Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.
Humans ; Gastrointestinal Microbiome/physiology* ; Animals ; Carcinogenesis/metabolism* ; Colitis-Associated Neoplasms/microbiology* ; Fatty Acids, Volatile/metabolism* ; Bile Acids and Salts/metabolism* ; Colitis/microbiology*

OBJECTIVES: To investigate the therapeutic mechanism of Wendan Decoction for phlegm syndrome in rats with metabolic syndrome (MS). METHODS: Forty Wistar rats were randomly divided into normal control group (n=8) and 3 phlegm syndrome model groups (induced by high-fat, high-sugar, and high-salt feeding and a single-dose intraperitoneal STZ injection; n=24) treated with daily gavage of saline, Wendan Decoction (3.6 g/kg), or metformin (0.1 g/kg) for 4 weeks. General conditions and glucose and lipid metabolism parameters of the rats were monitored, and serum LPS, liver histopathology, hepatic expressions of FXR, CYP7A1 and FGFR4 and ileal expressions of FXR and FGF15 were examined. Gut microbiota structure was analyzed using 16S rDNA sequencing, and serum bile acids were quantified with UHPLC-MS/MS. RESULTS: The rat models of phlegm syndrome exhibited severe hepatic steatosis and necrosis, increased body weight, abdominal circumference, Lee's index, FBG, FINS, HOMA-IR, TG, TC, LDL and LPS, and decreased HDL level. The abundance of Bacteroidetes, Megamonas, and Bacteroides in gut microbiota increased while Firmicutes, Lachnospiraceae_NK4A136_group, isohyodeoxycholic acid, and glycohyodeoxycholic acid decreased significantly; hepatic FXR and FGFR4 expressions and ileal FXR and FGF15 expressions decreased while hepatic CYP7A1 expression increased significantly in the rat models. Treatment with Wendan Decoction effectively alleviated hepatic pathology, reduced body weight and abdominal circumference, improved glucose and lipid metabolic profiles and gut microbiota structure, and reversed the changes in hepatic and ileal protein expressions. Correlation analysis revealed that Firmicutes and Lachnospiraceae_NK4A136_group were positively correlated while Bacteroidetes, Megamonas and Bacteroides were negative correlated with the levels of isohyodeoxycholic acid and hyodeoxycholic acid. CONCLUSIONS Wendan Decoction can significantly improve metabolic profiles in rats with phlegm syndrome of MS possibly by regulating the intestinal flora-bile acid axis to modulate the intestinal flora structure and maintain bile acid homeostasis via the FXR signaling pathway.
Animals ; Gastrointestinal Microbiome/drug effects* ; Metabolic Syndrome/microbiology* ; Bile Acids and Salts/metabolism* ; Rats, Wistar ; Drugs, Chinese Herbal/therapeutic use* ; Rats ; Male ; Fibroblast Growth Factors/metabolism* ; Liver/metabolism* ; Cholesterol 7-alpha-Hydroxylase/metabolism* ; Receptors, Cytoplasmic and Nuclear/metabolism*

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases currently in the context of obesity worldwide, which contains a spectrum of chronic liver diseases, including hepatic steatosis, non-alcoholic steatohepatitis and hepatic carcinoma. In addition to the classical "Two-hit" theory, NAFLD has been recognized as a typical gut microbiota-related disease because of the intricate role of gut microbiota in maintaining human health and disease formation. Moreover, gut microbiota is even regarded as a "metabolic organ" that play complementary roles to that of liver in many aspects. The mechanisms underlying gut microbiota-mediated development of NAFLD include modulation of host energy metabolism, insulin sensitivity, and bile acid and choline metabolism. As a result, gut microbiota have been emerging as a novel therapeutic target for NAFLD by manipulating it in various ways, including probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, and herbal components. In this review, we summarized the most recent advances in gut microbiota-mediated mechanisms, as well as gut microbiota-targeted therapies on NAFLD.
Animals ; Bile Acids and Salts ; metabolism ; Choline ; metabolism ; Dietary Supplements ; Energy Metabolism ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Humans ; Insulin Resistance ; Intestines ; microbiology ; Non-alcoholic Fatty Liver Disease ; microbiology ; therapy

Poliumoside is representative of phenylethanoid glycosides, which are widely found in many plants. Poliumoside is also regarded as the main active component of Callicarpa kwangtungensis Chun (CK), though its oral bioavailability in rat is extremely low (0.69%) and its in vivo and in vitro metabolism has not yet been systematically investigated. In the present study, an ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method was employed to identify the metabolites and investigate the metabolic pathways of poliumoside in rat after oral administration 1.5 g·kg of poliumoside. As a result, a total of 34 metabolites (30 from urine, 17 from plasma, and 4 from bile) and 9 possible metabolic pathways (rearrangment, reduction, hydration, hydrolyzation, dehydration, methylation, hydroxylation, acetylation, and sulfation) were proposed in vivo. The main metabolite, acteoside, was quantified after incubated with rat intestinal bacteria in vitro. In conclusion, the present study systematically explored the metabolites of poliumoside in vivo and in vitro, proposing metabolic pathways that may be significant for further metabolic studies of poliumoside.
Administration, Oral ; Animals ; Bacteria ; metabolism ; Bile ; chemistry ; Caffeic Acids ; administration & dosage ; blood ; chemistry ; urine ; Callicarpa ; chemistry ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; metabolism ; Glycosides ; administration & dosage ; blood ; chemistry ; urine ; Intestines ; microbiology ; Male ; Mass Spectrometry ; methods ; Molecular Structure ; Plasma ; chemistry ; Rats ; Rats, Sprague-Dawley ; Urine ; chemistry

Bile acid is a type of metabolite degraded from cholesterol in liver. Its accumulation in liver could cause liver diseases, liver damage and liver fibrosis. In this experiment, dimethyl nitrosamine (DMN) liver fibrosis was established in rats. The rats were delivered into the normal group, the model group and four treated groups. After the four-week modeling, the treated groups were orally administered with drugs for 2 weeks, whereas the model and normal groups were given equal amount of sterile water at the same time. In the experiment, serum bile acid was taken the as marker, and liver function indexes and changes in bile acid metabolism were detected and observed to identify liver damage-related bile acid targets. It was the first time to evaluate the reverse effect of artificial CsB and its components on liver fibrosis in rats with bile acid metabolic level, and discuss its potential mechanism. The main study contents and results are as follows: a quantitative analysis was made on totally 17 endogenous bile acids, including taurocholic acid conjugated bile acid, glycine conjugated bile acid and free bile acid, and a liver damage evaluation was made for the model according to the detection of serum biochemical indexes and the pathological biopsy. After modeling, ALT, AST activity and TBil content significantly increased, whereas Alb significantly decreased. According to the pathological biopsy HE staining, the model group showed damage in normal hepatic lobule structure, liver cell edema and connective tissue proliferation in portal area; The treated groups showed mitigation in pathological changes to varying degrees. Cordyceps sinensis and its components may impact the bile acid metabolism in rats by activating HDCA, TCA, TCDCA, TLCA, TUDCA, UDCA, THDCA metabolim-related receptors or blocking relevant signaling pathway.
Animals ; Bile Acids and Salts ; metabolism ; Biological Factors ; administration & dosage ; Cordyceps ; chemistry ; physiology ; Humans ; Liver Cirrhosis ; drug therapy ; metabolism ; Male ; Moths ; chemistry ; microbiology ; Rats ; Rats, Wistar

An 80-year-old woman with hilar cholangiocarcinoma was hospitalized due to sudden-onset abdominal pain. Computed tomography revealed hepatic necrosis accompanied with emphysematous change in the superior segment of the right liver (S7/S8), implying spontaneous rupture, based on the presence of perihepatic free air. Although urgent percutaneous drainage was performed, neither pus nor fluids were drained. These findings suggest emphysematous hepatitis with a hepatic mass. Despite the application of intensive care, the patient's condition deteriorated rapidly, and she died 3 days after admission to hospital. Liver gas has been reported in some clinical diseases (e.g., liver abscess) to be caused by gas-forming organisms; however, emphysematous hepatitis simulating emphysematous pyelonephritis is very rare. The case reported here was of fatal emphysematous hepatitis in a patient with hilar cholangiocarcinoma.
Aged, 80 and over ; Anti-Bacterial Agents/therapeutic use ; Bile Duct Neoplasms/complications/diagnosis ; Bile Ducts, Intrahepatic/pathology ; Cefotaxime/therapeutic use ; *Cholangiocarcinoma/complications/diagnosis ; Clostridium Infections/drug therapy/microbiology ; Clostridium perfringens/isolation & purification ; Emphysema/complications/*diagnosis ; Escherichia coli/isolation & purification ; Escherichia coli Infections/drug therapy/microbiology ; Female ; Hepatitis/complications/*diagnosis ; Humans ; Metronidazole/therapeutic use ; *Pneumoperitoneum/complications/diagnosis ; Tomography, X-Ray Computed

OBJECTIVETo illustrate the bacteriology and their susceptibility to antibiotics in patients with biliary tract diseases and provide information for antibiotic choices.

METHODSThe bile specimens were cultured and pathogens' susceptibility to antibiotics was obtained intraoperatively from 195 patients undergoing operations on biliary tract and 24 healthy liver donors from June 2007 to March 2008.

RESULTSAmong 195 bile specimens collected from the patients intraoperatively, 44 ones were found bacterial growth by culture (22.6%), in which 11 ones were mixed infections (25.0%). Fifty-five bacterial strains belonging to 16 species were identified from these bile specimens. They included 34 Gram negative strains (61.8%), 19 Gram positive strains (34.6%) and 2 fungal strains (3.6%). The commonest pathogens were Escherichia coli (27.3%), Enterobacter cloacae (12.7%), Enterococcus faecalis (12.7%) and Enterococcus faecium (10.9%). Among 24 bile specimens collected from the healthy liver donors, one was found Escherichia coli growth by culture (4.2%). The results of susceptibility test showed that the resistant rates of Gram negative strains to Meropenem was 2.8%, followed by Imipenem (5.6%), Sulperazone (22.8%) and Amikacin (28.7%). In this study Gram negative strains were highly resistant to Penicillins, Quinolones, some third generation Cephalosporins and so on (>50.0%). None of Gram positive strains were resistant to Vancomycin and Teicoplanin. They were highly resistant to Penicillins, Quinolones, Clindamycin and so on (>40.0%).

CONCLUSIONS(1) Gram negative strains remain the commonest pathogens in biliary tract infection in Renji Hospital and the commonest pathogen is Escherichia coli. The infection of enterococcus is going up. The mixed infection cases happen mostly in acute biliary infection. (2) To treat biliary infection the broad-spectrum antibiotics which are effective to Escherichia coli are optimal choices. Ceftazidime or Ciprofloxacin may be used in mild biliary infection. Sulperazone or Amikacin may be used in severe biliary infection. Imipenem and Vancomycins may be used as second choice to treat the infection which other drugs are ineffective to.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents ; therapeutic use ; Bile ; microbiology ; Biliary Tract Diseases ; drug therapy ; microbiology ; surgery ; Biliary Tract Surgical Procedures ; Drug Resistance, Bacterial ; Female ; Humans ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Young Adult

BACKGROUND/AIMS: White bile is colorless, translucent fluid found occasionally in malignant bile duct obstruction (MBO). Little information is available on the cause and effect of white bile. The aim of this study was to determine the frequency and clinical significance of white bile in MBO. METHODS: Bile was aspirated during endoscopic retrograde cholangiopancreatography in consecutive patients with MBO. White bile was defined as bile bilirubin <1.5 mg/dL and yellow bile was defined as bile bilirubin >or=1.5 mg/dL in the bile. Two groups were compared prospectively for the duration of jaundice, itching, cholangitis, level of obstruction, and decremental rate of bilirubin after the insertion of 7 Fr endoscopic nasobiliary drainage until the insertion of metal stent or 10 Fr plastic stent. RESULTS: Among 60 patients with MBO, 16 (26.7%) had white bile. WBC count in blood was higher (9,456/mm3 vs. 7,400/mm3, p=0.029) and cholangitis was more common (11/16 vs. 7/44, p=0.000) in white than yellow bile group. Proximal portion of MBO had no communication with GB in 9/16 patients with white bile group and 17/44 patients with yellow bile group (p>0.05). Mean survival of the inoperable 35 patients was 242 days in yellow bile and 227 days in white bile group (p>0.05). CONCLUSIONS: White bile in MBO was not rare and was associated with cholangitis. Gallbladder did not seem to play a role in the formation of white bile. Further study for the pathogenesis and prognosis of white bile in MBO will be necessary.
Aged ; Bile/*chemistry/microbiology ; Bile Duct Neoplasms/*diagnosis/etiology/mortality ; Bilirubin/analysis ; Cholangiopancreatography, Endoscopic Retrograde ; Cholangitis/diagnosis/etiology/mortality ; Cholestasis/*diagnosis/etiology/mortality ; Data Interpretation, Statistical ; Drainage ; Female ; Humans ; Male ; Middle Aged ; Stents ; Survival Analysis

BACKGROUND/AIMS: Bacterial infection of biliary tract may cause severe inflammatory response or sepsis. An immediate bile culture and appropriate antibiotic administration are important to control the biliary tract infection. The objective of the study was to identify organisms in bile and the features of antibiotic susceptibility in patients with biliary tract infection. METHODS: We retrospectively reviewed the clinical records of 212 patients whose bile had been cultured for variable biliary tract diseases at Inje University Ilsan Paik Hospital from Jan. 2000 to Feb. 2007. Bile samples were obtained from percutaneous transhepatic biliary drainage (PTBD, n=89), percutaneous transhepatic gallbladder drainage (PTGBD, n=14) or endoscopic naso-biliary drainage (ENBD, n=49). RESULTS: The overall positive rate of bile culture was 71.7% (152 cases). The organisms cultured were Escherichia coli (25.0%), Enterococcus spp. (13.4%), Klebsiella spp. (11.1%), Pseudomonas spp. (11.1%), and coagulase-negative Staphylococcus (9.7%) in decreasing order. Effective antibiotics for Gram-negative organisms were amoxicillin/clavulanic acid, amikacin, imipenem, and piperacillin/tazobactam in order of effectiveness. Of the cultured blood samples from 160 patients, fifty (31.2%) showed positive bacterial growth. The organisms isolated from blood were similar to those found in the bile. CONCLUSIONS: A broad spectrum penicillin/beta-lactamase inhibitor is a recommendable antimicrobial for empirical treatment for biliary tract infection. However, Gram-positive bacteria such as Enterococcus spp. or methicillin-resistant Staphylococcus aureus are emerging as causative microorganisms. If these organisms are isolated, antimicrobial drugs should be replaced by narrower-spectrum antimicrobials.
Aged ; Aged, 80 and over ; Anti-Bacterial Agents/*pharmacology ; Bacteremia/epidemiology/microbiology ; Bacterial Infections/*microbiology ; Bile/*microbiology ; Bile Duct Diseases/*microbiology ; Cholangiopancreatography, Endoscopic Retrograde ; Female ; Humans ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Retrospective Studies

OBJECTIVEDuodenogastric reflux (DGR) is a reverse flow of duodenal juice into stomach through pylorus composed of bile acid, pancreatic secretion, and intestinal secretion. The increased entero-gastric reflux results in mucosal injury that may relate not only to reflux gastritis but also esophagitis, gastric ulcers, carcinoma of stomach and esophagus. However, the exact mechanisms of gastric mucosal damage caused by DGR are still unknown. The objective of the present study is to investigate the pathogenic effect of primary DGR on gastric mucosa in children, and to explore the correlation of DGR with clinical symptoms, Hp infection and intragastric acidity.

METHODTotally 81 patients with upper gastrointestinal manifestations were enrolled and they were graded according to the symptom scores and underwent endoscopic, histological examinations and 24-hour intra-gastric bilirubin was monitored with Bilitec 2000. Of the 81 cases, 51 underwent the 24-hour intra-gastric pH monitoring by ambulatory pH recorder simultaneously. The total fraction time of bile reflux was considered as a marker to evaluate the severity of DGR. The total fraction time of bile reflux was compared between the patients with positive and negative results under endoscopy and histologically, respectively. The correlations of the total fraction time of bile reflux with clinical symptom score, Hp infection, intragastric acidity were analyzed respectively.

RESULTThe total fraction time of bile reflux in the patients with hyperemia and yellow stain gastric antral mucosa under endoscopy was significantly higher than that without those changes [17.1% (0.5% approximately 53.2%) vs. 6.5% (0 approximately 58.6%), Z = -1.980, P < 0.05; 19.8% (0.5% approximately 58.6%) vs. 8.8% (0 approximately 38.0%), Z = -2.956, P < 0.01 respectively]. Histologically, the cases with intestinal metaplasia had significantly higher total fraction time of bile reflux than in the cases without intestinal metaplasia [29.0% (1.9% approximately 58.6%) vs. 14.3% (0 approximately 53.7%), Z = -2.026, P < 0.05], but no significant difference was found either between the cases with and without chronic inflammation (P > 0.05) or between the cases with and without active inflammation (P > 0.05). The severity of bile reflux was positively correlated with the score of abdominal distention (r = 0.258, P < 0.05), but no correlation with either the severity of intragastric acid (r = -0.124, P > 0.05), or Hp infection (r = 0.016, P > 0.05) was found.

CONCLUSIONPrimary DGR could cause gastric mucosal lesions manifested mainly as hyperemia and bile-stained gastric antral mucosa under endoscopy and the gastric antral intestinal metaplasia histologically in children. There was no significant correlation between DGR and gastric mucosal inflammatory infiltration. DGR had no relevance to Hp infection and intragastric acidity. We conclude that DGR is probably an independent etiological factor and might play a synergistic role in the pathogenesis of gastric mucosal lesions along with gastric acid and Hp infection.

Adolescent ; Bile Reflux ; pathology ; physiopathology ; Child ; Child, Preschool ; Duodenogastric Reflux ; microbiology ; pathology ; physiopathology ; Female ; Gastric Mucosa ; microbiology ; pathology ; Helicobacter Infections ; Helicobacter pylori ; Humans ; Hydrogen-Ion Concentration ; Male