Diets high in sugar and fats cause microbiota dysbiosis, which impairs gut immune tolerance and contributes to increased risk of metabolic disorders (1). Being the primary metabolic organ, high-fat diet (HFD)-induced impairment in the metabolic profile of the liver can promote lipogenesis and inhibit free fatty acid (FFA) oxidation, which eventually progresses to non-alcoholic fatty liver disease (NAFLD) (2). NAFLD is a hepatic manifestation of metabolic syndrome and has become one of the most common causes of liver disease worldwide (3), accounting for a considerable burden on healthcare systems (4). Intracellular fat accumulation-induced steatosis and altered metabolic homeostasis are the primary features of NAFLD (5). A high prevalence of NAFLD (33.6%) was observed in patients with inflammatory bowel disease (IBD) (6). This suggests that an integrated coordination of the gut-liver axis (GLA) exists and is important for the maintenance of immune-metabolic homeostasis. This makes the GLA a promising therapeutic target for treating NAFLD.

As disturbances in gut integrity and dysbiosis impair the physiological function of the liver along the GLA, restoration of the microenvironment in the lower gut can be a potential and efficacious approach to ameliorating NAFLD (7), including dietary interventions aimed at maintaining gut microbiota composition, mucosal function, and barrier integrity, particularly prebiotics. Resistant starches (RSs) have been widely found in food sources rich in carbohydrates, such as corn, potato, and banana, which are often processed into a broad variety of foods (i.e., breads, cereals, pasta, snacks, and beverages). RSs are indigestible carbohydrates but fermentable for gut microbiota; thus, they are widely believed to be effective prebiotics that improve the production of short-chain fatty acids (SCFAs), which benefits the gut microbiome structure and overall human health (8). Current findings suggest that dietary supplementation with probiotics, functional oligosaccharides, and dietary fibers can help maintain gut bacterial balance and improve immune homeostasis in the gut, which is potentially beneficial for NAFLD amelioration (5, 9). However, the role and underlying mechanism of RSs in ameliorating NAFLD by enhancing gut microenvironment homeostasis remain largely unknown. This review aims to provide insights into RSs as a dietary strategy to alleviate liver disease conditions of NAFLD, with a particular focus on intestinal microecological changes from the perspective of the GLA (10).

The underlying mechanisms for the development and progression of NAFLD are complex. The interdependence between the gut and liver forms a close integration of their molecular and physiological functions, playing a key role in the integrated pathogenesis of NAFLD, as shown in Figure 1 (10, 11). The excessive intake of high calories promotes the accumulation of fat in visceral and subcutaneous adipose tissues, where the amounts of FFAs and total glycerol are dramatically increased. As such, NAFLD eventually developed. Moreover, there is a clear causal link between NAFLD and dysbiosis of the gut microbiota. Patients with NAFLD tend to have increased intestinal permeability and microbiota dysbiosis (12, 13). Dysfunction and dysregulation of the intestinal barrier and dysbiosis impair mucosal immune tolerance, leading to systemic inflammation and disturbing liver immune metabolism homeostasis.

The intestinal barrier is a complex functional unit composed of lumen and mucosal components (i.e., epithelial cell layer, mucosal barrier, and innate and acquired immune components), neurointestinal, vascular, and endocrine systems, digestive enzymes, and gut microbiota (14). In addition to the epithelial layer and mucus, recent evidence has characterized the gut-vascular barrier, which prevents the translocation of bacteria directly into portal circulation (15). However, the loss of gut barrier integrity and mediated translocation of the gut microbiome evokes a toll-like receptors (TLR)-mediated pro-inflammatory cascade in the liver (16–18). In addition, pathogenic bacteria from the intestinal microbiota can interactively regulate IL-17A production from immune or non-immune cells, which plays a major role in regulating gut mucosal immunity and pathogenesis of NAFLD, and thus accelerates the progression of NAFLD, a highly related complication of atherosclerosis (19–22). Moreover, pathogenic bacterial metabolites [i.e., lipopolysaccharides (LPS) and ethanol] from the lumen to the circulation rapidly relay information to the brain and damage the periphery, mainly in the liver and adipose tissues, by altering the central neurotransmitter systems (5). The vagus nerve in the gut can be directly activated by inflammatory signals to impair insulin sensitivity and hepatic steatosis associated with liver inflammation by altering the central neurotransmitter system (23). Available research demonstrates the role of enterohepatic axis dysfunction in the development of NAFLD; the underlying mechanisms can be summarized as: (1) alterations in the gut microbiome profile and immune responses; (2) the effects of gut bacterial components and metabolites, such as LPS, endogenous ethanol (EnEth), and SCFAs; and (3) the impairment of intestinal barrier function and bile acid (BA) homeostasis (24). Owing to the inflammatory tone, metabolic homeostasis and functionality of the liver are impaired, leading to an increased risk of developing metabolic disorders, particularly NAFLD.

Resistant starches are defined as the total amount of starch and starch degradation products that resist digestion in the small intestine, and are therefore recognized as a typical prebiotic (25). Naturally occurring RSs are widely found in cereal grains, seeds, heated starches, and starch-containing foods (26). Furthermore, RSs are classified into five types (RS1–RS5) according to their source and processing procedure. RS1 are starch granules that occur in some indigestible plant materials, such as whole grains; RS2 are native granular starches, such as raw potatoes, green bananas, gingko, or high-amylose maize; RS3 are retrograded amylose starch or crystallized starches, such as cooked and cooled starchy foods; RS4 are chemically modified starches produced via esterification, cross-linking, or transglycosylation; and RS5 are amylose-lipid complex, amylose, and long branch chains of amylopectin from single-helical complexes with fatty acids and fatty alcohols when the starch molecules interact with lipids (27, 28). As humans do not have the enzymes to digest RSs, gut microbes ferment RSs to benefit the host by selectively stimulating the growth of intestinal epithelial cells and probiotic strains in the lower gut, thereby improving the overall health of the host (29). The gut bacterial fermentation of prebiotics increases the concentration of SCFAs in the cecum and portal vein blood, which are eventually transported through the blood circulation to various internal organs and tissues, as shown in Figure 2. Simultaneously, the altered intestinal metabolomic profiles and associated bioactive metabolites may be involved in the regulation of signaling cascades in the GLA, exerting beneficial effects on the host (Figure 2). Emerging evidence from animal studies strongly demonstrates the efficacy of RSs in the prevention or treatment of various diseases [e.g., IBD, inflammatory bowel syndrome, colon cancer, obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease]; however, the data in humans remain ambiguous. The possible mechanism of RSs in ameliorating NAFLD from the perspective of the GLA is still unknown, warranting further in-depth studies.

Lifestyle interventions, such as eating a healthy diet and regular exercise, are among the most effective and safe ways to mitigate NAFLD, as well as other types of metabolic disorders. Recent evidence has highlighted the preventive and therapeutic effects of some plant foods, particularly those rich in bioactive polyphenols, carotenoids, oleic acid, n-3 polyunsaturated fatty acids, and fiber (30–32). RSs, being food components, have physiological properties similar to those of fermentable dietary fibers. It has been found that RS intake reduces fat accumulation to improve insulin sensitivity, thereby maintaining blood glucose levels and lipid metabolic homeostasis (27, 33). A human study confirmed that RSs significantly improved insulin and low-density lipoprotein cholesterol (LDL-C) levels in obese patients (34). Furthermore, supplementation of green bananas rich in RSs in NAFLD model mice was shown to improve SCFAs production and reduce hepatic steatosis by regulating the transporters involved in lipid excretion and adipogenesis (35). A previous finding illustrated that RSs exhibit the ability to lower serum cholesterol by interacting with BAs, which might be related to the increased expression of hepatic cholesterol 7α-hydroxylase (CYP7A1) and fecal BA excretion (33). Overall, RSs may be a promising dietary approach for the alleviation of NAFLD by maintaining lipid metabolic homeostasis (Table 1). However, the understanding of how RS intake contributes to ameliorating NAFLD remains scarce. It is necessary to explore the molecular basis of RSs sustaining the integrated gut homeostasis involved in the symbiotic microbiota, mucosal immune response, and metabolism toward prevention or mitigate NAFLD. Moreover, clinical studies are needed to investigate the regulatory effects of RS intake in patients with NAFLD.

The intestinal microecology, consisting of intestinal microbiota, intestinal epithelial cells, and the immune system, may play a role in energy metabolism (36). Recent human and rodent studies on obesity-related metabolic disorders have suggested that the gut microbiome plays a key role in NAFLD pathogenesis (37). The long-term consumption of diets high in calories and saturated fat may lead to dysbiosis in the gut microbiota. This, in turn, would evoke an imbalance in the BA pool and a dysfunctional intestinal barrier, followed by increased translocation of bacteria and accumulation of bacterial-derived products in the liver, which play significant roles in the development of NAFLD as summarized in Figure 2. RSs are an energy source for symbiotic microbiota and are fermented to release SCFAs, which in turn are beneficial for the growth of colonic cells, thus enhancing the mucosal barrier function. The regulatory effects of RSs on NAFLD mainly occur in the gut, where RSs contribute to the restoration of microbiota structure, an increase in SCFA release, and enhanced gut barrier integrity. The specific mechanisms by which RSs alleviate NAFLD by promoting overall gut health are described in the following sections.

Non-alcoholic fatty liver disease imposes a substantial economic burden on developing or developed countries worldwide. The high prevalence of NAFLD and less effective pharmaceutical treatments have led to new and alternative therapeutic approaches for NAFLD based on multiple factors, including dietary impact, gut microbiota structure, hormone secretion, and intestinal and systemic immune responses (96). The mechanism underlying the development of impaired liver function depends on the host-microbe-metabolic interplay along the GLA, a critical basis for rationalizing the use of dietary supplementation as a therapeutic strategy. A review of recent literature shows that dietary RSs, as prebiotics, contribute to the restoration of a healthy gut microbiota structure, beneficial for maintaining gut barrier integrity and mucosal immune tolerance. This eventually leads to the prevention of pathogenic invasion and endotoxemia-mediated metabolic syndrome. Moreover, gut bacterial metabolites released after RS intake promote the growth of intestinal epithelial cells and act as key molecules that interact with a broad range of sensing receptors along the GLA, including GPR41, GPR43, FXR, PXR, and TGR5. Upon ligand binding, SCFAs and secondary BA elicit a series of signaling cascades in the intestine and liver to sustain immune metabolic homeostasis (Figure 3). These findings strengthen our understanding of how interactions between the gut microbiota and host regulate immune-metabolic crosstalk in the GLA at the molecular level. This provides insights into the dietary-immune-metabolic interplay by which the gut microbiome profiles and immune-metabolic homeostasis are well maintained. However, existing studies on the health-promoting effects of RSs on NAFLD are still scarce; thus, the differences among various types of RSs in NAFLD prevention are unclear. In addition, a variety of microbiota-derived metabolites may permeate the blood–brain barrier and enter the central nervous system; however, their implication in the pathogenesis of NAFLD is still unknown. Future research on the role of RSs in NAFLD should focus on the following: (1) elucidating the effect of different types of RSs and the roles of their distinct metabolite profiles after colonic fermentation; (2) analyzing the effect of the particular metabolic profile of different RSs on microbiota composition at the species level; and (3) understanding the relationship between specific RSs and typical gut microbial strains and how they modulate factors associated with NAFLD.

WZ: conceptualization and writing the review. YZ: data collection and original draft of the manuscript. RT: writing the review and editing. HD: writing and funding acquisition. HZ: project administration, manuscript revising and editing, and funding acquisition. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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