Gut microbiota in gastrointestinal diseases: Insights and therapeutic strategies

Abstract

Considering the bidirectional crosstalk along the gut-liver axis, gut-derived microorganisms and metabolites can be released into the liver, potentially leading to liver injury. In this editorial, we comment on several studies published in the recent issue of the World Journal of Gastroenterology. We focus specifically on the roles of gut microbiota in selected gastrointestinal (GI) diseases that are prevalent, such as inflammatory bowel disease, metabolic dysfunction-associated steatotic liver disease, and hepatitis B virus-related portal hypertension. Over the past few decades, findings from both preclinical and clinical studies have indicated an association between compositional and metabolic changes in the gut microbiota and the pathogenesis of the aforementioned GI disorders. However, studies elucidating the mechanisms underlying the host-microbiota interactions remain limited. The purpose of this editorial is to summarize current findings and provide insights regarding the context-specific roles of gut microbiota. Ultimately, the discovery of microbiome-based biomarkers may facilitate disease diagnosis and the development of personalized medicine.

Key Words: Gut microbiota; Inflammatory bowel disease; Metabolic dysfunction-associated steatotic liver disease; Hepatitis B virus; Portal hypertension

Core Tip: Alterations in gut microbiota are closely associated with the pathogenesis of various gastrointestinal diseases. A deeper understanding of host-microbiota interactions could aid in the development of therapeutic interventions for humans.

TO THE EDITOR

The human gut microbiota, composed of bacteria, archaea, bacteriophages, eukaryotic virus and fungi, participates multiple aspects of host physiology throughout life[1]. The composition of gut microbiota can be affected by many factors, such as birth mode, diet, medication, environment, and the genetics of the host[2]. With the vast majority of microbiota resides in the gastrointestinal tract, perturbation of host-microbe interaction is associated with the pathogenesis of a variety of gastrointestinal diseases[3]. The liver receives portal blood from the gastrointestinal tract, making it the first organ exposed to intestinal microorganisms and their products. Additionally, the liver produces bile, which can be secreted into the biliary system and released directly into the small intestine[4]. The development of metabolic and infectious liver diseases is associated with the disturbed gut-liver axis through different mechanisms, such as alterations in bacterial composition, dysregulation of bile acid metabolism, diet, environmental influences, and genetic predispositions[5,6].

Here, we discuss the taxonomic and functional characteristics of the gut microbiota in selected gastrointestinal diseases that are pandemically spread during the past few decades, such as inflammatory bowel disease (IBD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatitis B virus (HBV)-related portal hypertension (PH). By evaluating recent publications, we summarize the main findings describing the associations between alterations in gut microbiota and the pathogenesis of diseases. Understanding the microbiota-host interactions may lead to substantial progress in precision medicine.

Gut microbiota and IBD

IBD, consisting of Crohn’s disease (CD) and ulcerative colitis, is a set of chronic inflammatory conditions with unknown etiology. The occurrence of IBD results from a combination of genetic predisposition, environmental influences, and gut microbiota, with each component being essential yet individually inadequate to trigger the disease[7]. An increasing number of studies suggest that alterations in the composition and function of gut microbiota are associated with the pathogenesis of IBD, which is characterized by lower microbial diversity and overgrowth of facultative anaerobes[8,9]. Additionally, recent research has underscored the significance of mesenteric adipose tissue (MAT) and creeping fat in the development of CD[10]. Wu et al[11] investigated the interplay among MAT, creeping fat, intestinal inflammation, and gut microbiota in patients with CD. Histopathological analyses indicated that there were distinct pathological characteristics of MAT in colons affected by CD compared to those that were not. Transplantation of fetal microbiota (FMT) from healthy donors into mice with colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) led to a notable improvement in colitis symptoms. In contrast, FMT sourced from CD patients worsened the symptoms in these mice. Importantly, the process of FMT had an impact on intestinal permeability, barrier integrity, and the concentrations of proinflammatory factors and adipokines. Additionally, FMT derived from CD patients aggravated the fibrotic alterations observed in the colonic tissues of mice with TNBS-induced colitis. This novel study emphasizes the important roles of gut microbiota in regulating MAT and creeping fat in the context of CD. Targeting these elements may offer therapeutic benefits in clinic.

Gut microbiota and chronic liver diseases

MASLD, formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by the presence of SLD alongside one or more cardiometabolic risk factors without excess alcohol intake[12]. As treatments for MASLD advance, the role of traditional Chinese medicine has gained increasing interest. The Fanlian Huazhuo Formula (FLHZF) is a traditional Chinese medicine formula that has been utilized for managing type 2 diabetes mellitus[13]. Niu et al[14] investigated the effects of FLHZF on NAFLD pathogenesis in vivo and in vitro. In mice fed with high-fat diet (HFD), FLHZF treatment significantly improved lipid accumulation. Further analyses revealed that FLHZF treatment improved HFD-induced lipid dysregulation by decreasing oxidative stress, activating AMPK and autophagy, while reducing hepatocyte apoptosis. This study broadens the application of FLHZF and provides an additional therapeutic option for NAFLD. Future studies are required to verify the effects of FLHZF in patients with NAFLD, and the potential toxic effects should also be examined to avoid side effects.

In patients with MASLD, coronavirus disease 2019 (COVID-19) increases the risk of liver injury and the development of COVID-19-associated cholangiopathy[15]. Previous studies suggest that angiotensin-converting expression enzyme 2 (ACE2) is critical for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attachment and host cell invasion[16]. To determine whether hepatic ACE2 expression is altered in patients with MASLD or COVID-19, Jacobs et al[17] analyzed the protein levels and localization of ACE2 in MASLD patients across different spectrum. They showed that the levels of the ACE2 protein were increased in non-fibrotic metabolic dysfunction-associated steatotichepatitis (MASH) when compared to healthy controls. However, this elevation was not observed in patients with fibrotic MASH or cirrhosis. In patients with COVID-19, hepatic ACE2 levels were also increased, and there was a clear association between lipid content and the presence of virus. Consistently, a previous study showed that the SARS-CoV-2 virus may use lipid droplets as a template for intra-hepatic viral replication, potentially leading to direct viral-induced liver injury or by disrupting mitochondrial function[18]. Therefore, the current study provides further evidence linking COVID-19 infection with the progression of MASLD. Patients with MASLD should remain vigilant regarding COVID-19 infection and associated cholangiopathy.

In addition to MASLD, the role of gut microbiota has also been implicated in patients with PH secondary to liver cirrhosis[19]. Liver cirrhosis can be caused by alcohol-related liver disease, MASLD, and hepatitis C infection worldwide, while it is mainly caused by HBV infection in China[20]. The most effective treatment for complications associated with PH is the transjugular intrahepatic portosystemic shunt (TIPS) procedure, as recommended by current guidelines. Zhao et al[21] investigated the alterations of gut microbiota profile in patients with HBV-related PH after TIPS procedure. Among all patients received TIPS, 8 of them developed hepatic encephalopathy (HE), and 22 patients did not (non-HE group). At the phylum level, there was no difference between the two groups. In the HE group, the abundance of Haemophilus and Eggerthella increased, while the abundance of Anaerostipes, Dialister, Butyricicoccus, and Oscillospira decreased. In the non-HE group, the abundance of Eggerthella, Streptococcus, and Bilophila increased, whereas the levels of Roseburia and Ruminococcus decreased. This study highlights the potential role of gut microbiota in predicting the occurrence of HE following the TIPS procedure. Targeting specific microbiota may be beneficial for the prevention and treatment of HE.

In summary, the gut microbiota has critical physiological roles in host immunity, digestion, and metabolism[22]. With the advancement of high-throughput sequencing technology, both observational and experimental data illuminate the contribution of gut microbiota in gastrointestinal diseases. Here, we reviewed studies focusing on the role of gut microbiota in three common conditions, CD, MASLD, and PH induced by HBV-associated liver cirrhosis. These studies not only characterized the taxonomic alterations of gut microbiota, but also provide additional information for clinical therapy. Future studies in larger cohorts are necessary to validate these findings. Beyond the association studies, investigating the mechanisms underlying the host-microbiota interactions is challenging yet informative. Finally, development of microbiome-based medicine or integrating microbiota manipulation with other treatment options will be intriguing for better therapeutic effects.