The nonenergy - producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.

Transjugular intrahepatic portosystemic shunt (TIPS) placement alleviates portal hypertension symptoms. Hepatic encephalopathy (HE) is a common complication of TIPS, impacting patient quality of life and the healthcare burden. Post-TIPS HE is associated with portosystemic shunting, elevated blood ammonia levels, and inflammation. Increasing attention has been given to the liver and intestinal circulation in recent years. An imbalance in intestinal microecology plays a role in the occurrence of HE and may be a new target for treatment. This review discusses the causes, diagnosis, and treatment strategies for post-TIPS HE and focuses on exploring treatment strategies and their relationships with the gut microbiota, suggesting an innovative approach to address this complication.

Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.

The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.

The gut microbiome primarily generates short-chain fatty acids (SCFAs) by fermenting dietary fibers. Though previous studies have linked SCFAs to blood pressure, there remains a lack of research on the relationship between SCFAs levels in the serum of elderly individuals and blood pressure. Based on this, we investigated the associations of serum SCFAs with blood pressure in Chinese older adults in a cross-sectional study. In this report, we recruited 1013 older adults over 60 years of age from June to September 2016 in Lu 'an City, China. Using Ultra High Performance Liquid Chromatography-Quadrupole-Exactive-Orbitrap-Mass Spectrometry (UHPLC-QE-Orbitrap MS), we measured the level of various SCFAs, including acetic acid (AA), propanoic acid (PA), butyric acid (BA), isobutyric acid (iso-BA), valeric acid (VA), isovaleric acid (iso-VA), and caproic acid (CA), in serum samples collected from Chinese elderly adults. The study recruited 1013 older adults in total. Multiple logistic regression analysis shows that AA (OR = 0.696, 95%CI: 0.501-0.966) and VA (OR = 0.713, 95%CI: 0.516-0.985) are negatively associated with hypertension. Linear regression analysis shows a negative correlation between AA (β = -3.89, 95% CI: -7.12 - -0.66) and the systolic blood pressure (SBP) levels, and a significant negative association between iso-VA (β = -2.11, 95% CI: -3.94 - -0.29) and diastolic blood pressure (DBP) levels. Whether in unadjusted or adjusted linear regression models, we all observe significant positive associations between CA and blood pressure levels. In the Bayesian kernel-machine regression (BKMR) models, the trends between the mixture of SCFAs and hypertension, SBP are inverse, but not significant; we also observe a significant negative correlation between AA and SBP, and a significant negative association between iso-VA and DBP levels, while CA is significantly positively correlated with SBP and DBP. Collectively, our results advocate for considering SCFA as a potential intervention to lower blood pressure, and especially AA may be a possible target for research. This may provide new perspectives for understanding the role of SCFAs in hypertension.

Alcohol-associated liver disease (ALD) poses a significant global public health challenge, with high patient mortality rates and economic burden. The gut microbiome plays an important role in the onset and progression of alcohol-associated liver disease. Excessive alcohol consumption disrupts the intestinal barrier, facilitating the entry of harmful microbes and their products into the liver, exacerbating liver damage. Dysbiosis, marked by imbalance in gut bacteria, correlates with ALD severity. Promising microbiota-centered therapies include probiotics, phages, and fecal microbiota transplantation. Clinical trials demonstrate the potential of these interventions to improve liver function and patient outcomes, offering a new frontier in ALD treatment.

The Kasai portoenterostomy (KPE) aims to re-establish bile flow in biliary atresia (BA); however, BA remains the commonest indication for liver transplantation in pediatrics. Gut microbiota-host interplay is increasingly associated with outcomes in chronic liver disease. This study characterized fecal microbiota and fatty acid metabolites in BA.

Fecal samples were prospectively collected in newly diagnosed BA infants (n = 55) before and after KPE. Age-matched healthy control (n = 19) and cholestatic control (n = 21) fecal samples were collected. Fecal 16S rRNA gene amplicon sequencing for gut microbiota and gas chromatography for fecal fatty acids was performed.

Increased abundance of Enterococcus in pre-KPE BA and cholestatic control infants, compared to healthy infants, was demonstrated. At the early post-KPE time points, increased alpha diversity was revealed in BA versus healthy cohorts. A lower relative abundance of Bifidobacterium and increased Enterococcus, Clostridium, Fusobacterium, and Pseudomonas was seen in infants with BA. Fecal acetate was reduced, and fecal butyrate and propionate were elevated in early post-KPE BA infants. Higher post-KPE alpha diversity was associated with nonfavorable clinical outcomes (6-month jaundice and liver transplantation). A higher relative abundance of post-KPE Streptococcus and Fusobacterium and a lower relative abundance of Dorea, Blautia, and Oscillospira were associated with nonfavorable clinical outcomes. Blautia inversely correlated to liver disease severity, and Bifidobacterium inversely correlated to fibrosis biomarkers. Bifidobacterium abundance was significantly lower in infants experiencing cholangitis within 6 months after KPE.

Increased diversity, enrichment of pathogenic, and depletion of beneficial microbiota early post-KPE are all factors associated with nonfavorable BA outcomes. Manipulation of gut microbiota in the early postsurgical period could provide therapeutic potential.

The pathogenesis of alcohol-associated liver disease (ALD) is complex and multifactorial. Several intracellular, intrahepatic, and extrahepatic factors influence development of early fatty liver injury leading to inflammation and fibrosis. Alcohol metabolism, cellular stress, and gut-derived factors contribute to hepatocyte and immune cell injury leading to cytokine and chemokine production. The pathogenesis of alcohol-associated hepatitis (AH), an advanced form of acute-on-chronic liver failure due to excessive chronic intake in patients with underlying liver disease, is not well understood. While pathogenic mechanisms in early ALD are studied, the pathogenesis of AH requires further investigation to help design effective drugs for patients.

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage.

Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.

The regulatory role of gut microbiota and gut-derived metabolites through the gut-liver axis in the development of cirrhotic portal hypertension (PH) has received increasing attention.

The review summarized a series of investigations on effects of metabolites derived from microbiota and medicines targeting microbiome including rifaximin, VSL#3, statins, propranolol, FXR agonists as well as drugs derived from bile acids (BAs) on PH progression.

Patients with PH exhibit alterations in gut microbial richness and differential overall microbiota community, and several results clearly displayed the correlation of PH with enrichment of Veillonella dispar or depletion of Clostridiales, Peptostreptococcaceae, Alistipes putredinis, Roseburia faecis and Clostridium cluster IV. The gut-derived metabolites including hydrogen sulfide, tryptophan metabolites, butyric acid, secondary BAs and phenylacetic acid (PAA) participate in a range of pathophysiology process of PH through modulating intrahepatic vascular resistance and portal blood flow associated with the formation and progression of PH. Established and emerging drugs targeting on bacterial translocation and intestinal eubiosis are gradually identified as potential strategies for treatments of liver cirrhosis and PH by modulating intestinal inflammation, splanchnic arterial vasodilation and endothelial dysfunction.

Future explorations should further characterize the alteration of the fecal microbiome and metabolite profiles in PH and elucidate the regulatory mechanism of the intestinal microbiome, gut-derived metabolites and gut microbiota targeted pharmaceutical treatments involved in PH.

Gut dysbiosis and abnormal cytokine profiles are common in cirrhosis. This study aimed to evaluate the correlations between them.

In the blood plasma of cirrhosis patients and controls, 27 cytokines were examined using a multiplex assay. The plasma levels of nitrites (stable metabolites of the endothelial dysfunction biomarker nitric oxide) and lipopolysaccharide (LPS) were examined. The fecal microbiota was assessed by 16S rRNA gene sequencing.

Levels of IL-1b, IL-2, IL-6, IL-13, IP-10, IFN-g, TNF-a, LPS, and nitrites were higher in cirrhosis patients than in controls, while levels of IL-4, IL-7, and PDGF-BB were lower. The LPS level was directly correlated with the levels of IL-1b, IL1-Ra, IL-9, IL-17, PDGF-BB, IL-6, TNF-a, and nitrites. The nitrite level was significantly directly correlated with the levels of TNF-a, GM-CSF, IL-17, and IL-12, and inversely correlated with the IL-7 level. TNF-a levels were directly correlated with ascites severity and the abundance of Negativicutes, Enterobacteriaceae, Veillonellaceae, and Klebsiella, while inversely correlated with the abundance of Firmicutes, Clostridia, and Subdoligranulum. IFN-g levels were directly correlated with the abundance of Bacteroidaceae, Lactobacillaceae, Bacteroides, and Megasphaera, and inversely correlated with the abundance of Verrucomicrobiota, Akkermansiaceae, Coriobacteriaceae, Akkermansia, Collinsella, and Gemella. IL-1b levels were directly correlated with the abundance of Comamonadaceae and Enterobacteriaceae and inversely correlated with the abundance of Marinifilaceae and Dialister. IL-6 levels were directly correlated with the abundance of Enterobacteriaceae, hepatic encephalopathy, and ascites severity, and inversely correlated with the abundance of Peptostreptococcaceae, Streptococcaceae, and Streptococcus.

The abundance of harmful gut microbiota taxa and endotoxinemia directly correlates with the levels of proinflammatory cytokines.

The efficacy of cancer treatments has links to the intestinal microbiome. Mucositis is a dose-limiting intestinal pro-inflammatory side effect of cancer treatments, that increases the risk of diarrhoea, mucositis, and in severe cases, febrile neutropenia.

The effect of cancer treatments on Quality of Life (QoL) was assessed using the FACT C questionnaire that included patient wellbeing and gut adverse symptoms (e.g. diarrhoea). Participants rated faecal samples via the Bristol Stool Chart. In addition, bacterial DNA was extracted from faecal samples, sequenced, and taxonomically examined. The incidence / severity of neutropenia was assessed with white blood cell and neutrophil counts. Circulating SCFAs and plasma lipopolysaccharide (LPS) endotoxin levels were recorded and correlated to intestinal mucositis.

Improvement in bowel function, with reduction in constipation and or diarrhoea or absence of significant disturbance to bowel function was recorded in 85% of the participants. One participant developed febrile neutropenia and two developed bowel toxicity during the study, that was unrelated to the test formulation. No significant changes in microbiota alpha- and beta-diversity at the phylum and species levels respectively from baseline to end of study treatment was observed. None of the participants had raised plasma-endotoxin levels from baseline to the first and subsequent treatment cycles for their cancers. Probiotics in this cohort were deemed safe and tolerable. Significant improvement in emotional QoL scores (p = 0.015) was reported with increased number of chemotherapy cycles. In a related observational study of exceptional responders to chemotherapy, participants were found to have had a high intake of fruits, vegetables, and fibre possibly indicative of a more balanced intestinal microbiota.

A multi-strain probiotic formulation was safe and tolerated in this chronically ill cohort that were undergoing oncological treatment. The probiotic formulation alleviated diarrhoea, constipation and maintained stool consistency/frequency during the multiple treatments with chemotherapy and radiotherapy. Intestinal dysbiosis that is characterised by decreased microbial diversity and increased pro-inflammatory species was not observed. Probiotic supplementation may have helped reduce dysbiosis during cancer treatments. These improvements may have been critical with the observation that emotional wellbeing was significantly improved from baseline. Hence albeit that the study had limitations, the probiotic intervention provided adjunctive treatment support to the patients. What is of scientifically plausible interest is that probiotics have a long association historically with human hosts and as such ratify their inclusion offering a significant adjunctive therapeutic potential. Future studies warrant larger sample sizes, control groups and should limit recruitment to a largely homogenous group of patients.

Although the associations between a patient's body mass index (BMI) and metabolic diseases, as well as their breath test results, have been studied, the relationship between breath hydrogen/methane levels and metabolic diseases needs to be further clarified. We aimed to investigate how the composition of exhaled breath gases relates to metabolic disorders, such as diabetes mellitus, dyslipidemia, hypertension, and nonalcoholic fatty liver disease (NAFLD), and their key risk factors. An analysis was performed using the medical records, including the lactulose breath test (LBT) data of patients who visited the Ajou University Medical Center, Suwon, Republic of Korea, between January 2016 and December 2021. The patients were grouped according to four different criteria for LBT hydrogen and methane levels. Of 441 patients, 325 (72.1%) had positive results for methane only (hydrogen < 20 parts per million [ppm] and methane ⩾ 3 ppm). BMIs and NAFLD prevalence were higher in patients with only methane positivity than in patients with hydrogen and methane positivity (hydrogen ⩾ 20 ppm and methane ⩾ 3 ppm). According to a multivariate analysis, the odds ratio of only methane positivity was 2.002 (95% confidence interval [CI]: 1.244-3.221,P= 0.004) for NAFLD. Our results demonstrate that breath methane positivity is related to NAFLD and suggest that increased methane gas on the breath tests has the potential to be an easily measurable biomarker for NAFLD diagnosis.

Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique sinusoidal capillary network of the liver. Early sinusoidal vasoregulatory changes in MASLD lead to increased intrahepatic vascular resistance and represent the beginning of portal hypertension. In addition, the composition and function of gut microbiota in MASLD are distinctly different from the healthy state, and multiple lines of evidence demonstrate the association of dysbiosis with these vasoregulatory changes. The gut microbiota is involved in the biotransformation of nutrients, production of de novo metabolites, release of microbial structural components, and impairment of the intestinal barrier with impact on innate immune responses, metabolism, inflammation, fibrosis, and vasoregulation in the liver and beyond. The gut-liver axis is a conceptual framework in which portal circulation is the primary connection between gut microbiota and the liver. Accordingly, biochemical and hemodynamic attributes of portal circulation may hold the key to better understanding and predicting disease progression in MASLD. However, many specific details remain hidden due to limited access to the portal circulation, indicating a major unmet need for the development of innovative diagnostic tools to analyze portal metabolites and explore their effect on health and disease. We also need to safely and reliably monitor portal hemodynamics with the goal of providing preventive and curative interventions in all stages of MASLD. Here, we review recent advances that link portal metabolomics to altered sinusoidal vasoregulation and may allow for new insights into the development of portal hypertension in MASLD.

The gut microbiota plays an important role in maintaining human health and in the pathogenesis of several diseases. Antibiotics are among the most commonly prescribed drugs and have a significant impact on the structure and function of the gut microbiota. The understanding that a healthy gut microbiota prevents the development of many diseases has also led to its consideration as a potential therapeutic target. At the same time, any factor that alters the gut microbiota becomes important in this approach. Exercise and antibacterial therapy have a direct effect on the microbiota. The review reflects the current state of publications on the mechanisms of intestinal bacterial involvement in the pathogenesis of cardiovascular, metabolic, and neurodegenerative diseases. The physiological mechanisms of the influence of physical activity on the composition of the gut microbiota are considered. The mechanisms of the common interface between exercise and antibacterial therapy will be considered using the example of several socially important diseases. The aim of the study is to show the physiological relationship between the effects of exercise and antibiotics on the gut microbiota.

The role of gut microbiota in human health has been intensively studied and more recently shifted from emphasis on composition towards function. Function is partly mediated through formed metabolites. Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate as well as their branched analogues represent major products from gut fermentation of dietary fibre and proteins, respectively. Robust and high-throughput analysis of SCFAs in small volume blood samples have proven difficult. Major obstacles come from the ubiquitous presence of SCFAs that leads to contaminations and unstable analytical results because of the high volatility of these small molecules. Comprehensive and comparable data on the variation of SCFAs in blood samples from different blood matrices and mammal species including humans is lacking. Therefore, our aim was to develop and evaluate a stable and robust method for quantitation of 8 SCFAs and related fermentation products in small volume blood plasma samples and to investigate their variation in humans and different animal species.

Derivatization was a successful approach for measurement of SCFAs in biological samples but quenching of the derivatization reaction was crucial to obtain long-term stability of the derivatized analytes. In total 9 compounds (including succinic acid) were separated in 5 min. The method was linear over the range 0.6-3200 nM formic (FA), acetic (AA), 0.3-1600 nM propionic (PA), and 0.16-800 nM for butyric (BA)-, isobutyric (IBA)-, valeric (VA)-, isovaleric (IVA)-, succinic (SA) and caproic acid (CA). The precision ranged ≤12 % within days and ≤28 % between days (except for CA and VA) in three different plasma quality control (QC) samples (29 batches analyzed over 3 months). The extraction recovery was on average 94 % for the different SCFAs. Typical interquartile range (IQR) concentrations (μM) of SCFAs in human plasma samples were 168 μM (FA), 64 μM (AA), 2.2 μM (PA), 0.54 μM (BA), 0.66 μM (IBA), 0.18 μM (VA), 0.40 μM (IVA), and 0.34 μM (CA). In total, 55 samples per batch/day were successfully analyzed and in total 5380 human plasma samples measured over a 3-year timespan.

The developed UHPLC-MS based method was suitable for measuring SCFAs in small blood volume samples and enabled robust quantitative data.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and β-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are closely related liver conditions that have become more prevalent globally. This review examines the intricate interplay between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH. The combination of these two factors creates a synergistic situation referred to as "double trouble", which promotes the accumulation of lipids in the liver and the subsequent progression from simple steatosis (NAFLD) to inflammation (NASH). Microbiome dysbiosis, characterized by changes in the composition of gut microbes and increased intestinal permeability, contributes to the movement of bacterial products into the liver. It triggers metabolic disturbances and has anti-inflammatory effects. Understanding the complex relationship between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH is crucial for advancing innovative therapeutic approaches that target these underlying mechanisms.

Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.

To determine the prevalent microbiological profile of biliary atresia (BA) patients at the time of its occurrence by studying their intestinal flora.

A total of 118 gut microbiota samples from three groups of 43 BA patients, 33 disease controls (DC) with other cholestatic diseases and 42 healthy controls (HC), were analyzed by deep mining of public data. Subsequently, a total of 23 fecal samples from three groups of clinically collected patients (11 BA, 6 DC and 6 HC) were sequenced for 16S rRNA gene amplification and analyzed for serum butyrate (BU) level by liquid chromatography.

Taxonomic analysis revealed significant differences in the composition of the intestinal microbiota between BA patients and controls, with a reduction in diversity and a higher abundance of Proteobacteria, Streptococcus and Lactobacillus in the BA group. Database and clinical data analyses concluded that Streptococcus/Bacteroides (AUC = 0.9035, 95% CI 0.8347-0.9722, P < 0.0001) or Streptococcus/Eggerthella (AUC = 0.8333, 95% CI 0.6340-1.000, P = 0.027) was the best microbiota to differentiate between BA and DC. Serum butyrate levels were low in the BA and DC groups and differed from the HC group (P = 0.01, P = 0.04). Butyrate levels in BA were negatively correlated with jaundice clearance and cholangitis, but not statistically significant.

Our study reveals changes in the composition of the gut microbiota in BA, especially the butyrate-producing microbiota, and suggests the potential for using gut microbiota as a noninvasive diagnostic benefit for BA. Low levels of serum butyrate in BA may indicate a poor prognosis.

Patients with acute ischemic stroke (AIS) with non-alcoholic fatty liver disease (NAFLD) frequently have poor prognosis. Many evidences suggested that the changes in gut microbiota may play an important role in the occurrence and development of AIS patients with NAFLD. The purpose of this study was to explore microbial characteristics in patients of AIS with NAFLD, and the correlation between gut microbiota and functional outcomes.

The patients of AIS were recruited and divided into NAFLD group and non-NAFLD group. The stool samples and clinical information were collected. 16 s rRNA sequencing was used to analyze the characteristics of gut microbiota. The patients of AIS with NAFLD were followed-up to evaluate the functional outcomes of disease. The adverse outcomes were determined by modified Rankin scale (mRS) scores at 3 months after stroke. The diagnostic performance of microbial marker in predicting adverse outcomes was assessed by recipient operating characteristic (ROC) curves.

Our results showed that the composition of gut microbiota between non-NAFLD group and NAFLD group were different. The characteristic bacteria in the patients of AIS with NAFLD was that the relative abundance of Dorea, Dialister, Intestinibacter and Flavonifractor were decreased, while the relative abundance of Enorma was increased. Moreover, the characteristic microbiota was correlated with many clinical parameters, such as mRS scores, mean arterial pressure and fasting blood glucose level. In addition, ROC models based on the characteristic microbiota or the combination of characteristic microbiota with independent risk factors could distinguish functional dependence patients and functional independence patients in AIS with NAFLD (area under curve is 0.765 and 0.882 respectively).

These findings revealed the microbial characteristics in patients of AIS with NAFLD, and further demonstrated the predictive capability of characteristic microbiota for adverse outcomes in patients of AIS with NAFLD.

In recent years, the obesity epidemic has escalated into a serious public health catastrophe that is only getting worse. However, research into the pathophysiological pathways behind the obesity development and the illnesses that it is associated with is ongoing. In the last decades, it is now clear that the gut microbiota plays a significant role in the genesis and progression of obesity and obesity-related illnesses, particularly changes in its metabolites and composition as obesity progresses. Here, we provide a summary of the processes by which variations in gut metabolite levels and the composition of gut microbiota affect obesity and associated disorders. The bacteria residing in the gut release several chemicals that influence the appetite control, metabolism, and other systems. Since it can either encourage or restrict the deposition of fat in several different ways, the gut microbiota's role in obesity is debatable. Additionally, we go over potential therapeutic approaches that could be utilized to alter gut microbiota composition and focus on the important metabolic pathways associated with obesity and metabolic disorders linked to obesity.

Polycystic ovarian syndrome (PCOS) is a known endocrine disorder that has affected many women of childbearing age, and is accompanied by various neurodegenerative conditions. Hence, this study investigates the impact of butyrate in reversing hypothalamic-related disorder, possibly through γ aminobutyric acid (GABA) in a rat model of PCOS. Eight-week-old female Wistar rats were allotted into four groups (n = 5), which include control, butyrate, letrozole, and letrozole + butyrate groups. PCOS was induced by administering 1 mg/kg of letrozole (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Rats with PCOS were characterized by elevated levels of plasma insulin and testosterone. Increases in plasma and hypothalamic triglyceride levels, inflammatory biomarker (SDF-1), apoptotic marker (caspase-6), and decreased plasma GnRH were observed. Additionally, a decrease in hypothalamic GABA was revealed. Nevertheless, the administration of butyrate attenuated these alterations. The present study suggests that butyrate ameliorates hypothalamic inflammation in an experimental model of PCOS, a beneficial effect that is accompanied by enhanced GABA production.

Common critical illnesses are a growing economic burden on healthcare worldwide. However, therapies targeting the gut microbiota for critical illnesses have not been developed on a large scale. This study aimed to investigate the changes in the characteristics of the gut microbiota in critically ill children after short-term pediatric intensive care unit (PICU) treatments.

Anal swab samples were prospectively collected from March 2021 to March 2022 from children admitted to the PICU of Xinhua Hospital who received broad-spectrum antibiotics on days 1 (the D1 group) and 7 (the D7 group) of the PICU treatment. The structural and functional characteristics of the gut microbiota of critically ill children were explored using metagenomic next-generation sequencing (mNGS) technology, and a comparative analysis of samples from D1 and D7 was conducted.

After 7 days of PICU admission, a significant decrease was noted in the richness of the gut microbiota in critically ill children, while the bacterial diversity and the community structure between groups remained stable to some extent. The relative abundance of Bacilli and Lactobacillales was significantly higher, and that of Campylobacter hominis was significantly lower in the D7 group than in the D1 group. The random forest model revealed that Prevotella coporis and Enterobacter cloacae were bacterial biomarkers between groups. LEfSe revealed that two Gene Ontology entries, GO:0071555 (cell wall organization) and GO:005508 (transmembrane transport), changed significantly after the short-term treatment in the PICU. In addition, 30 KEGG pathways were mainly related to the activity of enzymes and proteins during the processes of metabolism, DNA catabolism and repair, and substance transport. Finally, 31 antimicrobial resistance genes had significantly different levels between the D7 and D1 groups. The top 10 up-regulated genes were Erm(A), ErmX, LptD, eptB, SAT-4, tetO, adeJ, adeF, APH(3')-IIIa, and tetM.

The composition, gene function, and resistance genes of gut microbiota of critically ill children can change significantly after short PICU treatments. Our findings provide a substantial basis for a better understanding of the structure and function of gut microbiota and their role in critical illnesses.

The gut microbiome is a salient contributor to the development of obesity, and diet is the greatest modifier of the gut microbiome, which highlights the need to better understand how specific diets alter the gut microbiota to impact metabolic disease. Increased dietary fiber intake shifts the gut microbiome and improves energy and glucose homeostasis. Dietary fibers are found in various plant-based flours which vary in fiber composition. However, the comparative efficacy of specific plant-based flours to improve energy homeostasis and the mechanism by which this occurs is not well characterized.

In experiment 1, obese rats were fed a high fat diet (HFD) supplemented with four different plant-based flours for 12 weeks. Barley flour (BF), oat bran (OB), wheat bran (WB), and Hi-maize amylose (HMA) were incorporated into the HFD at 5% or 10% total fiber content and were compared to a HFD control. For experiment 2, lean, chow-fed rats were switched to HFD supplemented with 10% WB or BF to determine the preventative efficacy of flour supplementation.

In experiment 1, 10% BF and 10% WB reduced body weight and adiposity gain and increased cecal butyrate. Gut microbiota analysis of WB and BF treated rats revealed increases in relative abundance of SCFA-producing bacteria. 10% WB and BF were also efficacious in preventing HFD-induced obesity; 10% WB and BF decreased body weight and adiposity, improved glucose tolerance, and reduced inflammatory markers and lipogenic enzyme expression in liver and adipose tissue. These effects were accompanied by alterations in the gut microbiota including increased relative abundance of Lactobacillus and LachnospiraceaeUCG001, along with increased portal taurodeoxycholic acid (TDCA) in 10% WB and BF rats compared to HFD rats.

Therapeutic and preventative supplementation with 10%, but not 5%, WB or BF improves metabolic homeostasis, which is possibly due to gut microbiome-induced alterations. Specifically, these effects are proposed to be due to increased concentrations of intestinal butyrate and circulating TDCA.

Cardiovascular diseases, including heart failure, coronary artery disease, atherosclerosis, aneurysm, thrombosis, and hypertension, are a great economic burden and threat to human health and are the major cause of death worldwide. Recently, researchers have begun to appreciate the role of microbial ecosystems within the human body in contributing to metabolic and cardiovascular disorders. Accumulating evidence has demonstrated that the gut microbiota is closely associated with the occurrence and development of cardiovascular diseases. The gut microbiota functions as an endocrine organ that secretes bioactive metabolites that participate in the maintenance of cardiovascular homeostasis, and their dysfunction can directly influence the progression of cardiovascular disease. This review summarizes the current literature demonstrating the role of the gut microbiota in the development of cardiovascular diseases. We also highlight the mechanism by which well-documented gut microbiota-derived metabolites, especially trimethylamine N-oxide, short-chain fatty acids, and phenylacetylglutamine, promote or inhibit the pathogenesis of cardiovascular diseases. We also discuss the therapeutic potential of altering the gut microbiota and microbiota-derived metabolites to improve or prevent cardiovascular diseases.

Liver damage characterized by fibrosis and necrosis can worsen the condition of liver disease. Liver disease is associated with impaired immune response and may affect short-chain fatty acid (SCFA) gut metabolites. Hepatogomax enteral formula was developed, which contains brain-chain amino acids (BCAAs) and middle-chain triglycerides (MCTs), which could repair liver tissue damage, improve the inflammatory status, and modulate SCFA in liver damage. The study aimed to determine the effect of hepatogomax on liver tissue repair, inflammation (TNF-α and IL-6), and SCFA levels in thioacetamide (TAA)-induced rats. The induction of TAA causes liver steatosis, increasing TNF-α and IL-6, and decreasing SCFA levels. Hepatogomax at a dose of 14.6 g/200 gBW significantly reduces TNF-α and IL-6 levels and increases SCFA levels (p < 0.05). The number of steatosis between groups P2 and P3 was lower as compared to a group of negative control [K2] (p < 0.05). Hepatogomax, in a dose-dependent manner, may repair liver tissue and improve inflammatory response and SCFA levels in TAA-induced rats.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continually increasing due to the global obesity epidemic. NAFLD comprises a systemic metabolic disease accompanied frequently by insulin resistance and hepatic and systemic inflammation. Whereas simple hepatic steatosis is the most common disease manifestation, a more progressive disease course characterized by liver fibrosis and inflammation (i.e. non-alcoholic steatohepatitis) is present in 10-20% of affected individuals. NAFLD furthermore progresses in a substantial number of patients towards liver cirrhosis and hepatocellular carcinoma. Whereas this disease now affects almost 25% of the world's population and is mainly observed in obesity and type 2 diabetes, NAFLD also affects lean individuals. Pathophysiology involves lipotoxicity, hepatic immune disturbances accompanied by hepatic insulin resistance, a gut dysbiosis, and commonly hepatic and systemic insulin resistance defining this disorder a prototypic systemic metabolic disorder. Not surprisingly many affected patients have other disease manifestations, and indeed cardiovascular disease, chronic kidney disease, and extrahepatic malignancies are all contributing substantially to patient outcome. Weight loss and lifestyle change reflect the cornerstone of treatment, and several medical treatment options are currently under investigation. The most promising treatment strategies include glucagon-like peptide 1 receptor antagonists, sodium-glucose transporter 2 inhibitors, Fibroblast Growth Factor analogues, Farnesoid X receptor agonists, and peroxisome proliferator-activated receptor agonists. Here, we review epidemiology, pathophysiology, and therapeutic options for NAFLD.

The purpose of this study was to describe the changes in the gut microbiome of patients with cirrhosis and hepatic encephalopathy (HE), as well as quantify the variations in short-chain fatty acid (SCFA) and tryptophan metabolite levels in serum and faeces.

Fresh faeces and serum were collected from 20 healthy volunteers (NC group), 30 cirrhosis patients (Cir group), and 30 HE patients (HE group). Then, 16S rRNA sequencing and metabolite measurements were performed using the faeces. Gas chromatography‒mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry were used to measure SCFA and tryptophan levels, respectively. The results were analysed by SIMCA16.0.2 software. Differences in species were identified using MetaStat and t tests. The correlations among the levels of gut microbes and metabolites and clinical parameters were determined using Spearman correlation analysis.

Patients with cirrhosis and HE had lower microbial species richness and diversity in faeces than healthy volunteers; these patients also had altered β-diversity. Serum valeric acid levels were significantly higher in the HE group than in the Cir group. Serum SCFA levels did not differ between the Cir and NC groups. Serum melatonin and 5-HTOL levels were significantly higher in the HE group than in the Cir group. The Cir and NC groups had significant differences in the levels of eight serum tryptophan metabolites. Furthermore, the levels of faecal SCFAs did not differ between the HE and Cir groups. Faecal IAA-Ala levels were significantly lower in the HE group than in the Cir group. There were significant differences in the levels of 6 faecal SCFAs and 7 faecal tryptophan metabolites between the Cir and NC groups. Certain gut microbes were associated with serum and faecal metabolites, and some metabolites were associated with certain clinical parameters.

Reduced microbial species richness and diversity were observed in patients with HE and cirrhosis. In both serum and faeces, the levels of different SCFAs and tryptophan metabolites showed varying patterns of change. In HE patients, the levels of some serum tryptophan metabolites, and not SCFAs, were correlated with liver function and systemic inflammation. Systemic inflammation in patients with cirrhosis was correlated with faecal acetic acid levels. In summary, this study identified metabolites important for HE and cirrhosis.

The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial, wide-spectrum liver disorder. Small intestinal bacterial overgrowth (SIBO) is characterized by an increase in the number and/or type of colonic bacteria in the upper gastrointestinal tract. SIBO, through energy salvage and induction of inflammation, may be a pathophysiological factor for NAFLD development and progression.

Consecutive patients with histological, biochemical, or radiological diagnosis of any stage of NAFLD (non-alcoholic fatty liver [NAFL], non-alcoholic steatohepatitis [NASH], cirrhosis) underwent upper gastrointestinal endoscopy. Duodenal fluid (2cc) was aspirated from the 3rd-4th part of duodenum into sterile containers. SIBO was defined as ≥103 aerobic colony-forming units (CFU)/mL of duodenal aspirate and/or the presence of colonic-type bacteria. Patients without any liver disease undergoing gastroscopy due to gastroesophageal reflux disease (GERD) comprised the healthy control (HC) group. Concentrations (pg/mL) of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-6 were also measured in the duodenal fluid. The primary endpoint was to evaluate the prevalence of SIBO in NAFLD patients, while the comparison of SIBO prevalence among NAFLD patients and healthy controls was a secondary endpoint.

We enrolled 125 patients (51 NAFL, 27 NASH, 17 cirrhosis, and 30 HC) aged 54 ± 11.9 years and with a weight of 88.3 ± 19.6 kg (NAFLD vs. HC 90.7 ± 19.1 vs. 80.8 ± 19.6 kg, p = 0.02). Overall, SIBO was diagnosed in 23/125 (18.4%) patients, with Gram-negative bacteria being the predominant species (19/23; 82.6%). SIBO prevalence was higher in the NAFLD cohort compared to HC (22/95; 23.2% vs. 1/30; 3.3%, p = 0.014). Patients with NASH had higher SIBO prevalence (6/27; 22.2%) compared to NAFL individuals (8/51; 15.7%), but this difference did not reach statistical significance (p = 0.11). Patients with NASH-associated cirrhosis had a higher SIBO prevalence compared to patients with NAFL (8/17; 47.1% vs. 8/51; 15.7%, p = 0.02), while SIBO prevalence between patients with NASH-associated cirrhosis and NASH was not statistically different (8/17; 47.1% vs. 6/27; 22.2%, p = 0.11). Mean concentration of TNF-α, IL-1β, and IL-6 did not differ among the different groups.

The prevalence of SIBO is significantly higher in a cohort of patients with NAFLD compared to healthy controls. Moreover, SIBO is more prevalent in patients with NASH-associated cirrhosis compared to patients with NAFL.

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.

We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age.

A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA.

The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF (n = 22) and STF (n = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P = 0.02].

We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size.

The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com.

Humans possess abundant amounts of microorganisms, including bacteria, fungi, viruses, and archaea, in their gut. Patients with nonalcoholic fatty liver disease (NAFLD) exhibit alterations in their gut microbiome and an impaired gut barrier function. Preclinical studies emphasize the significance of the gut microbiome in the pathogenesis of NAFLD. In this overview, we explore how adjusting the gut microbiome could serve as an innovative therapeutic strategy for NAFLD. We provide a summary of current information on untargeted techniques such as probiotics and fecal microbiota transplantation, as well as targeted microbiome-focused therapies including engineered bacteria, prebiotics, postbiotics, and phages for the treatment of NAFLD.

Goats raised for meat production are often transported long distances. Twelve-month-old male Spanish goats were used to determine the effects of habituation to trailers on plasma metabolomic profiles when transported for extended periods. In a split-plot design, 168 goats were separated into two treatment (TRT; whole plot) groups and maintained on two different paddocks. Concentrate supplement was fed to one group inside two livestock trailers (habituated group, H), while the other group received the same quantity of concentrate, but not inside the trailers (non-habituated, NH). Goats were subjected to a 10-h transportation stress in 4 replicates (n = 21 goats/replicate/TRT) after 4 weeks of habituation period. Blood samples were collected prior to loading, 20 min after loading (0 h), and at 2, 4, 6, 8, and 10 h of transportation (Time; subplot). A targeted quantitative metabolomics approach was employed to analyze the samples. The data were analyzed using R software and MIXED procedures in SAS. Several amino acids (alanine, serine, glycine, histidine, glutamate, trans-hydroxyproline, asparagine, threonine, methylhistidine, ornithine, proline, leucine, tryptophan) were higher (p < 0.05) in the H group compared to the NH group. Six long-chain acylcarnitines were higher (p < 0.05), while free (C0) and short-chain (C3, C5) carnitines were lower (p < 0.05) in the NH goats compared to the H goats. In general, amino acid concentrations decreased and long-chain acylcarnitine (>C10) levels increased with transportation time (p < 0.05). Butyric acid, α-ketoglutaric acid, and α-aminoadipic acid concentrations were lower (p < 0.05) and β-hydroxybutyric acid concentrations were higher in the NH goats compared to the H goats. Plasma glucose, non-esterified fatty acid (NEFA) and urea nitrogen concentrations were significantly influenced by Time (p < 0.01). Plasma NEFA concentrations were significantly lower (p < 0.01) in the H group than the NH group. Habituation to trailers can be beneficial in enhancing stress coping abilities in goats due to higher concentrations of metabolites such as butyrate and certain amino acids that support antioxidant activities and immune function. Plasma long-chain acylcarnitines may be good indicators of stress during long-distance transportation in goats.

An understanding of connections between gut microbiome and liver has provided important insights into the pathophysiology of liver diseases. Since gut microbial dysbiosis increases gut permeability, the metabolites biosynthesized by them can reach the liver through portal circulation and affect hepatic immunity and inflammation. The immune cells activated by these metabolites can also reach liver through lymphatic circulation. Liver influences immunity and metabolism in multiple organs in the body, including gut. It releases bile acids and other metabolites into biliary tract from where they enter the systemic circulation. In this review, the bidirectional communication between the gut and the liver and the molecular cross talk between the host and the microbiome has been discussed. This review also provides details into the intricate level of communication and the role of microbiome in Gut-Liver-Brain, Gut-Liver-Kidney, Gut-Liver-Lung, and Gut-Liver-Heart axes. These observations indicate a complex network of interactions between host organs influenced by gut microbiome.