Dietary Influences on Gut Microbiota and Their Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.

Keywords: Mediterranean diet; Western diet; gut bacteria; intermittent fasting; ketogenic diet; liver disease.

Figure 1

Gut microbiota and hepatic inflammation. Overabundance of enteric microbial species such as Escherichia, Shigella, Anaeoplasma, and Butyricicoccus up-regulate inflammatory pathways such as NF-κB and NLRP3. This occurs through LPS-mediated activation of TLR4 and lipoteichoic-acid-mediated activation of TLR-2. The resulting microbial dysbiosis concurrently leads to gut barrier permeability, increased unfavorable gut metabolites such as TMAO, and activation of pro-inflammatory cytokines that enter nearby systemic circulation via the portal venous system. Once in the liver, these pro-inflammatory cytokines may activate hepatic stellate cells, triggering hepatic inflammation, lipid deposition, and fibrosis. Over time, this drives steatotic changes within the liver. Conversely, increased abundances of favorable microbiota such as Lactobacillus, Blautia, and Akkermansia have been shown to mitigate these adverse effects. Abbreviations: HSC, hepatic stellate cells; TMAO, trimethylamine-N-oxide; LPS, lipopolysaccharides; TLR4, toll-like receptor 4; TL2, toll-like receptor 2; NLRP3, NOD-, LRR-, and pyrin-domain-containing protein 3.

Figure 2

Gut microbial influence on lipogenesis and hepatic steatosis. Microbial dysbiosis induced by overgrowth of enteric bacterial genera including Escherichia, Salmonella, Streptococcus, and Fusobacterium leads to the overproduction of harmful bacterial metabolites such as 2-oleoylglycerol. These metabolites up-regulate lipogenic pathways in the liver. Specifically, expression of transcription factors SREBP1c and ChREBP are enhanced, which activates the lipogenic regulatory enzymes ACC and FAS. In turn, these enzymes increase triglyceride production and may result in fatty deposition in the liver. Alternatively, enhanced expression of SREBP1c and ChREBP increases cholesterol synthesis through increasing activity of HMG-CoA reductase, leading to increased formation of LDL, which may deposit in the liver to promote the development of hepatic steatosis. In contrast, favorable bacterial species such as Akkermansia, Lactobacillus, Dubosiella, and Alistipes may enhance AMPK expression, which inhibits lipogenic pathways to attenuate hepatic fat accumulation. Abbreviations: 2-OG, 2-oleoylglycerol; SREBP1c, sterol-regulatory-element-binding protein 1; ChREBP, carbohydrate-response-element-binding protein; ACC, acetyl-coenzyme A carboxylase; FAS, fatty acid synthase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; TG, triglycerides; LDL, low-density lipoprotein; AMPK, AMP-activated protein kinase.

Figure 3

Gut microbiota influence on bile acid pool and impact on hepatic steatosis. Bile acids are formed from cholesterol derivates via enzymes such as CYP7A1 and CYP8B1. This enzymatic conversion to bile acids yields CDCA and CA, which may be further modified by sequential enzymatic reactions or within the intestinal tract by gut microbial species. Once formed, bile acids are secreted from the liver into the small intestine, traveling to the terminal ileum where around 95% are reabsorbed through the portal venous system and returned to the liver. Conversely, in the intestinal tract, bile acids are subject to conjugation, primarily with the addition of glycine to produce GCA and GDCA or taurine to produce TCA or TDCA prior to being returned to the liver. Increased conjugation of bile acids disrupts bile acid metabolism and worsens hepatic steatosis. In states of dysbiosis, microbes with bile salt hydrolase enzymatic activity are relatively reduced, diminishing bacterial ability to deconjugate these conjugated bile acids, further worsening the cycle. This also leads to decreased activation of TGR5 and FXR bile acid receptors, leading to the up-regulation of inflammatory signaling pathways and hepatic fat accumulation. Meanwhile, supplementation of beneficial bacteria such as Eubacterium, Ruminococcus, or Bacteroides is shown to promote UDCA formation from CDCA through inherent hydroxysteroid dehydrogenase activity. UDCA is beneficial in attenuating hepatic steatosis. Abbreviations: CYP7A1, cholesterol 7α-hydroxylase; CYP8B1, sterol 12-α-hydroxylase; CDCA, chenodeoxycholic acid; CA, cholic acid; HSDH, hydroxysteroid dehydrogenase; UDCA, ursodeoxycholic acid; GCA, glycocholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; GCDCA, glycochenodeoxycholic acid; TGR5, Takeda G protein-coupled receptor 5; FXR, Farsenoid X receptor; Bsh, bile salt hydrolase; NLRP3, NOD-, LRR-, and pyrin-domain-containing protein 3.

Figure 4

Oxidative stress, hepatocyte damage, and hepatic steatosis. Lactobacillus spp. improve microbial barrier through production of butyrate. Butyrate can increase sirtunin 2 activity, which influences nuclear-factor-erythroid-2-related factor 2 (Nrf2) through deacetylation reactions, allowing its dissociation from inhibitor Kelch-like ECH-associated protein 1. This allows Nrf2 to translocate into the nucleus, activate the antioxidase response element, and increase transcription of antioxidases to mitigate oxidative stress and thereby improve hepatic steatosis. Conversely, dysbiosis, observed through overabundance of Clostridium sensu, Escherichia, and Enterococcus, can deplete glycine, an important precursor of a main antioxidase, glutathione. Similarly, this can induce reactive oxygen species formation and the up-regulation of NF-κB-mediated inflammation. Therefore, dysbiosis can reduce antioxidase production, increase reactive oxygen species, and induce inflammation within hepatocytes to worsen hepatic steatosis. Abbreviations: SIRT2, sirtunin 2; Nrf2, nuclear-factor-erythroid-2-related factor 2; KEAP1, Kelch-like ECH-associated protein 1; ARE, antioxidase response element; ROS, reactive oxygen species; NF-κB, nuclear factor kappa beta.

Figure 5

Effects of harmful dietary patterns on gut microbiota in MASLD. A high-fructose diet is shown to increase lipogenic pathways, impair fat oxidation, and induce inflammation and cellular stress. Low-protein diets deplete amino acid pools and induce inflammation. Saturated fatty acids confer lipotoxicity and cellular stress in hepatocytes while inducing insulin resistance. High-cholesterol diets also confer lipotoxicity, as well as mitochondrial and microcirculatory dysfunction. The Western diet impairs lipid metabolism, enhances lipid accumulation in the liver, and worsens oxidative stress and inflammation. Associated microbiota changes are shown within the figure. Abbreviations: ↑, increased abundance; ↓, decreased abundance.

Figure 6

Effects of beneficial dietary patterns on gut microbiota in MASLD. The Mediterranean diet is shown to improve systemic inflammation and improve metabolic parameters, observed through increased insulin sensitivity with the reduction of lipogenesis and associated hepatic fat accumulation. A ketogenic diet is shown to increase abundances of BSH-active bacterial species, thereby improving bile acid metabolism, improving MASLD parameters. Intermittent fasting enhances autophagy; clears excess lipid droplets from hepatocytes; and reduces oxidative stress, inflammation, and fibrosis. Diets high in fiber augment mitochondrial function and attenuate metabolic stress while mitigating systemic and hepatic inflammation. The microbial changes from these dietary interventions can slow the progression of MASLD through these mechanisms. Abbreviations: MedDiet, Mediterranean diet; KETO, ketogenic diet; ↑, increased abundance; ↓, decreased abundance, X, mitigates or reduces.