The Relationship between Helicobacter pylori Infection of the Gallbladder and Chronic Cholecystitis and Cholelithiasis: A Systematic Review and Meta-Analysis

Helicobacter pylori (H. pylori) is proved to be the main pathogenic agent of various diseases, including chronic gastritis, gastric ulcer, duodenal ulcer, and gastric cancer. In addition, chronic cholecystitis and cholelithiasis are common worldwide, which are supposed to increase the total mortality of patients. Epidemiologic evidence on the relationship between H. pylori infection of the gallbladder and chronic cholecystitis/cholelithiasis still remains unclear. We conducted a systematic review and meta-analysis of overall studies to investigate the relationship between H. pylori infection of the gallbladder and chronic cholecystitis/cholelithiasis. Two researchers searched PubMed, Embase, and Cochrane Library databases to obtain all related and eligible studies published before July 2020. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by the random-effects model. Subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also conducted. Twenty studies were included in the meta-analysis, involving 1735 participants and 1197 patients with chronic cholecystitis/cholelithiasis. Helicobacter species infection of the gallbladder was positively correlated with increased risk of chronic cholecystitis and cholelithiasis, especially H. pylori (OR = 3.05; 95% CI, 1.81–5.14; I2 = 23.5%). Besides, country-based subgroup analysis also showed a positive correlation between the gallbladder H. pylori positivity and chronic cholecystitis/cholelithiasis risk. For Asian and non-Asian country studies, the ORs were 4.30 (95% CI, 1.76–10.50; I2 = 37.4%) and 2.13 (95% CI, 1.23–3.70; I2 = 0.0%), respectively. The association was more obvious using the bile sample and urease gene primer. In conclusion, this meta-analysis provided evidence that there is a positive correlation between H. pylori infection in the gallbladder and increased risk of chronic cholecystitis and cholelithiasis

Biosynthetic pathway of the final Er product, Er-A.

<p>Three DEBSs, EryAI-AIII, are responsible for the generation of the 16-membered lactone, 6-dEB; Tailoring enzymes catalyze sequential reactions, including two hydroxylations, two glycosylations, and one methylation, to obtain the final product, Er-A.</p

Identification and Characterization of a New Erythromycin Biosynthetic Gene Cluster in <i>Actinopolyspora erythraea</i> YIM90600, a Novel Erythronolide-Producing Halophilic Actinomycete Isolated from Salt Field

<div><p>Erythromycins (Ers) are clinically potent macrolide antibiotics in treating pathogenic bacterial infections. Microorganisms capable of producing Ers, represented by <i>Saccharopolyspora erythraea</i>, are mainly soil-dwelling actinomycetes. So far, <i>Actinopolyspora erythraea</i> YIM90600, a halophilic actinomycete isolated from Baicheng salt field, is the only known Er-producing extremophile. In this study, we have reported the draft genome sequence of <i>Ac. erythraea</i> YIM90600, genome mining of which has revealed a new Er biosynthetic gene cluster encoding several novel Er metabolites. This Er gene cluster shares high identity and similarity with the one of <i>Sa. erythraea</i> NRRL2338, except for two absent genes, <i>eryBI</i> and <i>eryG</i>. By correlating genotype and chemotype, the biosynthetic pathways of 3′-demethyl-erythromycin C, erythronolide H (EH) and erythronolide I have been proposed. The formation of EH is supposed to be sequentially biosynthesized via C-6/C-18 epoxidation and C-14 hydroxylation from 6-deoxyerythronolide B. Although an <i>in vitro</i> enzymatic activity assay has provided limited evidence for the involvement of the cytochrome P450 oxidase EryF^Ac (derived from <i>Ac. erythraea</i> YIM90600) in the catalysis of a two-step oxidation, resulting in an epoxy moiety, the attempt to construct an EH-producing <i>Sa. erythraea</i> mutant via gene complementation was not successful. Characterization of EryK^Ac (derived from <i>Ac. erythraea</i> YIM90600) <i>in vitro</i> has confirmed its unique role as a C-12 hydroxylase, rather than a C-14 hydroxylase of the erythronolide. Genomic characterization of the halophile <i>Ac. erythraea</i> YIM90600 will assist us to explore the great potential of extremophiles, and promote the understanding of EH formation, which will shed new insights into the biosynthesis of Er metabolites.</p></div

The identified Er metabolites in <i>Ac. erythraea</i> YIM90600.

<p>EB and Er-C are normal Er intermediates, while 3′-<i>N</i>-demethyl-Er-C, EH, and EI are novel Er congeners that have rarely been reported.</p

HPLC-ESI-MS analysis of the fermentation culture of <i>Sa. erythraea</i> EX103.

<p>Total ion current chromatogram (<i>i</i>), and reconstructed base peak chromatograms for 6-deoxy-Er-A (<i>ii</i>), Er-A (<i>iii</i>), 6-deoxy-Er-B (<i>iv</i>), Er-B (<i>v</i>), 6-deoxy-Er-C (<i>vi</i>), Er-C (<i>vii</i>), 6-deoxy-Er-D (<i>viii</i>), and Er-D (<i>ix</i>) are recorded. Note that 6-deoxy-Er-A and Er-B, as well as 6-deoxy-Er-C and Er-D share the same molecular weights and similar polarities, their base peaks are thus overlapping.</p

HPLC-ESI-MS analyses of the fermentation cultures of <i>Sa. erythraea</i> EX101 and EX102.

<p>(A) Total ion current chromatogram (<i>i</i>), and reconstructed base peak chromatogram for 6-dEB (<i>ii</i>) of the fermentation products of EX101. ESI-MS data recorded at the retention time of 27.06 min (<i>iii</i>). (B) Total ion current chromatogram (<i>iv</i>), and reconstructed base peak chromatogram for EB (<i>v</i>) of the fermentation products of EX102. ESI-MS data recorded at the retention time of 15.96 min (<i>vi</i>).</p

Bacterial strains and plasmids used and constructed in this study.

<p>Bacterial strains and plasmids used and constructed in this study.</p

HPLC-ESI-MS analyses of the <i>in vitro</i> enzymatic reactions catalyzed by EryK^Sa and EryK^Ac, respectively.

<p>Total ion current chromatograms indicating standard Er-B (red circle, <i>i</i>) and Er-A (blue lozenge, <i>ii</i>), the <i>in vitro</i> conversion of Er-B to Er-A in the absence of active EryK^Sa (<i>iii</i>), in the presence of active EryK^Sa (<i>iv</i>), in the absence of active EryK^Ac (<i>v</i>), or in the presence of active EryK^Ac (<i>vi</i>).</p