Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), encompasses patients who have hepatic steatosis and have at least one of five cardiometabolic risk factors, corresponding to an inclusion diagnosis (1). It includes a spectrum of liver conditions, including metabolic dysfunction-associated steatotic liver (MASL) or simple steatosis, and metabolic dysfunction-associated steatohepatitis (MASH) (2). The latter is characterized by inflammation and hepatocyte injury, representing a more severe process of liver damage. MASH is often accompanied by fibrosis and has the potential to progress to cirrhosis (3). The global prevalence of MASLD is estimated to be 30% and has increased 50.4% in the last three decades (4), highlighting its significance as a public health concern. On the other hand, obesity is one of the major health and socioeconomic problems in humans, and it is strongly correlated with MASLD (5). Indeed, the prevalence of MASLD is 50%−90% among individuals with obesity, and the prevalence of obesity in MASLD is 51% (6).

The pathophysiology of MASLD is complex and partially understood (7). Various contributing factors play a role in the development and progression of MASLD, including genetic factors, oxidative stress, impaired adipose tissue function, dysregulation of the immune system, and alterations in the microbiota-gut-liver axis (8, 9). The latter is associated to disruption of the intestinal barrier function provoked by an altered microbiota that leads to an increased gut permeability (10, 11). As a consequence, increased translocation of bacterial products to the liver allows Kupffer cells activation mediated by pattern recognition receptors, such as Toll-like receptors (TLRs), triggering an inflammatory response in the liver (12, 13). Likewise, hepatocytes, hepatic stellate cells, and endothelial cells are also activated, promoting pro-inflammatory and pro-fibrotic reactions and cellular stress by similar mechanism (13–15).

MASLD and obesity are significantly associated with small intestinal bacterial overgrowth (SIBO) (5, 16). SIBO is defined as the presence of abnormal and excessive amount of bacteria in the small intestine (17), which is associated with changes in microbiota composition (18, 19). Several studies have evaluated the role of microbiota modulation through probiotics and synbiotics and reported and improvement in the liver function and metabolic parameters of MASLD patients (20).

The role of SIBO in MASLD progression in obese patients remains unknown, especially regarding its relationship with the fibrotic pathogenic process.

In this study, we aimed to determine the association between SIBO and the severity of MASLD in obese patients.

The results of our study demonstrated that obese patients with MASLD had notably higher prevalence rates of SIBO when compared to obese patients without MASLD. This finding is consistent with previous studies that have reported a positive correlation between MASLD and SIBO (16, 23). Additionally, this study found no correlation between the presence of SIBO and the severity of hepatic steatosis in MASLD patients, contrary to the results of Sabaté et al. which observed that the presence of SIBO is associated with the liver steatosis degree in MASLD patients (24). SIBO was positively correlated with the presence of fibrosis (p = 0.0026), highlighting the potential role of the SIBO and intestinal microbiota in the progression of MASLD toward liver fibrosis. Indeed, it has been previously reported that patients with liver fibrosis exhibits microbiome characteristics and corresponding alterations in functionality, which could potentially facilitate the development of oxidative stress and a state of inflammation (25). Also, there are studies of association between severity of fibrosis and changes in the intestinal microbiota (26). It is worth mentioning that many observational studies have shown that biopsy-confirmed liver fibrosis is a major predictor of liver-related and overall mortality in MASLD patients (27). Regarding underlying mechanisms, animal studies provides potential links between intestinal dysbiosis and liver fibrosis, including an increased 2-oleoylglycerol macrophage priming (28) unfavorable intrahepatic immune microenvironment, characterized by abnormal distribution and the activation of immune cell subsets due to T cell receptor immune repertoire rearrangement (29); this mechanisms ultimately leads to hepatic stellate cells activation and hepatic fibrogenesis. This evidence suggests that SIBO might contribute to HSC activation and fibrogenesis. Further research is needed to elucidate the underlying mechanisms linking SIBO and MASLD.

On the other hand, it has been suggested that SIBO may contribute to the development of MASLD by inducing gut permeability and systemic inflammation, leading to the development of metabolic disorders, including insulin resistance (30–32). Also, gut microbiota differences between obese patients with or without MASLD has been previously reported by Jin and Xu (33), the gut microbiota composition was similar between obesity with MASLD and simple obesity, but the Faecalibacterium prausnitzii colony number was much lower in the obesity with MASLD than in the simple obesity. Modulation of microbiota through probiotics such as Lactobacillus used as a therapeutic approach for MASLD may be beneficial, and has been proved to be beneficial in experimental MASLD (34). Other microbiota modulation approaches may be beneficial, in humans Gravina et al. investigated the effects of bicarbonate–sulfate–calcium–magnesium water, low in sodium, on the microbiota and potential metabolic outcomes in patients with MASLD. Following a six-month intervention, they observed an increase in GLP-1 levels. However, no significant changes were observed in the degree of steatosis, insulin resistance, transaminase levels, or BMI values. Notably, the study reported a significant reduction in the microbiota genus of Blautia, Collinsella, and Bifidobacterium adolescentis, typically decreased in MASLD, while an increase was observed in the genus of Subdoligranulum and Dorea, typically decreased in MASLD patients (35). And furthermore, Gravina et al. (36) also reported a positive impact on functional gastrointestinal symptoms in patients with MASLD.

SIBO is usually treated with antibiotics, such as rifaximin, which also has been shown to reduce endotoxemia levels and liver enzymes in MASLD patients (37). In the study of Gangaparu et al. (38) the treatment of 42 patients diagnosed with MASLD using rifaximin at a dosage of 1,200 mg for 28 days, resulted in a significant reduction in both endotoxemia levels and serum transaminases in the treated patients. While the duration of rifaximin treatment used in the study by Gangarapu et al. differs from the standard duration typically used in SIBO treatment which is generally shorter, usually around 2 weeks, the findings highlight the potential significance of evaluating SIBO treatment in patients with MASLD as a therapeutic approach to ameliorate the disease progression toward fibrosis. However, further studies are necessary to evaluate the role of SIBO treatment in MASLD progression.

It has been proposed that SIBO could promote MASLD through increased inflammation, bile salt deconjugation, decreased intestinal barrier integrity, increased bacterial translocation, and endotoxemia. Likewise, MASLD may promote SIBO through increased oro-cecal transit time, altered bile acid metabolism, and increased insulin resistance. The connection between these two conditions highlights the similarity in the pro-inflammatory signaling pathways associated with both MASLD and SIBO (37).

MASLD in humans is associated with increased gut permeability. This abnormality is related to the increased prevalence of SIBO in these patients (39). In patients with morbid obesity and MASLD, a greater frequency of SIBO is observed with an increasing degree of hepatic steatosis and associated with higher circulating levels of LPS-binding protein (LBP) (40). While our study did not find a correlation between SIBO and the degree of steatosis in MASLD, previous evidence suggests that increased endotoxemia may play a role in SIBO induced progression of MASLD toward fibrosis. A study conducted by Scarpellini et al. (41) investigated the relationship between SIBO, endotoxemia levels, and the severity of liver fibrosis. Their findings demonstrated a significant association between the prevalence of SIBO, elevated levels of endotoxemia, and liver fibrosis. This evidence suggests that SIBO-related endotoxemia may contribute to fibrosis progression in MASLD.

However, it is important to note that the underlying mechanisms linking SIBO, endotoxemia, and fibrosis progression in MASLD are not fully understood and require further investigation. Additional studies are needed to elucidate the complex interactions between gut microbiota, intestinal permeability, endotoxin release, and the development and progression of liver fibrosis in MASLD. In contrast, Guimarães et al. (42) found no significant association between SIBO and elevated serum endotoxin levels in non-cirrhotic patients with MASLD.

It is important to consider that the relationship between SIBO and MASLD is complex and multifactorial. Various factors, such as differences in study populations, diagnostic criteria, and methodologies used, could contribute to the conflicting results observed across different studies.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by Ethical Committee of the University of Chile Clinical Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

NO-L: Data curation, Formal analysis, Writing – original draft, Writing – review & editing, Conceptualization, Investigation. AM: Conceptualization, Investigation, Supervision, Formal analysis, Writing – original draft, Writing – review & editing, Data curation, Methodology, Resources, Validation. LA: Data curation, Writing – original draft, Writing – review & editing, Formal analysis. AZ: Writing – review & editing, Methodology, Formal analysis, Software. GS: Investigation, Methodology, Writing – original draft, Writing – review & editing, Formal analysis. LV-P: Conceptualization, Writing – original draft, Writing – review & editing, Formal analysis. JP: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Investigation. CB: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Data curation, Formal analysis, Resources, Software.