Gut microbiota from nCAL patients promotes colon anastomotic healing by inducing collagen synthesis in epithelial cells

Jin, Xiangren; Liu, Yang; Shi, Shang; Liu, Lujia; Lin, Baiqiang; Guo, Xing; Cai, Ting; Wei, Yunwei

doi:10.1111/jgh.15946

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…AL usually leads to significant local and systemic sepsis,31 and we show that the postoperative inflammatory reaction was indeed exacerbated in AL patients, as evidenced by the higher levels of TNF-α and IL-β measured in rectal swabs obtained after surgery. Our finding is in agreement with recent findings showing that FMT in mice using postoperative stool samples from patients with AL induced poor anastomotic healing in rats 32. Similar relationship between the presence of proinflammatory cytokines such as TNF-α, and deficient mucosal repair25 have been reported in chronic inflammatory gut conditions, namely in inflammatory bowel disease 33.…”

Section: Discussionsupporting

confidence: 93%

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines

Hajjar

Gonzalez

Fragoso

et al. 2022

Gut

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ObjectiveColorectal cancer (CRC) is the third most diagnosed cancer, and requires surgical resection and reconnection, or anastomosis, of the remaining bowel to re-establish intestinal continuity. Anastomotic leak (AL) is a major complication that increases mortality and cancer recurrence. Our objective is to assess the causal role of gut microbiota in anastomotic healing.DesignThe causal role of gut microbiota was assessed in a murine AL model receiving faecal microbiota transplantation (FMT) from patients with CRC collected before surgery and who later developed or not, AL. Anastomotic healing and gut barrier integrity were assessed after surgery. Bacterial candidates implicated in anastomotic healing were identified using 16S rRNA gene sequencing and were isolated from faecal samples to be tested bothin vitroandin vivo.ResultsMice receiving FMT from patients that developed AL displayed poor anastomotic healing. Profiling of gut microbiota of patients and mice after FMT revealed correlations between healing parameters and the relative abundance ofAlistipes onderdonkiiandParabacteroides goldsteinii. Oral supplementation withA. onderdonkiiresulted in a higher rate of leaks in mice, while gavage withP. goldsteiniiimproved healing by exerting an anti-inflammatory effect. Patients with AL and mice receiving FMT from AL patients presented upregulation of mucosal MIP-1α, MIP-2, MCP-1 and IL-17A/F before surgery. Retrospective analysis revealed that patients with AL present higher circulating neutrophil and monocyte counts before surgery.ConclusionGut microbiota plays an important role in surgical colonic healing in patients with CRC. The impact of these findings may extend to a vast array of invasive gastrointestinal procedures.

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Section: Discussionsupporting

confidence: 93%

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines

Hajjar

Gonzalez

Fragoso

et al. 2022

Gut

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“…The classical bacterial pathogens implicated in CAL belong to the genera Enterococcus , Pseudomonas and Bifidobacterium [12, 14, 29–31], and in the present study, all were identified by traditional cultivation methods in the anastomotic drainage fluid or in the faeces. The introduction of 16S rDNA sequencing techniques revealed a much more complex ecosystem than was initially expected [12, 32, 33]. Previous studies using this technology indicated an abundance of Lachnospiraceae in patients with CAL, whereas Prevotella copri and the Streptococcus genus negatively correlated [30, 34, 35].…”

Section: Discussionmentioning

confidence: 99%

Anastomotic leak in colorectal cancer surgery: Contribution of gut microbiota and prediction approaches

Hernández‐González,

Barquín,

Ortega‐Ferrete

et al. 2023

Colorectal Disease

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AimTo monitor prospectively the occurrence of colorectal anastomotic leakage (CAL) in patients with colon cancer undergoing resectional surgery, characterizing the microbiota in both faeces and mucosal biopsies of anastomosis. In a second stage, we investigated the ability to predict CAL using machine learning models based on clinical data and microbiota composition.MethodA total of 111 patients were included, from whom a faecal sample was obtained, as well as biopsy samples from proximal and distal sites in the healthy margins of the tumour piece. The microorganisms present in the samples were investigated using microbial culture and 16S rDNA massive sequencing. Collagenase and protease production was determined, as well as the presence of genes responsible for expressing enzymes with these activities. Machine learning analyses were developed using clinical and microbiological data.ResultsThe incidence of CAL was 9.0%, and CAL was associated with collagenase/protease‐producing Enterococcus. Significant differences were found in the microbiota composition of proximal and distal biopsy samples, but not in faecal samples, among patients who developed CAL. Clinical predictors of CAL were 5‐day C‐reactive protein and heart disease, whereas 3‐day C‐reactive protein and diabetes were negative predictors.ConclusionBiopsy samples from surgical margins, rather than faecal samples, are the most appropriate samples for exploring the contribution of the intestinal microbiota to CAL. Enterococci are only enriched in the anastomosis after surgery, and their collagenases and proteases are involved in the degradation of the anastomotic scar.

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“…16 s rRNA gene sequencing and bioinformatic analysis 16 s rRNA gene sequencing and bioinformatic analysis were followed as previously described (Jin et al, 2022). The human CRC samples were collected, and microbial DNA was extracted using TRIzol ® Reagent according to the manufacturer's instructions (Invitrogen).…”

Section: Bacterial Cultivation and Heat-killedmentioning

confidence: 99%

Fusobacterium nucleatum induces colon anastomosis leak by activating epithelial cells to express MMP9

et al. 2022

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BackgroundDespite advances in anastomotic techniques and perioperative care, the incidence of anastomotic leak (AL) has not substantially decreased over time. Although it is known that AL etiology is multifactorial and the mechanisms involved remain unclear, there is accumulating evidence pointing at AL related to gut microbiota.MethodWe firstly performed a clinical study to analyze the gut microbiota between colorectal cancer patients who developed AL and those who did not (nAL) using 16S-rRNA sequencing and quantitative real-time PCR to identify AL risk bacterial taxa. Then we built a rat anastomosis model and performed a bacteria transplantation to ensure the cause-effect relationship. The anastomotic healing score was used to evaluate the healing of anastomosis. In addition, we assessed the adhesion ability of bacteria by staining with fluorescein isothiocyanate and attachment assay. The expression of matrix metalloproteinase 9 (MMP9) was detected by western blot, and the activity was detected by gelatin zymography.ResultsWe found that the abundance and positive rate of Fusobacterium nucleatum (Fn) were higher in the AL patients. Exposure of the rat’s colon anastomosis to Fn contributes to the loss of submucosa collagen I and III, leading to AL’s pathogenesis. Fn can attach to the gut epithelial cells and stimulate intestinal MMP9 expression in vitro and in vivo. We further confirmed that these effects of Fn depended on the E-cadherin/β-catenin signaling pathway.ConclusionThis work demonstrates that Fn attaches and then stimulates the expression of epithelial cells MMP9 by the E-cadherin/β-catenin signaling pathway. These effects contribute to collagen break down in the intestinal tissue, finally leading to AL.

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Gut microbiota from nCAL patients promotes colon anastomotic healing by inducing collagen synthesis in epithelial cells

Cited by 9 publications

References 28 publications

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines

Anastomotic leak in colorectal cancer surgery: Contribution of gut microbiota and prediction approaches

Fusobacterium nucleatum induces colon anastomosis leak by activating epithelial cells to express MMP9

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