocytes possibly underlies diseases such as type 2 diabetes and obesity. Here, we review the current knowledge on bMVs in the microbiota's effects on host energy/substrate metabolism with a focus on etiological roles in the onset and progression of metabolic disease. We furthermore illustrate that vesicle production by bacterial microbiota could potentially be modulated through lifestyle intervention to improve host metabolism.

Postbiotics as Metabolites and Their Biotherapeutic Potential.

This review highlights the role of postbiotics, which may provide an underappreciated avenue doe promising therapeutic alternatives. The discovery of natural compounds obtained from microorganisms needs to be investigated in the future in terms of their effects on various metabolic disorders and molecular pathways, as well as modulation of the immune system and intestinal microbiota in children and adults. However, further studies and efforts are needed to evaluate and describe new postbiotics. This review provides available knowledge that may assist future research in identifying new postbiotics and uncovering additional mechanisms to combat metabolic diseases.

Blautia Coccoides is a Newly Identified Bacterium Increased by Leucine Deprivation and has a Novel Function in Improving Metabolic Disorders.

Gut microbiota is linked to human metabolic diseases. The previous work showed that leucine deprivation improved metabolic dysfunction, but whether leucine deprivation alters certain specific species of bacterium that brings these benefits remains unclear. Here, this work finds that leucine deprivation alters gut microbiota composition, which is sufficient and necessary for the metabolic improvements induced by leucine deprivation. Among all the affected bacteria, B. coccoides is markedly increased in the feces of leucine-deprived mice. Moreover, gavage with B. coccoides improves insulin sensitivity and reduces body fat in high-fat diet (HFD) mice, and singly colonization of B. coccoides increases insulin sensitivity in gnotobiotic mice. The effects of B. coccoides are mediated by metabolizing tryptophan into indole-3-acetic acid (I3AA) that activates the aryl hydrocarbon receptor (AhR) in the liver. Finally, this work reveals that reduced fecal B. coccoides and I3AA levels are associated with the clinical metabolic syndrome. These findings suggest that B. coccoides is a newly identified bacterium increased by leucine deprivation, which improves metabolic disorders via metabolizing tryptophan into I3AA.

The effects of synbiotics on the liver steatosis, inflammation, and gut microbiome of metabolic dysfunction-associated liver disease patients-randomized trial.

INTRODUCTION: Metabolic Dysfunction-associated Liver Disease (MASLD) represents a spectrum of conditions from simple fat accumulation to non-alcoholic steatohepatitis. The possible role of the intestinal microbiome on MASLD development has been in focus. Our study aimed to examine the effects of synbiotics on the liver steatosis, inflammation, and stool microbiome. METHODS: A double-blind, placebo-controlled study was conducted involving 84 MASLD patients, defined by an elastometric attenuation coefficient (ATT) greater than 0.63 dB/cm/MHz with an alanine aminotransferase level above 40 U/L for men and 35 U/L for women. The patients were divided into an intervention group treated with a synbiotic with 64x109 CFU of Lactobacillus and Bifidobacterium and 6.4g of inulin and a control group treated with a placebo. RESULTS: Using synbiotics for 12 weeks significantly decreased liver steatosis (ΔATT -0.006±0.023 vs -0.016±0.021 dB/cm/MHz, p=0.046). The group of patients treated with synbiotics showed a significant decrease in the level of high-sensitive C-reactive protein (Δhs-CRP 0 vs -0.7 mg/L, p≤0.001). Synbiotics enriched the microbiome of patients in the intervention group with the genera Lactobacillus, Bifidobacterium, Faecalibacterium, and Streptococcus, by 81%, 55%, 51%, and 40%, respectively, with a reduction of Ruminococcus and Enterobacterium by 35% and 40%. Synbiotic treatment significantly shortened the gut transition time (ΔGTT -5h vs. -10h, p=0.031). CONCLUSION: Synbiotics could be an effective and safe option that could have place in MASLD treatment.

A comprehensive systematic review of the effectiveness of Akkermansia muciniphila, a member of the gut microbiome, for the management of obesity and associated metabolic disorders.

AIMS AND BACKGROUND: Obesity is recognised as a significant public health burden worldwide. Recently the cross-talk between gut microbiota and obesity has attracted much attention. To that end, Akkermansia muciniphila has been proposed as a promising microbe to manage obesity. In the present systematic review, we evaluated evidence on the effectiveness and mechanisms of action of Akkermansia muciniphila supplementation in the management of obesity. METHODS: Electronic databases of MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar were searched thought March 2020 to identify relevant published articles, and eligible articles were systematically reviewed. RESULTS AND CONCLUSIONS: Fifteen studies were included in the present study. Findings from the present review, which included human and animal (rodent) models support the effectiveness of Akkermansia supplementation as a novel therapeutic approach for the management of obesity and metabolic complications associated with obesity. However, future clinical trials are warranted to verify these outcomes.

A review on the effect of gut microbiota on metabolic diseases.

Human gut microbiota are a huge and complex microbial community, which is recognized to play a significant role in regulating host metabolism. However, the destruction of gut microbiota leads to the pathological response of host, and thus results in a variety of metabolic diseases. This article gives a brief review of research progress on gut microbiota and some main metabolic diseases, including osteoporosis, obesity, type 2 diabetes, non-alcoholic fatty liver, and hypertension, with a specific focus on the effect of gut microbiota on diseases' occurrence and development. In addition, this review article also shows some case studies on the regulation of gut microbiota by new means, such as fecal microbiota transplantation and oral probiotics. Although gut microbiota are considered as a promising novel target for the treatment of metabolic diseases, it is also necessary to encourage further studies to provide more valuable data for guiding the application of gut microbiota on disease therapy in future.

Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice.

OBJECTIVE: To investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice. DESIGN: We analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live D. welbionis J115T on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice. RESULTS: This newly identified bacterium was detected in 62.7%-69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of Dysosmobacter genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live D. welbionis J115T, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live D. welbionis J115T administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition. CONCLUSIONS: These results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.

Prevalence of Blastocystis and its association with Firmicutes/Bacteroidetes ratio in clinically healthy and metabolically ill subjects.

BACKGROUND: Blastocystis is a typical anaerobic colon protist in humans with controversial pathogenicity and has relation with alterations in the intestinal microbiota composition (dysbiosis), whose eventual indicator is the Firmicutes/Bacteroidetes ratio (F/B ratio); this indicator is also linked to complications such as diabetes, obesity, or inflammatory bowel disease. The present study investigated the prevalence of Blastocystis and its association with Firmicutes/Bacteroidetes ratio in healthy and metabolic diseased subjects. METHODS: Fecal and blood samples were collected consecutively from 200 healthy subjects and 84 subjects with metabolic disease; Blastocystis and its most frequent subtypes were identified by end-point PCR and the two most representative phyla of the intestinal microbiota Firmicutes and Bacteroidetes by real-time PCR. RESULTS: The prevalence of Blastocystis in healthy subjects was 47.0, and 65.48% in subjects with metabolic disease; the most prevalent subtype in the total population was ST3 (28.38%), followed by ST1 (14.86%), ST4, ST5, and ST7 (each one of them with 14.19% respectively), and finally ST2 (8.78%). The low F/B ratio was associated with the prevalence of Blastocystis in the two cohorts FACSA (OR = 3.78 p < 0.05) and UNEME (OR = 4.29 p < 0.05). Regarding the subtype level, an association between the FACSA cohort ST1 and ST7 with low Firmicutes/Bacteroidetes ratio was found (OR = 3.99 and 5.44 p < 0.05, respectively). CONCLUSIONS: The evident predatory role of Blastocystis over Firmicutes phylum was observed in both cohorts since the abundance of bacterial group's Bacteroidetes increases in the groups colonized by this eukaryote and, therefore, may have a beneficial effect.

Human Gut Microbiota in Health and Selected Cancers.

The majority of the epithelial surfaces of our body, and the digestive tract, respiratory and urogenital systems, are colonized by a vast number of bacteria, archaea, fungi, protozoans, and viruses. These microbiota, particularly those of the intestines, play an important, beneficial role in digestion, metabolism, and the synthesis of vitamins. Their metabolites stimulate cytokine production by the human host, which are used against potential pathogens. The composition of the microbiota is influenced by several internal and external factors, including diet, age, disease, and lifestyle. Such changes, called dysbiosis, may be involved in the development of various conditions, such as metabolic diseases, including metabolic syndrome, type 2 diabetes mellitus, Hashimoto's thyroidis and Graves' disease; they can also play a role in nervous system disturbances, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and depression. An association has also been found between gut microbiota dysbiosis and cancer. Our health is closely associated with the state of our microbiota, and their homeostasis. The aim of this review is to describe the associations between human gut microbiota and cancer, and examine the potential role of gut microbiota in anticancer therapy.

Emerging connections between gut microbiome bioenergetics and chronic metabolic diseases.

The conventional viewpoint of single-celled microbial metabolism fails to adequately depict energy flow at the systems level in host-adapted microbial communities. Emerging paradigms instead support that distinct microbiomes develop interconnected and interdependent electron transport chains that rely on cooperative production and sharing of bioenergetic machinery (i.e., directly involved in generating ATP) in the extracellular space. These communal resources represent an important subset of the microbial metabolome, designated here as the "pantryome" (i.e., pantry or external storage compartment), that critically supports microbiome function and can exert multifunctional effects on host physiology. We review these interactions as they relate to human health by detailing the genomic-based sharing potential of gut-derived bacterial and archaeal reference strains. Aromatic amino acids, metabolic cofactors (B vitamins), menaquinones (vitamin K2), hemes, and short-chain fatty acids (with specific emphasis on acetate as a central regulator of symbiosis) are discussed in depth regarding their role in microbiome-related metabolic diseases.

Gut microbiome status of urban and rural Filipino adults in relation to diet and metabolic disorders.

Here, we aim to understand the condition of the gut microbiome of Filipino adults in relation to their diet and metabolic status. Compared to rural Albay (n = 67), the gut microbiome of subjects living in urban Manila (n = 25) was more colonized by the order Clostridiales, which was negatively correlated with host carbohydrate consumption. Principal component analysis using the genus composition of the 92 total subjects indicated four microbiome types: one type driven by Prevotella, which was associated with high rice consumption and mainly consisted of healthy Albay subjects, one Clostridiales-driven group containing a number of type 2 diabetes mellitus (T2D) subjects from both Manila and Albay who showed lower butyrate levels in association with a decrease in Mediterraneibacter faecis, and the other two types showing dysbiosis-like microbiomes with Lactobacillus and Bifidobacterium overgrowth, with a high ratio of T2D and obese subjects. Multivariate logistic regression analysis suggested high dietary energy intake, and two Veillonellaeae genera, Dialister and Megasphaera, as T2D risk factors, while Prevotella and M. faecis as anti-T2D factors. In conclusion, low-carbohydrate diets restructured the Prevotella-driven gut microbiome, which may predispose Filipino people with high energy diet to T2D.

Synthetic Microbiomes on the Rise-Application in Deciphering the Role of Microbes in Host Health and Disease.

The intestinal microbiota conveys significant benefits to host physiology. Although multiple chronic disorders have been associated with alterations in the intestinal microbiota composition and function, it is still unclear whether these changes are a cause or a consequence. Hence, to translate microbiome research into clinical application, it is necessary to provide a proof of causality of host-microbiota interactions. This is hampered by the complexity of the gut microbiome and many confounding factors. The application of gnotobiotic animal models associated with synthetic communities allows us to address the cause-effect relationship between the host and intestinal microbiota by reducing the microbiome complexity on a manageable level. In recent years, diverse bacterial communities were assembled to analyze the role of microorganisms in infectious, inflammatory, and metabolic diseases. In this review, we outline their application and features. Furthermore, we discuss the differences between human-derived and model-specific communities. Lastly, we highlight the necessity of generating novel synthetic communities to unravel the microbial role associated with specific health outcomes and disease phenotypes. This understanding is essential for the development of novel non-invasive targeted therapeutic strategies to control and modulate intestinal microbiota in health and disease.

Akkermansia muciniphila: is it the Holy Grail for ameliorating metabolic diseases?

The increasing prevalence of metabolic diseases has become a severe public health problem. Gut microbiota play important roles in maintaining human health by modulating the host's metabolism. Recent evidences demonstrate that Akkermansia muciniphila is effective in improving metabolic disorders and is thus considered as a promising "next-generation beneficial microbe". In addition to the live A. muciniphila, similar or even stronger beneficial effects have been observed in pasteurized A. muciniphila and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and secreted protein P9. Hence, this paper presents a systemic review of recent progress in the effects and mechanisms of A. muciniphila and its components in the treatment of metabolic diseases, including obesity, type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease, as well as perspectives on its future study.

Alteration of Gut Microbiota Relates to Metabolic Disorders in Primary Aldosteronism Patients.

Purpose: This study aimed to determine the relationships among gut microbiota, primary aldosteronism (PA), and related metabolic disorders. Methods: The study enrolled 13 PA patients, 26 sex-matched primary hypertension patients, and 26 sex-matched healthy controls. Demographic and clinical characteristics such as age, body mass index (BMI), blood aldosterone-renin ratio, blood potassium, blood glucose, blood lipid parameters, and history of diabetes mellitus (DM) were compared between the three groups. The gut microbiota of each participant was examined by 16S rRNA gene sequencing. Spearman correlation analysis was performed to demonstrate the relationship between gut microbiota and clinical characteristics. Results: BMI and the percentage of DM in PA patients were higher than those in healthy controls (p < 0.05), but not higher than those in primary hypertension patients (p > 0.05). The gut microbiota of healthy controls and primary hypertension patients had a higher alpha diversity level than that of PA patients. PA patients had fewer short-chain fatty acid (SCFA)-producing genera (Prevotella, Blautia, Coprococcus, Anaerostipes, and Ruminococcus) and more inflammation-associated genera (Megamonas, Sutterella, and Streptococcus) than healthy controls (p < 0.05). The gut microbiota of PA patients was more inclined to encode microbial pathways involved in sugar metabolism, such as starch and sucrose metabolism and fructose and mannose metabolism. Blood potassium was negatively correlated with the relative abundance of Romboutsia (R = -0.364, q = 0.023). Diastolic blood pressure (DBP) was positively correlated with Romboutsia (R = 0.386, q = 0.015). Systolic blood pressure (SBP) was negatively correlated with Blautia (R = -0.349, q = 0.030). Conclusions: The alteration of gut microbiota in PA patients, especially bacteria and pathways involved in inflammation, SCFAs, and sugar metabolism, may be associated with chronic metabolic disorders.

Effects and Mechanisms of Probiotics, Prebiotics, Synbiotics, and Postbiotics on Metabolic Diseases Targeting Gut Microbiota: A Narrative Review.

Metabolic diseases are serious threats to public health and related to gut microbiota. Probiotics, prebiotics, synbiotics, and postbiotics (PPSP) are powerful regulators of gut microbiota, thus possessing prospects for preventing metabolic diseases. Therefore, the effects and mechanisms of PPSP on metabolic diseases targeting gut microbiota are worth discussing and clarifying. Generally, PPSP benefit metabolic diseases management, especially obesity and type 2 diabetes mellitus. The underlying gut microbial-related mechanisms are mainly the modulation of gut microbiota composition, regulation of gut microbial metabolites, and improvement of intestinal barrier function. Moreover, clinical trials showed the benefits of PPSP on patients with metabolic diseases, while the clinical strategies for gestational diabetes mellitus, optimal formula of synbiotics and health benefits of postbiotics need further study. This review fully summarizes the relationship between probiotics, prebiotics, synbiotics, postbiotics, and metabolic diseases, presents promising results and the one in dispute, and especially attention is paid to illustrates potential mechanisms and clinical effects, which could contribute to the next research and development of PPSP.

Microbiota-Immune Interactions Regulate Metabolic Disease.

Metabolic diseases are common worldwide and include diseases of overnutrition, such as obesity, or undernutrition, such as kwashiorkor. Both the immune system and the microbiota contribute to a variety of metabolic diseases; however, these two processes have largely been studied independently of one another in this context. The gastrointestinal system houses the greatest density of microbes but also houses one of the largest collections of immune molecules, especially Abs. The IgA isotype dominates the Ab landscape at mucosal sites, and a number of studies have demonstrated the importance of this Ab to the stability of the microbiota. In this article, we review the literature that demonstrates how homeostatic Ab responses control microbiota composition and function to influence metabolic disease. We propose that many metabolic diseases may arise from disruptions to homeostatic immune control of gut commensals and that further understanding this interaction can offer a novel opportunity for therapeutic interventions.

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad.

Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic ß-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.