Diammonium Glycyrrhizinate Ameliorates Obesity Through Modulation of Gut Microbiota-Conjugated BAs-FXR Signaling

Obesity is a worldwide epidemic metabolic disease. Gut microbiota dysbiosis and bile acids (BAs) metabolism disorder are closely related to obesity. Farnesoid X-activated receptor (FXR), served as a link between gut microbiota and BAs, is involved in maintaining metabolic homeostasis and regulating glucose and lipid metabolism. We previously reported that diammonium glycyrrhizinate (DG) could alter gut microbiota and prevent non-alcoholic fatty liver disease. However, it remains ambiguous how DG affects the gut microbiota to regulate host metabolism. In this present study, 16S rRNA Illumina NovaSeq and metabolomic analysis revealed that DG treatment suppressed microbes associated with bile-salt hydrolase (BSH) activity, which, in turn, increased the levels of taurine-conjugated BAs accompanied by inhibition of ileal FXR-FGF15 signaling. As a result, several obesity-related metabolism were improved, like lower serum glucose and insulin levels, increased insulin sensitivity, few hepatic steatosis and resistance to weight gain. Additionally, decreased level of serum lipopolysaccharide was observed, which contributed to a strengthened intestinal barrier. The effect of DG on weight loss was slightly enhanced in the antibiotics-treated obese mice. Collectively, the efficacy of DG in the treatment of obesity might depend on gut microbiota-conjugated BAs-FXR axis. Hence, it will provide a potential novel approach for the treatment of obesity.

A novel probiotics therapy for aging-related leaky gut and inflammation

Inflammaging characterized with increased low grade inflammation in older adults is common determinant of unhealthy aging; and is a major risk factor of morbidity and mortality in older adults. The precise origin of inflammation in older adults is not known, however, emerging evidence indicate that increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota could be one of the key source. However, no preventive and treatment therapies are available to reverse the leaky gut and microbiome dysbiosis in older adults. Here, we presented the evidence that a human-origin probiotics cocktail containing 5 Lactobacillus and 5 Enterococcus strains isolated from healthy human infant gut can ameliorate aging-related metabolic, physical and cognitive dysfunctions in older mice. We show that the Feeding this probiotic cocktail prevented high-fat diet–induced (HFD-induced) abnormalities in glycose metabolism and physical functions in older mice and reduced microbiota dysbiosis, leaky gut, inflammation. Probiotic-modulated gut microbiota reduced leaky gut by increasing tight junctions on intestinal epithelia, which in turn reduced inflammation. Mechanistically, probiotics increased bile salt hydrolase activity in older microbiota, which in turn increased taurine deconjugation from bile acids to increase free taurine abundance in the gut. We further show that taurine stimulated tight junctions and suppressed gut leakiness. Further, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function in Caenorhabditis elegans. Whether this novel human origin probiotic therapy could prevent or treat aging-related leaky gut and inflammation in the elderly by reversing microbiome dysbiosis requires evaluation.

Aberrant Gut-To-Brain Signaling in Irritable Bowel Syndrome - The Role of Bile Acids

Functional bowel disorders such as irritable bowel syndrome (IBS) are common, multifactorial and have a major impact on the quality of life of individuals diagnosed with the condition. Heterogeneity in symptom manifestation, which includes changes in bowel habit and visceral pain sensitivity, are an indication of the complexity of the underlying pathophysiology. It is accepted that dysfunctional gut-brain communication, which incorporates efferent and afferent branches of the peripheral nervous system, circulating endocrine hormones and local paracrine and neurocrine factors, such as host and microbially-derived signaling molecules, underpins symptom manifestation. This review will focus on the potential role of hepatic bile acids in modulating gut-to-brain signaling in IBS patients. Bile acids are amphipathic molecules synthesized in the liver, which facilitate digestion and absorption of dietary lipids. They are also important bioactive signaling molecules however, binding to bile acid receptors which are expressed on many different cell types. Bile acids have potent anti-microbial actions and thereby shape intestinal bacterial profiles. In turn, bacteria with bile salt hydrolase activity initiate the critical first step in transforming primary bile acids into secondary bile acids. Individuals with IBS are reported to have altered microbial profiles and modified bile acid pools. We have assessed the evidence to support a role for bile acids in the pathophysiology underlying the manifestation of IBS symptoms.

Inclusion of Soluble Fiber During Gestation Regulates Gut Microbiota, Improves Bile Acid Homeostasis, and Enhances the Reproductive Performance of Sows

Interaction between the dietary fiber and the gut microbes can regulate host bile acid metabolism. This study sought to explore the effects of guar gum combined with pregelatinized waxy maize starch (GCW) in a gestation diet on reproductive performance, gut microbiota composition, and bile acid homeostasis of sows. A total of 61 large white sows were randomly grouped into the control (n = 33) and 2% GCW (n = 28) groups during gestation. GCW diet increased birth-weight of piglets, and decreased the percentage of intrauterine growth restriction (IUGR) piglets. In addition, dietary GCW reduced gut microbial diversity and modulated gut microbial composition in sows on day 109 of gestation. The relative abundance of bile salt hydrolase (BSH) gene-encoding bacteria, Lactobacillus and Bacteroides decreased after GCW administration, whereas no significant difference was observed in the fecal level of total glycine-conjugated and taurine-conjugated bile acids between the two groups. Dietary GCW increased the relative abundance of Ruminococcaceae (one of few taxa comprising 7α-dehydroxylating bacteria), which was associated with elevated fecal deoxycholic acid (DCA) in the GCW group. GCW administration lowered the concentrations of plasma total bile acid (TBA) and 7α-hydroxy-4-cholesten-3-one (C4) (reflecting lower hepatic bile acid synthesis) at day 90 and day 109 of gestation compared with the control diet. Furthermore, the levels of plasma glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA) and glycohyocholic acid (GHCA) were lower in the GCW group compared with the control group. Spearman correlation analysis showed alterations in the composition of the gut microbiota by GCW treatment was associated with improved bile acid homeostasis and reproductive performance of sows. In conclusion, GCW-induced improves bile acid homeostasis during gestation which may enhance reproductive performance of sows.

Intestinal Transgene Delivery with Native E. coli Chassis Allows Persistent Physiological Changes

Live bacterial therapeutics (LBT) could reverse disease by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally-raised (CR) hosts have been unsuccessful, because engineered microbial organisms (i.e., chassis) cannot colonize the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli isolated from stool cultures of CR mice were modified to express functional bacterial (bile salt hydrolase) and eukaryotic (Interleukin-10) genes. Reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect host physiology and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to knock-in specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts, and enables LBT with curative intent.

Probiotics Improve Gastrointestinal Function and Life Quality in Pregnancy

We studied whether probiotics were beneficial for hormonal change-associated dysbiosis, which may influence the enteric nervous system and GI function during early pregnancy. The study was 16 days consisting of two cycles of six daily probiotics mainly Lactobacillus and 2 days without probiotics. Daily surveys were conducted to monitor GI function and life quality. A subset of the participants who contributed fecal specimens was used for microbiota metagenomic sequencing, metabolomics, and quantification of bacterial genes to understand potential underlying mechanisms. Statistical analyses were done by generalized linear mixed-effects models. Thirty-two obstetric patients and 535 daily observations were included. The data revealed that probiotic supplementation significantly reduced the severity of nausea, vomiting, constipation, and improved life quality. Moreover, a low copy number of fecal bsh (bile salt hydrolase), which generates free bile acids, was associated with high vomiting scores and probiotic intake increased fecal bsh. In exploratory analysis without adjusting for multiplicity, a low fecal α-tocopherol, as well as a high abundance of Akkemansia muciniphila, was associated with high vomiting scores and times, respectively. The potential implications of these biomarkers in pregnancy and GI function are discussed. Probiotics likely produce free bile acids to facilitate intestinal mobility and metabolism.

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently shifts the gut microbiome consistent with the progression of steatosis to steatohepatitis with fibrosis

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids including taurolithocholic acid and deoxycholic acid, microbial modified bile acids involved in host bile acid regulation signaling pathways. To investigate the effects of TCDD on the gut microbiota, cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and menaquinone biosynthesis genes. Analysis of gut microbiomes from cirrhosis patients identified increased abundance of these pathways as identified in the mouse cecum metagenomic analysis. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.

Characterization of potential probiotics isolated from fermented under-utilized Chrysophyllum albidum Linn kernels using microbiological, biochemical and molecular techniques

Chrysophyllum albidum is a crop of commercial value in Nigeria, however, the seeds are either used for local games or thrown away. This study aimed at exploring this under-utilized kernel as a novel source for obtaining health beneficial bacteria with desired probiotic characteristics. Isolation of potential probiotic bacteria from naturally fermented C. albidum seeds was carried out and followed by their safety evaluation, Gram staining, catalase test, acid tolerance, bile tolerance, cellular hydrophobicity and auto-aggregation assays. 16S rRNA sequencing and the detection of bile salt hydrolase (bsh) gene were the molecular methods applied for the bacteria characterization. Three potential probiotic bacteria were isolated from the fermented seeds. All isolates were non-haemolytic, Gram positive cocci, and catalase negative, grew in 1% bile, acidic pH of 3.5, and showed good auto-aggregation property. 16Sr RNA sequencing revealed isolates to be strains of Enterococcus durans, and the bsh gene was detected in all the strains. In conclusion, novel naturally fermented foods as seen in the fermented C. albidum kernels can serve as sources for the isolation of probiotic bacteria with great interest, and thus serve as starter culture to improve the organoleptic property of dairy and non-dairy foods.

Probiotic characterization and in vitro functional properties of lactic acid bacteria isolated in Thailand

Fourteen lactic acid bacteria from fermented foods and feces of healthy animals in Thailand were characterized for their potential as probiotics. All isolates could survive in simulated gastrointestinal fluid (pH 2) and bile salt solution (pH 8) more than 70% and 63%, when compare with initial cell concentration, respectively. Adhesion test showed more than 70% adhesive property an in vitro experiment. The susceptibility assay showed that all isolates were susceptible to amoxicillin, ampicillin, erythromycin, chloramphenicol, clindamycin, imipenem, kanamycin, norfloxacin, penicillin, tetracycline and vancomycin. Based on phenotypic and genetic characteristics, they belonged to the genera Lactiplantibacillus, Levilactobacillus, Capanilactobacillus, Pediococcus, Enterococcus, Limosilactobacillus and Lacticaseibacillus. The isolates exhibited antimicrobial ability against pathogenic bacteria; Gram positive strains (Staphylococcus aureus TISTR 1466 and Listeria monocytogenes TISTR 2196) and Gram negative (Escherichia coli TISTR 780, Salmonella enteritidis TISTR 2202 and Salmonella typhimurium TISTR 292). Limosilactobacillus reuteri MF67.1 and Companilactobacillus farciminis R7-1 showed bile salt hydrolase activity. Cell-free culture supernatants of all 14 isolates were screened for immunomodulating effects on Tumor Necrosis Factor Alpha (TNF-α) production. Twelve isolates were able to decrease TNF-α production at different levels, especially Lactiplantibacillus paraplantarum R26-3 and Lacticaseibacillus zeae M2/5 could high inhibit TNF-α production, showing 34 and 29% reduction, respectively. These results suggested that all 14 strains met the general criteria of probiotics and four strains, including Lacticaseibacillus zeae M2/5, Lactiplantibacillus paraplantarum R26-3, Limosilactobacillus reuteri MF67.1 and Companilactobacillus farciminis R7-1, represent interesting candidates for further studies as anti-inflammatory (M2/5, R26-3) or cholesterol reducing agents (MF67.1, R7-1) in vivo animal models.