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Mesenteric Adipose Tissue-Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System.

ABSTRACT: Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes, indicating that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in the MAT of patients with CD (CD-MAT), but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. Here it is shown that members of Enterobacteriaceae are highly enriched in CD-MAT compared with non-CD controls. Viable Klebsiella variicola in Enterobacteriaceae is isolated exclusively in CD-MAT and can induce a pro-inflammatory response in vitro and exacerbates colitis both in dextran sulfate sodium (DSS)-induced colitis mice model and IL-10^-/- spontaneous colitis mice model. Mechanistically, active type VI secretion system (T6SS) is identified in the genome of K. variicola, which can impair the intestinal barrier by inhibiting the zonula occludens (ZO-1) expression. Dysfunction of T6SS by CRISPR interference system alleviates the inhibitory effect of K. variicola on ZO-1 expression and attenuated colitis in mice. Overall, these findings demonstrate that a novel colitis-promoting bacteria exist in the mesenteric adipose tissue of CD, opening a new therapeutic avenue for colitis management.

SUBMITTER: Gong J

PROVIDER: S-EPMC10131791 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Mesenteric Adipose Tissue-Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System.

Gong Junli J Yu Jing J Yin Shengmei S Ke Jia J Wu Jinjie J Liu Chen C Luo Zhanhao Z Cheng Wai Ming WM Xie Yaozu Y Chen Yuan Y He Zhen Z Lan Ping P

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230219 12

Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes, indicating that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in the MAT of patients with CD (CD-MAT), but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. Here it is shown that members of Enterobacteriaceae ...[more]

PMID: 36802200

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Project description:BackgroundKlebsiella pneumoniae (KP) is an opportunistic pathogen that mainly causes respiratory and urinary tract infections. The frequent occurrence of simultaneously virulent and multiple drug-resistant isolates led WHO to include this species in the list of top priorities for research and development of therapeutic alternatives. The comprehensive knowledge of the molecular mechanisms underlying KP virulence may lead to the proposal of more efficient and specific drugs. One of its virulence factors is the Type VI Secretion System (T6SS), which contributes to bacterial competition, cell invasion and in vivo colonisation. Despite the few studies showing the involvement of T6SS in KP pathogenesis, little is known concerning the regulation of its expression. The understanding of regulatory mechanisms may give more clues about the function of the system and the possibilities of future interference in this process. This work aimed to standardise the annotation of T6SS genes in KP strains and identify mechanisms of their transcriptional regulation through computational predictions.ResultsWe analyzed the genomes of Kp52.145, HS11286 and NTUH-K2044 strains to perform a broad prediction and re-annotation of T6SS genes through similarity searches, comparative and linear discriminant analysis. 38 genes were found in Kp52.145, while 29 in HS11286 and 30 in NTUH-K2044. Genes coding for iron uptake systems are encoded in adjacencies of T6SS, suggesting that KP T6SS might also play a role in ion import. Some of the T6SS genes are comprised in syntenic regions. 17 sigma 70-dependent promoter regions were identified in Kp52.145, 12 in HS11286 and 12 in NTUH-K2044. Using VirtualFootprint algorithm, binding sites for 13 transcriptional regulators were found in Kp52.145 and 9 in HS11286 and 17 in NTUH-K2044. Six of them are common to the 3 strains: OxyR, H-NS, RcsAB, GcvA, Fis, and OmpR.ConclusionsThe data presented herein are derived from computational analysis. Although future experimental studies are required to confirm those predictions, they suggest that KP T6SS might be regulated in response to environmental signals that are indeed sensed by the bacteria inside the human host: temperature (H-NS), nutrition-limitation (GcvA and Fis), oxidative stress (OxyR) and osmolarity (RscAB and OmpR).

Project description:BackgroundSuperior mesenteric ischemia/reperfusion (I/R) causes barrier dysfunction and facilitates bacterial translocation (BT) in the small intestine, which can even lead to systemic sepsis. Our previous research showed that luminal administration of glucose and its anaerobic glycolytic metabolites exerted cytoprotective effects on epithelial cells and ameliorated I/R-induced BT in the liver and spleen. Notably, the reduction of BT occurs over the whole intestinal tract, not only restricted in the ligated glucose-containing loop.ObjectivesIn this study, we hypothesized that local jejunal glucose-contacting might confer on the remote intestinal epithelium regeneration potential, fortify their barrier function and goblet cell secretory activity.MethodsTwo 10-cm jejunal segments were isolated in Wistar rats. One segment was ligatured at both ends and infused with Krebs buffer containing 0- or 50-mM glucose (local loop), whereas the adjacent segment was left unaltered and not exposed to glucose (remote loop). The rats then underwent either a sham operation or I/R challenge by occlusion of the superior mesenteric artery for 20 min, followed by reperfusion for 1 h.ResultsEnteral addition of glucose in the local jejunum loop alleviated ischemia-induced barrier defects, histopathological scores, cell death, and mucosal inflammation (myeloperoxidase and inflammatory cytokine production) in the remote jejunum. After ischemia, goblet cells in the remote jejunum showed cavitation of mucin granules and low MUC2 expression. Local addition of glucose enhanced MUC2 synthesis and stimulated a jet-like mucus secretion in the remote jejunum, which was accompanied by the restoration of crypt activity.ConclusionsOur results showed local enteral glucose effectively mitigates I/R-induced barrier dysfunction, suggesting that local glucose-stimulated mucus secretion by remote goblet cells may serve to mitigate mucosal inflammation and BT. We provide a more precise barrier protection role of enteral glucose upon I/R challenge, presenting new opportunities for future therapeutic potential.

Project description:Klebsiella variicola is a member of the Klebsiella genus and often misidentified as Klebsiella pneumoniae or Klebsiella quasipneumoniae The importance of K. pneumoniae human infections has been known; however, a dearth of relative knowledge exists for K. variicola Despite its growing clinical importance, comprehensive analyses of K. variicola population structure and mechanistic investigations of virulence factors and antibiotic resistance genes have not yet been performed. To address this, we utilized in silico, in vitro, and in vivo methods to study a cohort of K. variicola isolates and genomes. We found that the K. variicola population structure has two distant lineages composed of two and 143 genomes, respectively. Ten of 145 K. variicola genomes harbored carbapenem resistance genes, and 6/145 contained complete virulence operons. While the β-lactam blaLEN and quinolone oqxAB antibiotic resistance genes were generally conserved within our institutional cohort, unexpectedly 11 isolates were nonresistant to the β-lactam ampicillin and only one isolate was nonsusceptible to the quinolone ciprofloxacin. K. variicola isolates have variation in ability to cause urinary tract infections in a newly developed murine model, but importantly a strain had statistically significant higher bladder CFU than the model uropathogenic K. pneumoniae strain TOP52. Type 1 pilus and genomic identification of altered fim operon structure were associated with differences in bladder CFU for the tested strains. Nine newly reported types of pilus genes were discovered in the K. variicola pan-genome, including the first identified P-pilus in Klebsiella spp.IMPORTANCE Infections caused by antibiotic-resistant bacterial pathogens are a growing public health threat. Understanding of pathogen relatedness and biology is imperative for tracking outbreaks and developing therapeutics. Here, we detail the phylogenetic structure of 145 K. variicola genomes from different continents. Our results have important clinical ramifications as high-risk antibiotic resistance genes are present in K. variicola genomes from a variety of geographic locations and as we demonstrate that K. variicola clinical isolates can establish higher bladder titers than K. pneumoniae Differential presence of these pilus genes inK. variicola isolates may indicate adaption for specific environmental niches. Therefore, due to the potential of multidrug resistance and pathogenic efficacy, identification of K. variicola and K. pneumoniae to a species level should be performed to optimally improve patient outcomes during infection. This work provides a foundation for our improved understanding of K. variicola biology and pathogenesis.

Dataset Information

Mesenteric Adipose Tissue-Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System.

Publications

Mesenteric Adipose Tissue-Derived Klebsiella variicola Disrupts Intestinal Barrier and Promotes Colitis by Type VI Secretion System.

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