A genetic variant in toll‐like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis

Nischalke, Hans Dieter; Fischer, Janett; Klüners, Alexandra; Matz‐Soja, Madlen; Krämer, Benjamin; Langhans, Bettina; Goeser, Felix; Soyka, Michael; Stickel, Felix; Spengler, Ulrich; Nattermann, Jacob; Strassburg, Christian P.; Berg, Thomas; Lutz, Philipp

doi:10.1111/liv.14980

Cited by 10 publications

(6 citation statements)

References 35 publications

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“…When evaluating cirrhotic patients, the most obvious change was seen for CXCL8, which showed up to 30-fold increased levels in serum of cirrhotic patients, as compared to healthy individuals. CXCL8 is a multipotent molecule with angiogenic and inflammatory properties, it is produced by a wide variety of cells, such as monocytes, macrophages and fibroblast, and it is associated with leaky gut-induced inflammation, all of which suggest that CXCL8 could be a potential factor for further investigation in its role of cirrhosis development [13][14][15]. The high levels of CXCL8 and MIF are also suggestive of involvement of tumor-associated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC

Beudeker

Groothuismink

Eijk

et al. 2022

Cancers

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Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies.

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Section: Discussionmentioning

confidence: 99%

Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC

Beudeker

Groothuismink

Eijk

et al. 2022

Cancers

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“… 94 A similar link was noticed with TLR5. 94 , 95 Literature on TLR3 signaling appears to show antitumor activity, suggesting therapeutic potential for HCC. 49 , 93 , 96 – 98 Collectively, TLR4, TLR9, TLR5, and TLR3 emerge as potential targets for therapeutic interventions, highlighting the intricate involvement of TLRs in hepatic steatosis, progression to fibrosis, and HCC pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

Gut microbiota in MAFLD: therapeutic and diagnostic implications

Alghamdi,

Mosli,

Alqahtani

2024

Therapeutic Advances in Endocrinology

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Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.

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“… 42 , 47 , 48 Notably, a single-nucleotide polymorphism of the TLR5 gene in humans was recently uncovered that affected immune responses to flagellin and was associated with steatohepatitis-dependent HCC. 49 Considering that regulation of the gut microbiota is predominately mediated by basolateral expression of TLR5 on intestinal epithelia, 26 , 50 future studies should explore how tissue-specific disruption of Tlr5 (ie, liver vs. intestine) impacts the gut microbiota and HCC progression in Fxr KO mice. Altogether, the current and prior reports support the concept of targeting TLR5 for stimulating immune responses, maintaining gut microbiota eubiosis, and better regulating bile acid metabolism to abate HCC.…”

Section: Discussionmentioning

confidence: 99%

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor–deficient mice

Golonka

Yeoh

Saha

et al. 2023

Hepatology Communications

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Background: HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, “dysbiosis,” is proposed as a probable diagnostic biomarker and a risk factor for HCC. However, whether gut microbiota dysbiosis is a cause or a consequence of HCC is unknown. Methods: To better understand the role of gut microbiota in HCC, mice deficient of toll-like receptor 5 (TLR5, a receptor for bacterial flagellin) as a model of spontaneous gut microbiota dysbiosis were crossed with farnesoid X receptor knockout mice (FxrKO), a genetic model for spontaneous HCC. Male FxrKO/Tlr5KO double knockout (DKO), FxrKO, Tlr5KO, and wild-type (WT) mice were aged to the 16-month HCC time point. Results: Compared with FxrKO mice, DKO mice had more severe hepatooncogenesis at the gross, histological, and transcript levels and this was associated with pronounced cholestatic liver injury. The bile acid dysmetabolism in FxrKO mice became more aberrant in the absence of TLR5 due in part to suppression of bile acid secretion and enhanced cholestasis. Out of the 14 enriched taxon signatures seen in the DKO gut microbiota, 50% were dominated by the Proteobacteria phylum with expansion of the gut pathobiont γ-Proteobacteria that is implicated in HCC. Conclusions: Collectively, introducing gut microbiota dysbiosis by TLR5 deletion exacerbated hepatocarcinogenesis in the FxrKO mouse model.

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A genetic variant in toll‐like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 10 publications

References 35 publications

Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC

Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC

Gut microbiota in MAFLD: therapeutic and diagnostic implications

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor–deficient mice

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