TRIF-dependent signaling and its role in liver diseases.

TIR domain-containing adaptor inducing IFN-ß (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-ß) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.

A universal plasma metabolites-derived signature predicts cardiovascular disease risk in MAFLD.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, which is more practical for identifying patients with fatty liver disease with high risk of disease progression. Fatty liver is a driver for extrahepatic complications, particularly cardiovascular diseases (CVD). Although the risk of CVD in MAFLD could be predicted by carotid ultrasound test, a very early stage prediction method before the formation of pathological damage is still lacking. METHODS: Stool microbiomes and plasma metabolites were compared across 196 well-characterized participants encompassing normal controls, simple MAFLD patients, MAFLD patients with carotid artery pathological changes, and MAFLD patients with diagnosed coronary artery disease (CAD). 16S rDNA sequencing data and untargeted metabolomic profiles were interrogatively analyzed using differential abundance analysis and random forest (RF) machine learning algorithm to identify discriminatory gut microbiomes and metabolomic. RESULTS: Characteristic microbial changes in MAFLD patients with CVD risk were represented by the increase of Clostridia and Firmicutes-to-Bacteroidetes ratios. Faecalibacterium was negatively correlated with mean-intima-media thickness (IMT), TC, and TG. Megamonas, Bacteroides, Parabacteroides, and Escherichia were positively correlated with the exacerbation of pathological indexes. MAFLD patients with CVD risk were characterized by the decrease of lithocholic acid taurine conjugate, and the increase of ethylvanillin propylene glycol acetal, both of which had close relationship with Ruminococcus and Gemmiger. Biotin l-sulfoxide had positive correlation with mean-IMT, TG, and weight. The general auxin pesticide beta-naphthoxyacetic acid and the food additive glucosyl steviol were both positively correlated with the increase of mean-IMT. The model combining the metabolite signatures with 9 clinical parameters accurately distinguished MAFLD with CVD risk in the proband and validation cohort. It was found that citral was the most important discriminative metabolite marker, which was validated by both in vitro and in vivo experiments. CONCLUSIONS: Simple MAFLD patients and MAFLD patients with CVD risk had divergent gut microbes and plasma metabolites. The predictive model based on metabolites and 9 clinical parameters could effectively discriminate MAFLD patients with CVD risk at a very early stage.

Rifaximin Prevents Intestinal Barrier Dysfunction and Alleviates Liver Injury in MCT-induced HSOS Mice.

OBJECTIVE: Rifaximin is an effective component of treatment strategies for liver and intestinal diseases. However, the efficacy of rifaximin in hepatic sinusoidal obstruction syndrome (HSOS) has not been explored. The present study aimed to investigate the efficacy and mechanism of rifaximin in HSOS. METHODS: An HSOS model was established in mice through the administration of monocrotaline (MCT, 800 mg/kg), and part of the HSOS mice were intragastrically administered with rifaximin. Then, the efficacy of rifaximin in HSOS was evaluated based on the liver pathological findings, liver proinflammatory cytokines, and alanine aminotransferase and aspartate aminotransferase levels. The Ussing chamber was used to evaluate the intestinal permeability, and tight junction (TJ) proteins were measured by Western blotting and real-time polymerase chain reaction to evaluate the intestinal barrier integrity. Then, the serum proinflammatory cytokine levels were evaluated by enzyme-linked immunosorbent assay. Afterwards, an in vitro experiment was performed to determine the relationship between rifaximin and TJ proteins. RESULTS: Rifaximin effectively alleviated the MCT-induced HSOS liver injury, suppressed the expression of liver proinflammatory cytokines, and reduced the serum levels of tumor necrosis factor-alpha and interleukin-6. Furthermore, rifaximin reduced the intestinal permeability, improved the intestinal barrier integrity, and promoted the expression of TJ proteins. CONCLUSION: The results revealed that the intestinal barrier integrity was destroyed in MCT-induced HSOS. The significant alleviation of MCT-induced HSOS induced by rifaximin might be correlated to the repairment of intestinal barrier integrity via the regulation of the TJ protein expression.

The Crosstalk between Gut Microbiota and Bile Acids Promotes the Development of Non-Alcoholic Fatty Liver Disease.

Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD.

A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.

The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.

Targeting Gut Microbiota for the Treatment of Primary Biliary Cholangitis: From Bench to Bedside.

Primary biliary cholangitis (PBC) is a complex cholestatic liver disease with an unresolved etiology. The gut microbiota is composed of a dynamic community of bacteria, archaea, fungi, and viruses that have a key role in physiological processes related to nutrition, immunity, and host defense responses. A number of recent studies found that the composition of the gut microbiota of PBC patients was significantly altered, and reported that gut dysbiosis might arise during PBC development because of the close interactions of the liver and the gut. In light of the growing interest in this topic, the focus of this review is to characterize PBC gut microbiota alterations, the correlation between PBC pathology and the gut microbiota, and prospective therapies that target the altered gut microbiota, such as probiotics and fecal microbiota transplantation.

The Novel Role of Phage Particles in Chronic Liver Diseases.

The gut microbiome is made up of bacteria, fungi, viruses and archaea, all of which are closely related with human health. As the main component of enterovirus, the role of bacteriophages (phages) in chronic liver disease has been gradually recognized. Chronic liver diseases, including alcohol-related liver disease and nonalcoholic fatty liver disease, exhibit alterations of the enteric phages. Phages shape intestinal bacterial colonization and regulate bacterial metabolism. Phages adjoining to intestinal epithelial cells prevent bacteria from invading the intestinal barrier, and mediate intestinal inflammatory response. Phages are also observed increasing intestinal permeability and migrating to peripheral blood and organs, likely contributing to inflammatory injury in chronic liver diseases. By preying on harmful bacteria, phages can improve the gut microbiome of patients with chronic liver disease and thus act as an effective treatment method.

Contribution of gut microbiota to drug-induced liver injury.

Drug-induced liver injury (DILI) is caused by various drugs with complex pathogenesis, and diverse clinical and pathological phenotypes. Drugs damage the liver directly through drug hepatotoxicity, or indirectly through drug-mediated oxidative stress, immune injury and inflammatory insult, which eventually lead to hepatocyte necrosis. Recent studies have found that the composition, relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly. It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation, and the alteration of microbial metabolites may cause or aggravate DILI. In addition, antibiotics, probiotics, and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota. In this review, we discussed how the altered gut microbiota participates in DILI.

Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS: The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW: Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.

Ferroptosis in non-alcoholic liver disease: Molecular mechanisms and therapeutic implications.

Ferroptosis refers to a novel modality of regulated cell death characterized by excessive iron accumulation and overwhelming lipid peroxidation, which takes an important part in multiple pathological processes associated with cell death. Considering the crucial roles of the liver in iron and lipid metabolism and its predisposition to oxidative insults, more and more studies have been conducted to explore the relationship between ferroptosis and various liver disorders, including non-alcoholic fatty liver disease (NAFLD). With increased morbidity and high mortality rates, NAFLD has currently emerged as a global public health issue. However, the etiology of NAFLD is not fully understood. In recent years, an accumulating body of evidence have suggested that ferroptosis plays a pivotal role in the pathogenesis of NAFLD, but the precise mechanisms underlying how ferroptosis affects NAFLD still remain obscure. Here, we summarize the molecular mechanisms of ferroptosis and its complicated regulation systems, delineate the different effects that ferroptosis exerts in different stages of NAFLD, and discuss some potential effective therapies targeting ferroptosis for NAFLD treatment, which putatively points out a novel direction for NAFLD treatment.

Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease.

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.

Change in onset age of first primary colorectal cancer in the USA.

PURPOSE: Identifying the onset age of cancer is essential for its early intervention. The aim of this study was to characterize the features and investigate the variation tendency of first primary colorectal cancer (CRC) onset age in the USA. METHODS: For this retrospective population-based cohort analysis, data on patients diagnosed with first primary CRC (n = 330,977) between 1992 and 2017 were obtained from the Surveillance, Epidemiology, and End Results dataset. Annual percent changes (APC) and average APCs were calculated to examine the changes in average age at CRC diagnosis using the Joinpoint Regression Program. RESULTS: From 1992 to 2017, the average age at CRC diagnosis decreased from 67.0 to 61.2 years, declining by 0.22% and 0.45% annually before and after 2000. The age at diagnosis was lower in the distal than in the proximal CRC cases and the age has the downward trends in all subgroups of sex, race, and stage. Over one-fifth of CRC patients were initially diagnosed with distantly metastatic CRC, with the age lower than that in localized CRC cases (63.5 vs 64.8 years). CONCLUSIONS: The first primary CRC onset age has decreased significantly in the USA over the last 25 years and the modern lifestyle may be responsible for the decline. Specifically, the age of proximal CRC is invariably higher than that of distal CRC. Moreover, the age of advanced stage is lower than that of the early stage. Clinicians should adopt earlier screening age and more effective screening techniques for CRC.

Modulating phenylalanine metabolism by L. acidophilus alleviates alcohol-related liver disease through enhancing intestinal barrier function.

BACKGROUND: Impaired metabolic functions of gut microbiota have been demonstrated in alcohol-related liver disease (ALD), but little is known about changes in phenylalanine metabolism. METHODS: Bacterial genomics and fecal metabolomics analysis were used to recognize the changes of phenylalanine metabolism and its relationship with intestinal flora. Intestinal barrier function was detected by intestinal alkaline phosphatase (IAP) activity, levels of tight junction protein expression, colonic inflammation and levels of serum LPS. Lactobacillus acidophilus was chosen to correct phenylalanine metabolism of ALD mice by redundancy analysis and Pearson correlation analysis. RESULTS: Using 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods, we identified elevated levels of phenylalanine and its' metabolites in the gut of alcohol-fed mice compared to control mice and were negatively correlated with the abundance of Lactobacillus, which mainly metabolized phenylalanine. The intestinal phenylalanine level was positively correlated with the colon inflammatory factors TNF-α and IL-6, and negatively correlated with ZO-1 and Occludin. While intestinal alkaline phosphatase (IAP) activity was negatively correlated with the colon inflammatory factors TNF-α, IL-6 and MCP-1, and positively correlated with ZO-1 and Occludin. Increased phenylalanine inhibited IAP activity, blocked LPS dephosphorylation, increased colonic inflammation and bacterial translocation. Phenylalanine supplementation aggravated alcohol-induced liver injury and intestinal barrier dysfunction. Among the 37 Lactobacillus species, the abundance of Lactobacillus acidophilus was most significantly decreased in ALD mice. Supplementation with L. acidophilus recovered phenylalanine metabolism and protected mice from alcohol-induced steatohepatitis. CONCLUSIONS: Recovery of phenylalanine metabolism through the oral supplementation of L. acidophilus boosted intestinal barrier integrity and ameliorated experimental ALD.

Differences in Bacterial Translocation and Liver Injury in Ethanol Versus Diet-Induced Liver Disease.

BACKGROUND: Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are two of the most common etiologies of chronic liver disease worldwide. Changes in intestinal permeability and increased gut microbial translocation have been posited as important contributors to inflammation in both ALD and NAFLD. However, gut microbial translocation has not been compared between the two etiologies and can lead to better understanding of the differences in their pathogenesis to liver disease. METHODS: We compared serum and liver markers in the following five models of liver disease to understand the differences in the role of gut microbial translocation on liver disease progression caused by ethanol versus Western diet: (1) 8-week chronic ethanol feeding model. (2) 2-week chronic-plus-binge (National Institute on Alcohol Abuse and Alcoholism (NIAAA)) ethanol feeding model. (3) 2-week chronic-plus-binge (NIAAA) ethanol feeding model in microbiota-humanized gnotobiotic mice colonized with stool from patients with alcohol-associated hepatitis. (4) 20-week Western-diet-feeding model of NASH. (5) 20-week Western-diet-feeding model in microbiota-humanized gnotobiotic mice colonized with stool from NASH patients. RESULTS: Translocation of bacterial lipopolysaccharide to the peripheral circulation was seen in both ethanol-induced and diet-induced liver disease, but translocation of bacteria itself was restricted to only ethanol-induced liver disease. Moreover, the diet-induced steatohepatitis models developed more significant liver injury, inflammation, and fibrosis compared with ethanol-induced liver disease models, and this positively correlated with the level of lipopolysaccharide translocation. CONCLUSIONS: More significant liver injury, inflammation, and fibrosis are seen in diet-induced steatohepatitis, which positively correlates with translocation of bacterial components, but not intact bacteria.

The role of NADPH oxidase 1 in alcohol-induced oxidative stress injury of intestinal epithelial cells.

Alcohol-mediated reactive oxygen species (ROS) play a vital role in intestinal barrier injury. However, the mechanism of ROS accumulation in enterocytes needs to be explored further. In our study, we found that chronic-binge ethanol-fed mice had increased levels of gut oxidative stress and high intestinal permeability. The transcription profiles of the colonic epithelial cells showed that the level of NADPH oxidase 1 (NOX1) was significantly elevated in alcohol-exposed mice compared with isocaloric-exposed mice. In vitro, NOX1 silencing alleviated ROS accumulation and the apoptosis of human colonic epithelial cells (NCM460), while NOX1 overexpression accelerated oxidative stress injury of NCM460 cells. Propionic acid was reduced in the gut of chronic-binge ethanol-fed mice, compared with isocaloric-fed mice, as observed through untargeted metabolomic analysis. Supplementation with propionate relieved ethanol-induced liver and intestinal barrier injuries and reduced the level of ROS accumulation and apoptosis of ethanol-induced colonic epithelial cells. Propionate alleviating NOX1 induced ROS injury of colonic epithelial cells, independent of G protein-coupled receptors. Propionate significantly inhibited histone deacetylase 2 (HDAC2) expressions both in ethanol-exposed colonic epithelial cells and TNF-α-treated NCM460. Chromatin immunoprecipitation (ChIP) assays showed that propionate suppressed the NOX1 expression by regulating histone acetylation in the gene promoter region. In conclusion, NOX1 induces oxidative stress injury of colonic epithelial cells in alcohol-related liver disease. Propionate, which can act as an endogenous HDAC2 inhibitor, can decrease levels of apoptosis of intestinal epithelial cells caused by oxidative stress.

Retrorsine Cooperates with Gut Microbiota to Promote Hepatic Sinusoidal Obstruction Syndrome by Disrupting the Gut Barrier.

Background and Aims: Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening syndrome, and a cause is exposure to pyrrolizidine alkaloid (PA)-containing products. It is well-established that retrorsine (RTS), a representative Pas, insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids. However, little known about the impact of Pas on gut microbiota and intestinal barrier and inflammation in HSOS. Methods: Mice were gavaged with or without nonabsorbable antibiotics (ABX), followed by a single dose of RTS. The gut microbiota was examined by 16S rDNA sequencing. Results: ABX pretreatment significantly reversed RTS-induced liver damage. RTS altered gut microbiota composition, increasing Gram-negative bacteria and resulting in a sharp elevation of circulating lipopolysaccharides (LPS) in HSOS mice. Gut decontamination with ABX alleviated RTS-induced intestine inflammation, protected against disruption of the intestinal epithelial barrier and gut vascular barrier (GVB), and suppressed hepatic LPS-NF-κB pathway activation in RTS-induced HSOS. Importantly, the LPS level was positively correlated with MELD score in patients with HSOS. Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were involved in the pathogenesis of HSOS. Conclusions: RTS, a PA, cooperated with gut dysbiosis to cause intestinal inflammation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein, which contributed to the pathology of HSOS. Modulating the gut microbiota, protecting the intestinal barrier, and suppressing intestinal inflammation with prebiotics or antibiotics might be a useful pharmacologic intervention in HSOS.

The critical role of gut microbiota in obesity.

Obesity is a global epidemic characterized by energy disequilibrium, metabolic disorder, fat mass development, and chronic low-grade inflammation, which significantly affects the health state of individuals of all ages and strains the socioeconomic system. The prevalence of obesity is rising at alarming rates and its etiology involves complicated interplay of diet, genetic, and environmental factors. The gut microbiota, as an important constituent of environmental factors, has been confirmed to correlate with the onset and progression of obesity. However, the specific relationship between obesity and the gut microbiota, and its associated mechanisms, have not been fully elucidated. In this review, we have summarized that the microbial diversity was significantly decreased and the Firmicutes/Bacteroidetes ratio was significantly increased in obesity. The altered gut microbiota and associated metabolites contributed to the progression of the disease by disrupting energy homeostasis, promoting lipid synthesis and storage, modulating central appetite and feeding behavior, as well as triggering chronic inflammation, and that the intentional manipulation of gut microbiota held promise as novel therapies for obesity, including probiotics, prebiotics, and fecal microbiota transplantation.

Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis.

Nonalcoholic steatohepatitis (NASH) is a chronic and progressive disease whose treatment strategies are limited. Although time-restricted feeding (TRF) is beneficial for metabolic diseases without influencing caloric intake, the underlying mechanisms of TRF action in NASH and its efficacy have not yet been demonstrated. We herein showed that TRF effectively alleviated NASH, producing a reduction in liver enzymes and improvements in liver pathology. Regarding the mechanisms by which TRF mitigates NASH, we ascertained that TRF inhibited ferroptosis and the expression of the circadian gene Per2. By adopting a hepatocyte-specific Per2-knockout (Per2△hep) mice model, we clarified the critical role of Per2 in exacerbating NASH. According to the results of our RNA-Seq analysis, the knockout of Per2 ameliorated NASH by inhibiting the onset of ferroptosis; this was manifested by diminished lipid peroxidation levels, decreased mRNA and protein levels for ferroptosis-related genes, and alleviated morphologic changes in mitochondria. Furthermore, using a ferroptosis inhibitor, we showed that ferroptosis significantly aggravated NASH and noted that this was likely achieved by regulation of the expression of peroxisome proliferator activated receptor (PPAR)α. Finally, we discerned that TRF and hepatocyte-specific knockout of Per2 promoted the expression of PPARα. Our results revealed a potential for TRF to effectively alleviate high-fat and high-fructose diet-induced NASH via the inhibition of Per2 and depicted the participation of Per2 in the progression of NASH by promoting ferroptosis, which was ultimately related to the expression of PPARα.

Gut Non-Bacterial Microbiota: Emerging Link to Irritable Bowel Syndrome.

As a common functional gastrointestinal disorder, irritable bowel syndrome (IBS) significantly affects personal health and imposes a substantial economic burden on society, but the current understanding of its occurrence and treatment is still inadequate. Emerging evidence suggests that IBS is associated with gut microbial dysbiosis, but most studies focus on the bacteria and neglect other communities of the microbiota, including fungi, viruses, archaea, and other parasitic microorganisms. This review summarizes the latest findings that link the nonbacterial microbiota with IBS. IBS patients show less fungal and viral diversity but some alterations in mycobiome, virome, and archaeome, such as an increased abundance of Candida albicans. Moreover, fungi and methanogens can aid in diagnosis. Fungi are related to distinct IBS symptoms and induce immune responses, intestinal barrier disruption, and visceral hypersensitivity via specific receptors, cells, and metabolites. Novel therapeutic methods for IBS include fungicides, inhibitors targeting fungal pathogenic pathways, probiotic fungi, prebiotics, and fecal microbiota transplantation. Additionally, viruses, methanogens, and parasitic microorganisms are also involved in the pathophysiology and treatment. Therefore, the gut nonbacterial microbiota is involved in the pathogenesis of IBS, which provides a novel perspective on the noninvasive diagnosis and precise treatment of this disease.

Acetate reprograms gut microbiota during alcohol consumption.

Liver damage due to chronic alcohol use is among the most prevalent liver diseases. Alcohol consumption frequency is a strong factor of microbiota variance. Here we use isotope labeled [1-13C] ethanol, metagenomics, and metatranscriptomics in ethanol-feeding and intragastric mouse models to investigate the metabolic impacts of alcohol consumption on the gut microbiota. First, we show that although stable isotope labeled [1-13C] ethanol contributes to fatty acid pools in the liver, plasma, and cecum contents of mice, there is no evidence of ethanol metabolism by gut microbiota ex vivo under anaerobic conditions. Next, we observe through metatranscriptomics that the gut microbiota responds to ethanol-feeding by activating acetate dissimilation, not by metabolizing ethanol directly. We demonstrate that blood acetate concentrations are elevated during ethanol consumption. Finally, by increasing systemic acetate levels with glyceryl triacetate supplementation, we do not observe any impact on liver disease, but do induce similar gut microbiota alterations as chronic ethanol-feeding in mice. Our results show that ethanol is not directly metabolized by the gut microbiota, and changes in the gut microbiota linked to ethanol are a side effect of elevated acetate levels. De-trending for these acetate effects may be critical for understanding gut microbiota changes that cause alcohol-related liver disease.