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Volume 22
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10.3390/ijms22136921
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Review

Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis

by
Norihisa Nishimura
*,
Kosuke Kaji
,
Koh Kitagawa
,
Yasuhiko Sawada
,
Masanori Furukawa
,
Takahiro Ozutsumi
,
Yukihisa Fujinaga
,
Yuki Tsuji
,
Hiroaki Takaya
,
Hideto Kawaratani
,
Kei Moriya
,
Tadashi Namisaki
,
Takemi Akahane
,
Hiroshi Fukui
and
Hitoshi Yoshiji
Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(13), 6921; https://doi.org/10.3390/ijms22136921
Submission received: 26 May 2021 / Revised: 22 June 2021 / Accepted: 24 June 2021 / Published: 28 June 2021
(This article belongs to the Special Issue Liver–Gut Axis)
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Abstract

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.
Keywords: leaky gut; endotoxins; alcoholic liver disease; nonalcoholic steatohepatitis; liver cirrhosis; hepatocarcinogenesis; Toll-like receptor 4 pathway leaky gut; endotoxins; alcoholic liver disease; nonalcoholic steatohepatitis; liver cirrhosis; hepatocarcinogenesis; Toll-like receptor 4 pathway

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MDPI and ACS Style

Nishimura, N.; Kaji, K.; Kitagawa, K.; Sawada, Y.; Furukawa, M.; Ozutsumi, T.; Fujinaga, Y.; Tsuji, Y.; Takaya, H.; Kawaratani, H.; et al. Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis. Int. J. Mol. Sci. 2021, 22, 6921. https://doi.org/10.3390/ijms22136921

AMA Style

Nishimura N, Kaji K, Kitagawa K, Sawada Y, Furukawa M, Ozutsumi T, Fujinaga Y, Tsuji Y, Takaya H, Kawaratani H, et al. Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis. International Journal of Molecular Sciences. 2021; 22(13):6921. https://doi.org/10.3390/ijms22136921

Chicago/Turabian Style

Nishimura, Norihisa, Kosuke Kaji, Koh Kitagawa, Yasuhiko Sawada, Masanori Furukawa, Takahiro Ozutsumi, Yukihisa Fujinaga, Yuki Tsuji, Hiroaki Takaya, Hideto Kawaratani, and et al. 2021. "Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis" International Journal of Molecular Sciences 22, no. 13: 6921. https://doi.org/10.3390/ijms22136921

APA Style

Nishimura, N., Kaji, K., Kitagawa, K., Sawada, Y., Furukawa, M., Ozutsumi, T., Fujinaga, Y., Tsuji, Y., Takaya, H., Kawaratani, H., Moriya, K., Namisaki, T., Akahane, T., Fukui, H., & Yoshiji, H. (2021). Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis. International Journal of Molecular Sciences, 22(13), 6921. https://doi.org/10.3390/ijms22136921

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