The occurrence and development of liver fibrosis (Figure 1) occurs in all chronic liver diseases and leads to liver cirrhosis or even liver cancer. The mortality rate of patients with liver cirrhosis is ranked 13th among all chronic diseases, suggesting that this condition has significant effects on quality of life (1). Studies have shown that liver fibrosis and early diagnosed cirrhosis can be reversed, particularly for those who require liver fibrosis treatment (2). Liver fibrosis is caused by excessive deposition of the extracellular matrix components and the disruption of hepatic sinusoidal endothelial cell functions. Hepatic sinusoidal endothelial cells are the gatekeepers of a stable liver environment under physiological conditions. The antifibrotic effects of the sinusoidal endothelial cells prevent Kupffer cell activation and the formation of hepatic stellate cells, enabling hepatic vascular resistance regulation and reducing venous pressure (3). The capillary vascularization of these hepatic sinusoidal endothelial cells in the endothelial basement membrane forms multiple pathological factors and occurs during the early stages of liver fibrosis, thereby altering liver function (4). Disorders of the intestinal flora can also lead to liver disease occurrence and development (5). Notably, the intestine and liver are inseparable from each other anatomically, and the intestine supplies 75% of the blood to the hepatic portal vein (6).
Moreover, the intestinal tract and liver functionally interact, and thus homeostasis of the intestinal flora is affected by liver fibrosis (7).
One study showed that liver fibrosis could lead to disorders of the intestinal flora, and NADPH oxidase 4 and RhoA could accelerate the development of liver fibrosis by activating the hepatic stellate cells, leading to dysbacteriosis (8). Under the pathological changes induced by liver fibrosis, an increase in altered Schaedler flora of the intestine accelerates fibrosis progression; this effect can be blocked by inhibiting the altered Schaedler flora and promoting the growth of the specific pathogen-free flora instead (9).
This review discusses the liver fibrosis treatment with traditional Chinese medicine (TCM) and highlights the limitations of current research on preventing liver fibrosis by regulating the intestinal flora via TCM. We also explore new approaches for treating liver diseases by regulating the intestinal flora with TCM to provide a theoretical basis and clinical practice guide.
We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/apm-20-2129).
Information on the literature review in this paper is shown in Table 1.
TCM regulates intestinal flora
Astragalus polysaccharide an effective extract of Astragalus membranaceus (10) and functions as an inflammatory reaction inhibitor by reducing the expression of proinflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α (11). Astragalus polysaccharides can also increase Lactobacillus and Bifidobacterium production in the intestinal tract and reduce Salmonella typhi count, which reduces inflammatory reaction occurrences (12). As a result of this reduction, Astragalus polysaccharides can exert anti-inflammatory effects by regulating the numbers of bacteria (13). Additionally, A. membranaceus can alter the intestinal flora’s structure and composition and enrich its diversity (14).
Scutellaria baicalensis is a traditional Chinese herbal medicine that has many beneficial effects; it is anti-inflammatory, antibacterial, and has antioxidants properties (15). S. baicalensis can effectively promote healthy bacterial growth (Bifidobacterium and Lactobacillus) in the intestinal tract (16). Notably, Lactobacillus rhamnosus, L. paracasei, and L. plantarum can effectively reduce liver fat percentage and halt the occurrence and/or development of alcoholic liver disease (17). Additionally, Bifidobacterium and L. Rhamnosus can reduce liver inflammation and block the occurrence of nonalcoholic fatty liver disease (18).
Pueraria lobata comes from the dried roots of leguminous plants and has been shown to have medicinal value. Pueraria polysaccharides are extracted from P. Lobata and can be consumed by intestinal microorganisms to benefit metabolism, ultimately affecting the body’s physiological function (19,20). After it is fermented and metabolized in the intestinal flora, this TCM can effectively improve drug properties and reduce drug toxicity (21).
P. Lobata reduces the expression of inflammatory factors, such as TNF-α and IL-6. The expression levels of these inflammatory factors after Bifidobacterium fermentation when using P. Lobata were shown to be significantly lower than those in Pueraria without fermentation (22). Also, in the small intestine and colon of mice fed with a high-fat diet, puerarin, a functional extract of P. Lobata, was shown to block the expression of the proinflammatory factors IL-6 and monocyte chemoattractant protein-1 and increase the expression of the anti-inflammatory factor IL-10 (23). Other studies have shown that Pueraria can regulate intestinal flora disorder (24) and prevent liver injury by reducing endotoxin contents in the intestinal tract (25).
The TCM aconite lateral root (Fuzi) has been widely used as an anti-inflammatory drug, analgesic, diuretic, and cardiotonic to treat colds, heart failure, edema, and other diseases (26). This medicine still retains a certain degree of toxicity and can cause toxicity-induced ventricular tachycardia; however, processed aconite’s toxicity is significantly reduced (27). Furthermore, experimental studies have confirmed that the content of monoester and diterpenoid alkaloids in processed Aconitum is reduced after being metabolized by the intestinal flora, resulting in lower toxicity (28). It has further been shown capable of inhibiting the pathogenicity of harmful bacteria, such as Staphylococcus aureus ATCC-25923, and exhibits antitumor effects, including the inhibition of HL-60, SMCC-7721, and SW480 tumor cell growth (29). The metabolism of this TCM after intestinal flora metabolism can be directly analyzed using real-time ionization combined with multistage tandem mass spectrometry, enabling a quantitative analysis (30). Aconite also has inhibitory effects on Escherichia coli and S. aureus (31,32).
Largehead Atractylodes rhizome
In contrast to Western medicine, TCM places more importance on the whole body as a concept, considering patients as an organic and unified whole; thus, TCM has significant system biology advantages (33). The metabolism of intestinal microorganisms is a key factor affecting the therapeutic effects of TCMs in vivo (34).
The TCM, Atractylodes macrocephala, has the effect of invigorating the spleen, promoting dampness, and stopping diarrhea; therefore, it is used to treat diarrhea caused by spleen weakness. After treatment with A. macrocephala, the pathogenic bacteria, such as Helicobacter pylori and Clostridium, are significantly reduced. In contrast, beneficial bacteria, such as Lactobacillus and Akerman’s bacteria, are significantly increased, indicating that A. macrocephala promotes probiotic reproduction and maintains the flora’s intestinal homeostasis (35).
The therapeutic effects of A. macrocephala in vivo are related to the regulation of E. coli, ShigellaI, and Alternaria, and the intestinal flora’s homeostasis (36). Also, A. macrocephala oil can reduce H. pylori biofilm formation, thereby inhibiting the proliferation of H. pylori and reducing the expression of the inflammatory factor IL-8 (37). A. macrocephala has also been shown to regulate intestinal microorganisms, stabilize the internal environment, and effectively alleviate chronic gastrointestinal diseases (38). A. macrocephala polysaccharides can also regulate disorders of the intestinal flora (39), and atractylodin can block E. coli, Bacillus subtilis, Candida albicans, and S. aureus activity (40,41).
Summary of the effects of TCMs on the intestinal flora
TCM and their effective compounds (Figure 2) have long been used to treat liver fibrosis, showing remarkable curative effects (42). According to existing literature, TCMs can regulate the intestinal flora’s homeostasis to prevent the occurrence and development of liver fibrosis. For example, Schisandra chinensis can protect the liver and block hepatic fibrosis by regulating intestinal microorganisms and reversing the abnormal bile acid spectrum (43,44).
The liver-intestine axis
There are anatomical and physiological connections between the liver and intestines in the human body (Figure 3). The chemical signals that connect these organs make up the liver-intestine axis and include biological processes, such as metabolism and supporting of the internal environment’s stability (45). Imbalances in the intestinal flora and hyperproliferation of these microorganisms can lead to the destruction of the intestinal barrier. Because the intestinal flora flows into the liver through the portal vein (46), disruptions of the intestinal flora lead to immune responses in the liver and aggravated liver fibrosis occurrence and development (47). However, homeostasis of the intestinal flora supports the stability of the immune system (48). Notably, the intestinal microflora of rats with hepatic fibrosis was found to be altered (49), and another study showed that dysfunction of the intestinal barrier and flow of intestinal microorganisms into the blood induces inflammatory reactions and eventually leads to liver injury and liver fibrosis (50). These changes also reduce the contents of bacterial metabolites, such as lysozyme and lysophosphatide, which can induce liver fibrosis and inhibit Kupffer cell activation (51).
The liver-intestine axis has a two-way regulation mechanism; that is, liver fibrosis can affect the intestinal microbiome, and the intestinal microbiome can affect liver fibrosis (52). In liver fibrosis caused by chronic hepatitis B, the abundance of the intestinal microbiota decreases, thereby affecting bile acid metabolism (53). Ursolic acid can increase the numbers of Lactobacillus and Bifidobacterium in the flora, improve bacterial malnutrition, support the stability of the bacterial flora, and inhibit liver fibrosis development (54,55). Moreover, supplementation with the probiotic L. rhamnosus was shown to reduce liver inflammation and fibrosis (56), and the composition of the intestinal flora has been associated with inflammation and liver fibrosis (57).
Summary of the liver-intestine axis
A summary of liver-intestine axis studies is shown in Table 2. Briefly, because of various stimulating factors, intestinal wall permeability increases, and the bacteria in the intestine enter the liver through portal vein circulation, leading to liver inflammation and subsequent liver fibrosis. The results of these experimental studies (58-67) have shown that TCM extracts can reduce the degree of liver fibrosis by regulating the proportion of intestinal microorganisms, such as Firmicutes. Additionally, liver fibrosis affects the homeostasis of intestinal flora (68).
Diagnosis of liver fibrosis in TCM
TCM refers primarily to traditional medicines created by Han people in China, and involves the study of human physiology, pathology, disease diagnosis, prevention, and treatment. Herbal medicine refers to the substances used in the prevention, treatment, and diagnosis of diseases, and the rehabilitation of patients under the guidance of TCM theory. In TCM, several drugs can be combined and decocted into a soup and administered as a prescription. The prescription is typically composed of four parts: “monarch”, “minister”, “adjuvant”, and “envoy” medicine.
Liver fibrosis is interpreted as “chest pain” and “jaundice” in TCM theory. The pathogenesis is typically stagnation of liver qi, blood stasis, and deficiency of liver yin. The pathogenesis of liver fibrosis is most commonly related to dampness, heat, phlegm, toxin, depression, blood stasis, qi deficiency (which acts on the liver meridian), and blood stasis blocking the liver vein (69).
Treatment of liver fibrosis with TCM
TCM is commonly used for the treatment of liver fibrosis (Figure 4). Studies have confirmed that Forsythia suspensa can reduce liver fibrosis progression through the transforming growth factor TGF-β/Smad signaling pathway and the Toll-like receptor TLR 4/MyD88/nuclear factor NF-κB signaling pathway (70,71). Emodin, an effective rhubarb extract, can block liver fibrosis progression through the TGF-β/Smad signaling pathway (72). Gan Shen Fu Fang can inhibit T6 hepatic stellate cell activation and block hepatic fibrosis (73). TCM has multichannel and multitarget pharmacological effects in the treatment of liver fibrosis.
Additionally, the method of syndrome differentiation and treatment in TCM has multiple advantages (74,75). For example, the Dahuang Zhechong pill can inhibit the development of hepatic fibrosis by deactivating hepatic stellate cells (76). Further, A. membranaceus can inhibit hepatic fibrosis by blocking the TGF-β/Smad signaling pathway (77). Also, Sophora flavescens, Ligustrum lucidum, licorice, Lonicera japonica Thunb, and Salvia miltiorrhiza Bge are TCMs used to treat liver fibrosis (78-81). Experimental studies have shown that S. miltiorrhiza can inhibit hepatic stellate cell activity by enhancing natural killer cell functions to block liver fibrosis (82). Moreover, TCMs can protect the liver and reduce liver fibrosis by improving inflammation and reducing steatosis (83).
Summary of studies of the effects of TCM on liver fibrosis
Researchers have evaluated the effects of active compounds, Chinese herbal medicines, and Chinese herbal formulae on liver fibrosis through animal experiments and clinical studies. TCM has been shown to reduce the secretion of inflammatory factors, regulate the TGF-β/Smad signaling pathway and TLR4/MyD88/NF-κB signaling pathway, inhibit the activation of hepatic stellate cells, and improve liver function, thereby blocking fibrosis and protecting the liver.
Intestinal flora-related mechanisms of TCM against liver fibrosis
TCM can effectively prevent liver fibrosis occurrence and development by regulating intestinal flora, inhibiting the intestinal barrier dysfunction, and reducing inflammatory reactions (84,85). Moreover, the hepatic intestinal axis has been shown to have bidirectional regulatory effects, and TCM has been proven to protect the liver through the liver-intestine axis (86). Notably, changes in intestinal flora can induce the development of liver fibrosis and liver injury. After liver fibrosis, intestinal permeability and the fecal flora change significantly (87). Additionally, increased intestinal bacterial translocation, as a marker of chronic liver disease, can lead to hepatitis and fibrosis (88).
Berberine alters the intestinal flora of Bacteroides, xenobiotics, and Verrucosa and reduces inflammatory factor expression (89). Coptis chinensis can protect against rat liver toxicity induced by cinnabar. These mechanisms may be related to endogenous metabolism, including energy metabolism, amino acid metabolism, and intestinal flora metabolism in rats (90).
Summary of the effects of TCM on liver fibrosis through the liver-intestine axis
Studies of TCMs have evaluated these medicines’ ability to protect against liver fibrosis by regulating intestinal microorganisms (Figure 5). These findings have supplied insights into novel treatment strategies and approaches for liver fibrosis. For example, the Simiao decoction can reduce inflammatory factor secretion and regulate intestinal flora homeostasis (91). Additionally, a TCM formula was found to reverse increases in scleroderma and Proteobacteria caused by a high-fat diet, resulting in a decreased scleroderma to Bacteroides ratio and an increased abundance of Bacteroides (92). Therefore, TCMs can effectively regulate the homeostasis of the intestinal flora, protect the intestinal wall’s permeability, increase the contents of probiotics, mediate inflammatory reactions and liver lipid metabolism, block liver fibrosis, and protect the liver.
In this review, we presented findings of earlier studies related to the use of TCMs to regulate intestinal microorganisms and protect against liver fibrosis. However, existing research is not comprehensive, and further studies are needed. Moreover, in future works, it will be necessary to combine the holistic view of the TCM theory and methods of syndrome differentiation and treatment to explore the effects of TCMs on liver fibrosis. Additionally, use nano-imaging technology may be need to track the path of TCMs in the intestines.
We thank our team at the Hunan University of Chinese Medicine for their aid.
Funding: This study received funding from the National Natural Science Foundation of China (No. 81704068).
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/apm-20-2129
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-2129). The authors have no conflicts of interest to declare.
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