Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

Nakamoto, Nobuhiro; Sasaki, Nobuo; Aoki, Ryo; Miyamoto, Kentaro; Suda, Wataru; Teratani, Toshiaki; Suzuki, Takahiro; Koda, Yuzo; Chu, Po–Sung; Taniki, Nobuhito; Yamaguchi, Akihiro; Kanamori, Mitsuhiro; Kamada, Nobuhiko; Hattori, Masahira; Ashida, Hiroshi; Sakamoto, Michiie; Atarashi, Koji; Narushima, Seiko; Yoshimura, Akihiko; Honda, Kenya; Sato, Toshiro; Kanai, Takanori

doi:10.1038/s41564-018-0333-1

Cited by 319 publications

(296 citation statements)

References 59 publications

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“…27 The increase in Parabacteroides is intriguing, as it has been demonstrated that this bile-tolerant taxon is linked to changes in cholesterol and bile acid metabolism. 32 We could demonstrate an extensive alteration of the microbial com- In previous studies of the mucosal microbiota in UC patients with and without PSC, city of origin was the main determinant of gut microbiota profile despite identical handling of all samples and no consistent differences between UC and PSC with colitis were observed. These findings confirm previously found associations, eg for the genera Veillonella 13,16 and Streptococcus.…”

Section: Diet Has Minor Impact On Microbial Community Alterations Imentioning

confidence: 57%

“…Other previously described associations of bacterial taxa with PSC could not be confirmed, such as the recently described association with the genus Klebsiella. 32 We could demonstrate an extensive alteration of the microbial community structure in patients with PSC, identifying 36 taxa with differential prevalence patterns associated with the disease, of which 32 were less present in PSC patients and including the genera Faecalibacterium and Clostridium IV. Both genera comprise butyrate-producing species, which provide an important energy source for intestinal epithelia and display an array of beneficial immunological properties.…”

Section: Diet Has Minor Impact On Microbial Community Alterations Imentioning

confidence: 90%

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Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis

Rühlemann¹,

Liwinski²,

Heinsen³

et al. 2019

Aliment Pharmacol Ther

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Summary Background Single‐centre studies reported alterations of faecal microbiota in patients with primary sclerosing cholangitis (PSC). As regional factors may affect microbial communities, it is unclear if a microbial signature of PSC exists across different geographical regions. Aim To identify a robust microbial signature of PSC independent of geography and environmental influences. Methods We included 388 individuals (median age, 47 years; range, 15‐78) from Germany and Norway in the study, 137 patients with PSC (n = 75 with colitis), 118 with ulcerative colitis (UC) and 133 healthy controls. Faecal microbiomes were analysed by 16S rRNA gene sequencing (V1‐V2). Differences in relative abundances of single taxa were subjected to a meta‐analysis. Results In both cohorts, microbiota composition (beta‐diversity) differed between PSC patients and controls (P < 0.001). Random forests classification discriminated PSC patients from controls in both geographical cohorts with an average area under the curve of 0.88. Compared to healthy controls, many new cohort‐spanning alterations were identified in PSC, such as an increase of Proteobacteria and the bile‐tolerant genus Parabacteroides, which were detected independent from geographical region. Associated colitis only had minor effects on microbiota composition, suggesting that PSC itself drives the faecal microbiota changes observed. Conclusion Compared to healthy controls, numerous microbiota alterations are reproducible in PSC patients across geographical regions, clearly pointing towards a microbiota composition that is shaped by the disease itself and not by environmental factors. These reproducibly altered microbial populations might provide future insights into the pathophysiology of PSC.

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Section: Diet Has Minor Impact On Microbial Community Alterations Imentioning

confidence: 57%

Section: Diet Has Minor Impact On Microbial Community Alterations Imentioning

confidence: 90%

Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis

Rühlemann¹,

Liwinski²,

Heinsen³

et al. 2019

Aliment Pharmacol Ther

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“…Recent published studies support a potential role for bacterial translocation from the gut to the liver due to intestinal barrier dysfunction. Nakamoto et al showed that klebsiella pneumoniae, proteus mirabilis and enterococcus gallinarum were prevalent in patients with PSC and responsible for bacterial translocation as well as for hepatobiliary inflammation in gnotobiotic mouse models. The progression of hepatobiliary disease was promoted via a TH17 response .…”

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

“…Nakamoto et al showed that klebsiella pneumoniae, proteus mirabilis and enterococcus gallinarum were prevalent in patients with PSC and responsible for bacterial translocation as well as for hepatobiliary inflammation in gnotobiotic mouse models. The progression of hepatobiliary disease was promoted via a TH17 response . Therefore antibiotic therapy might be beneficial in the natural course of PSC.…”

Section: Primary Sclerosing Cholangitismentioning

confidence: 99%

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Engel

Taubert

Jaeckel

et al. 2020

Liver International

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Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality.

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“…lipopolysaccharides, LPS) also contributes by involving innate immune responses [32][33][34][35]. Furthermore, a series of studies now strongly indicate that the gut microbiota may be involved in PSC pathogenesis [17,[36][37][38][39][40] giving rise to clinical trials involving fecal transplantation, non-absorbable antibiotics, and other means of manipulating the gut microbiome in patients [17,[41][42][43]. In the bile ducts, bacterial, and fungal colonization may follow cholestasis and endothelial damage, through the establishing of a pathogenic biliary microbiota further propagating inflammation and intercurrent infections [44].…”

Section: Pathophysiological Basis Of Therapymentioning

confidence: 99%

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

Vesterhus

Karlsen

2020

J Gastroenterol

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Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

Cited by 319 publications

References 59 publications

Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis

Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

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