Introduction

The human gut microbiota (GM) is a complex and diverse ecosystem essential to human health and overall well-being. It comprises an immense number of microorganisms, including bacteria, fungi, archaea, viruses, and helminths [1]. Collectively, these microorganisms are referred to as the gut microbiota, and their combined genetic material is termed the gut microbiome [2]. These microorganisms consist of up to 5000 different species and weigh approximately 1% of an adult human's body mass [3]. Indeed, the GM plays a vital role in supporting various physiological processes of the host. Its most significant contribution lies in supporting the intestine, which ensures optimal gut functionality across multiple aspects. These include aiding in digestion, harvesting energy from nutrients, enhancing mucosal immunity, maintaining the integrity of the intestinal barrier, defending against pathogens, and producing essential vitamins, neurotransmitters (NT), and potentially beneficial bioactive compounds, such as short-chain fatty acids (SCFAs), which are valuable molecules for the host [4,5,6,7,8]. The human gut microbiome closely interacts with different organs within the host body, such as the gut responsible for food digestion, the liver for processing after absorption, and adipose tissue for storage. This significant level of integration has led numerous researchers to assume the human GM to a microbial organ of human body [9]. The gut microbiota consists mainly of four primary categories of microorganisms: Firmicutes, Bacteroides, Actinomycetes, Verrucomicrobia, and Proteus [10] Among these, the ratio of Firmicutes to Bacteroidetes is commonly used as a critical parameter in identifying potential gut health disorders [11]. In recent years, the field of gut microbiota research has experienced significant progress, driven by advancements in molecular biology, genomics, bioinformatics analysis technology, and high-throughput sequencing technology. This review elaborates on the involvement of the gut microbiome in chronic diseases like non-alcoholic fatty liver disease (NAFLD) and explores how it can be diagnosed, treated, and managed for prevention.

Gut microbiota dysbiosis in non-alcoholic fatty liver disease

In gut, the microbiota community plays a crucial role in various physiological processes within the human digestive system. Importantly, this community significantly contributes to functions like digestion, metabolism, and protective mechanisms. Several studies illustrate that different pathway of the gut microbiome are involved in the progression of NAFLD [12, 13]. The gut microbiota’s utilization of enzymes is vital for the efficient conversion of undigested polysaccharides into monosaccharides and the conversion of dietary fibers into short-chain fatty acids (SCFAs). This process is crucial as it provides essential energy support to the host cells. These SCFAs form a group of organic acids produced through bacterial fermentation of dietary fibers within the colon (Fig. 1). They have attracted considerable interest due to their potential health benefits, particularly in regulating metabolism, immune responses, the absorption of electrolytes and nutrients, as well as exhibiting anti-inflammatory and antitumor characteristics [14]. The daily production of SCFAs in the colon varies based on the intake of dietary fiber, usually falling within the range of 500 to 600 mmol. Among these SCFAs, acetate, propionate, and butyrate are notable for being the most abundant within the intestinal tract [15].

Fig. 1
figure 1

The involvement of gut microbiota and their resulting substances in the progression of NAFLD. The products generated by gut microorganisms, encompassing monosaccharides, short-chain fatty acids (SCFAs), bile acids (BAs), and trimethylamine oxide (TMAO), assume crucial roles not only in the liver’s energy metabolism and the cellular lining of the intestines but also exert a direct influence on the production of liver fat and overall systemic inflammation. A range of molecular elements come into play, including adenosine monophosphate-dependent protein kinase (AMPK), carbohydrate-responsive element-binding protein (ChREBP), Cytochrome P450 7A1 (CYP7A1), farnesoid X receptor (FXR), glucagon-like peptide-1 (GLP-1), G protein-coupled receptor 41/43 (GPCR41/43), peptide YY (PYY), sterol regulatory element-binding protein 1 (SREBP-1), and Takeda G protein receptor 5 (TGR5). Collectively, these elements contribute to these effects

Full size image

Acetic acid plays a significant role as a vital energy source for the body, contributing roughly 10% of the daily energy requirement. In contrast, butyric acid assumes a crucial function in providing energy to support epithelial cells, thereby playing a vital role in upholding the integrity of the intestinal barrier. Furthermore, it acts as the primary metabolic substance for the gastrointestinal microbiota, meeting at least 60–70% of their energy demands for growth and differentiation [44].

Transient elastography (FibroScan)

assist in diagnosing liver diseases and provide information about the fat presence and liver stiffness, they cannot substitute for a liver biopsy when it comes to accurately determining the histological subtypes and to guide appropriate clinical management and monitoring [45].

Vibration-controlled transient elastography (VCTE)

VCTE is a non-invasive medical imaging technique used to assess the stiffness or elasticity of the liver [46, 47]. This quick and painless procedure offers valuable information on liver fibrosis and cirrhosis. VCTE also aids in guiding treatment decisions and monitoring disease progression. However, it does not identify the underlying cause of liver disease.

Liver biopsy

Liver biopsy plays an important role as a diagnostic tool in differentiating between simple fatty liver and NASH and in assessing the state of fibrosis in NAFLD patients. This enables assessment of the degree of fibrosis, which provides valuable prognostic information and improves the clinical management of NAFLD [48,49,50]. However, it carries some risks and discomfort for the patient. Therefore, non-invasive methods are also employed to assess liver health and fibrosis in NAFLD patients. These non-invasive techniques include imaging studies such as transient elastography and blood tests (Fibrosis-4 Index and enhanced liver fibrosis tests) [51]. These methods offer valuable information about liver stiffness and fibrosis levels without the need for a liver biopsy, and they play a significant role in the clinical evaluation of NAFLD patients, providing an alternative or complementary approach to liver biopsy when appropriate.

Loomba etal. investigated the potential correlation between the gut microbiome and liver disease associated with obesity [52]. To explore this connection, Loomba analyzed two distinct sets of patients. The initial group encompassed 86 patients who were diagnosed with non-alcoholic fatty liver disease (NAFLD) via biopsy. Among them, 72 had mild to moderate NAFLD, while 14 had advanced-stage disease. The team employed sequencing techniques to scrutinize the microbial genes derived from stool samples provided by each participant. This allowed them to pinpoint the species present and their relative proportions. Noteworthy findings emerged, as they identified 37 bacterial species that could differentiate between mild/moderate NAFLD and advanced-stage disease. Remarkably, this differentiation accurately predicted advanced-stage disease in patients with an impressive 93.6% accuracy. To validate this discovery, a subsequent study involving 16 patients with advanced NAFLD and 33 healthy individuals as a control group was conducted. This phase revealed nine bacterial species that set apart NAFLD patients from the healthy volunteers, achieving an accuracy rate of 88%. Notably, seven of these bacterial species aligned with the previously discovered 37. The study demonstrated that patients with advanced NAFLD exhibited a higher prevalence of Proteobacteria and a lower presence of Firmicutes in their stool compared to those with early-stage NAFLD. At a more specific level, the abundance of E. coli was notably three times higher in patients with advanced NAFLD compared to those in the early stages of the disease.

Treatment

In recent years, a multitude of trials have investigated diverse medications with varying mechanisms of action in the context of NAFLD/NASH, yielding encouraging results. Within this specific context, we aim to provide a comprehensive overview of key clinical findings, alongside stratified pharmacological mechanisms designed to specifically target NAFLD. Effective drugs like vitamin E and Pioglitazone exist for treating and preventing NAFLD [53]. Pioglitazone has shown efficacy in cases involving advanced NASH patients with type 2 diabetes; However, this underscores the lack of reliable clinical data to fully support its use in this particular context. Vitamins E and D show certain effectiveness although uncertainty remains regarding their long-term safety and therapeutic efficacy. On the other hand, Statins can lower serum LDL levels and mitigating cardiovascular problems, but they do not address the progression of liver disease. Currently, there is no FDA-approved treatment for NAFLD. However, targeted therapies are in different phases of clinical trials. Table 1 outlines a number of encouraging drug contenders at various stages of clinical development for NAFLD.

Table 1 The current clinical scenario involving the use of agents that focus on the gut microbiota for the treatment of NAFLD
Full size table

Fecal microbiota transplantation (FMT)

FMT presents a novel approach for restoring and rebalancing the diversity of the gut’s microorganisms, aiming to address various diseases, including Clostridioides difficile infection [79]. Additionally, FMT has shown promise in treating metabolic diseases, tumors, autoimmune disorders, and hepatic encephalopathy [80,81,82]. Studies on animals have indicated that FMT can effectively improve the manifestations of NAFLD by addressing gut microbiota dysbiosis [83,84,85]. As a result, FMT has become an appealing option for NAFLD patients. However, there have been only a limited number of studies exploring the clinical efficacy of FMT in NAFLD treatment. One randomized control trial revealed that FMT has the potential to reduce small intestinal permeability in NAFLD patients [86, 87]. Moreover, FMT from healthy donors has been found to impact hepatic gene expression and plasma metabolites related to inflammation and lipid metabolism, demonstrating the significant interplay between gut microbiota composition and NAFLD.

Management of gut dysbiosis

Patients with NAFLD often follow high-calorie diets rich in carbohydrates and fats, contributing to obesity. Mitigating NAFLD risk involves replacing saturated and trans fats with healthier unsaturated fats, particularly omega-3 fatty acids. Opting for low-glycemic index foods such as fruits, vegetables, and whole grains is recommended as they have a milder effect on blood glucose compared to high-glycemic index foods like white bread and potatoes. Sugary beverages, notably high in sucrose and fructose, are linked to NAFLD and should be avoided [88, 89]. NAFLD’s connection to obesity emphasizes the need for gradual weight loss through balanced eating and exercise. Shedding 7 to 10% of body weight through diet and physical activity notably improves NAFLD and its more severe form, NASH, decreasing liver fat content and addressing fibrosis.

Regular physical activity, aiming for 150 min of moderate-intensity or 75 min of vigorous-intensity exercise weekly, positively impacts gut microbiome and liver health [90]. Emerging research indicates the significance of probiotics, prebiotics, and synbiotics in gastrointestinal health. These therapies target disrupted gut microbiota, which plays a pivotal role in NAFLD development. Probiotic and prebiotic supplementation have shown promise in reducing liver enzymes AST and ALT in damaged liver patients [91,92,93,94]. The intricate gut microbiota is essential for digestion, vitamin synthesis, immune training, and pathogen prevention. Antibiotic use, particularly fluoroquinolones, can disrupt this ecosystem, leading to reduced diversity and opportunistic infections.

Conclusion

The human gut microbiota plays a crucial role in maintaining various physiological processes and overall health. The intricate interactions between the gut microbiome, liver function, and immune responses have significant implications for the development and progression of non-alcoholic fatty liver disease (NAFLD). The dysbiosis of gut microbiota, characterized by alterations in microbial composition and metabolic activity, has been associated with NAFLD through its influence on digestion, energy metabolism, inflammation, and immune function. This review article has highlighted the role of short-chain fatty acids (SCFAs), bile acids, and gut-derived endotoxins in the development of NAFLD. SCFAs, produced by the fermentation of dietary fibers, have been shown to influence energy homeostasis, lipid metabolism, and inflammation. Bile acids, beyond their role in digestion, regulate various aspects of liver health, including lipid metabolism and inflammation. Dysbiosis-related alterations in SCFAs and bile acids contribute to liver inflammation and lipid accumulation, pivotal factors in NAFLD progression. Moreover, the disruption of the intestinal barrier integrity allows the translocation of bacterial products, including lipopolysaccharides (LPS), into the liver. This initiates an inflammatory response and oxidative stress, further promoting liver damage. The interplay between gut microbiota and the immune system has been shown to impact the progression of NAFLD, with dysbiosis promoting inflammation through the activation of pattern recognition receptors.

Diagnosis and management of NAFLD have also seen advancements in recent years. Non-invasive techniques such as transient elastography and blood tests have emerged as alternatives to liver biopsy for assessing liver fibrosis. Targeted therapies, including FXR agonists and antagonists, GLP-1 agonists, and thyroid hormone receptor agonists, are being investigated for their potential to address NAFLD at the molecular level. Furthermore, the potential of fecal microbiota transplantation (FMT) has garnered attention as a novel approach to restoring gut microbiota balance in NAFLD patients. Promising results from animal studies and limited clinical trials suggest that FMT could influence gut-liver crosstalk and potentially mitigate NAFLD-associated conditions. Lifestyle interventions remain crucial for managing NAFLD. Dietary modifications, physical activity, and weight loss continue to be cornerstones of NAFLD management, as they can positively impact gut microbiota composition and diversity. Probiotics, prebiotics, and synbiotics also hold promise in improving gut health and mitigating NAFLD risk.

In summary, the intricate relationship between gut microbiota, liver health, and NAFLD underscores the importance of understanding these interactions for the development of targeted therapeutic strategies. Advances in diagnostic techniques, treatment options, and lifestyle interventions are paving the way for a comprehensive approach to managing NAFLD by addressing gut microbiota dysbiosis and its implications for overall health. Further research in this field holds the potential to revolutionize our approach to preventing and treating NAFLD, a growing global health concern.