Dynamic alterations in the gut microbiota and metabolomeduring the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis(NASH) development in mice fed a methionine-choline-deficient(MCD) diet. METHODS Twenty-four male C57 BL/6 J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk(Control 2 w group,n = 6) or 4 wk(Control 4 w group,n = 6) or the MCD diet for 2 wk(MCD 2 w group,n = 6) or 4 wk(MCD 4 w group,n = 6). Liver injury,fibrosis,and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16 s r RNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet,however,the mice developed prominent NASH with liver fibrosis,and the intestinal barrier was more impaired. Compared with the control diet,the MCD diet induced gradual gut microbiota dysbiosis,as evidenced by a marked decrease in the abundance of Alistipes and the(Eubacterium) coprostanoligenes group(P 0.001 and P 0.05,respectively) and a significant increase in Ruminococcaceae UCG 014 abundance(P 0.05) after 2 wk. At 4 wk,the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance(P 0.05,and P 0.01,respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk,arachidic acid,hexadecane,palmitic acid,and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group,and at 4 wk,cholic acid,cholesterol,arachidic acid,tetracosane,and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome.     

Focus on the gut-brain axis: multiple sclerosis,the intestinal barrier and the microbiome

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.     

基于“肺与大肠相表里”探讨肠道菌群与肺结核关系的研究进展

肺结核是常见的呼吸道传染疾病,肠道菌群紊乱是肺结核的常见合并症。肠道菌群紊乱会加重肺结核的病理损伤。从中医病机角度,二者之间的关系体现了“肺与大肠相表里”的经络理论、津液理论及气机升降理论。从生物学机制角度,肠道菌群可通过调节宿主固有免疫和适应性免疫,产生抗结核作用的代谢产物以限制肺结核进展;肺结核导致的肠道菌群改变或与血液循环及淋巴循环相关;抗结核药物治疗对肠道菌群的影响或与药物杀菌性相关。肠道菌群的相关疗法对肺结核诊疗具有一定临床价值。通过增加肠道益生菌、粪菌移植、合理使用抗结核药物、改善饮食结构等方法可调节肠道菌群以达到辅助治疗肺结核的目的。本文中,笔者将结合既往文献进行综述。     

Gut microbiota and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that poses a significant health concern. Although its etiology remains unknown, there is growing evidence that gut dysbiosis is involved in the development and exacerbation of IBS. Previous studies have reported altered microbial diversity, abundance, and composition in IBS patients when compared to controls. However, whether dysbiosis or aberrant changes in the intestinal microbiota can be used as a hallmark of IBS remains inconclusive. We reviewed the literatures on changes in and roles of intestinal microbiota in relation to IBS and discussed various gut microbiota manipulation strategies. Gut microbiota may affect IBS development by regulating the mucosal immune system, brain–gut–microbiome interaction, and intestinal barrier function. The advent of high-throughput multi-omics provides important insights into the pathogenesis of IBS and promotes the development of individualized treatment for IBS. Despite advances in currently available microbiota-directed therapies, large-scale, well-organized, and long-term randomized controlled trials are highly warranted to assess their clinical effects. Overall, gut microbiota alterations play a critical role in the pathophysiology of IBS, and modulation of microbiota has a significant therapeutic potential that requires to be further verified.     

Microbiota of the gastrointestinal tract: Friend or foe?

The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.     

Human Intestinal Microbiota and Type 1 Diabetes

The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.     

Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression

ABSTRACT

Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear.

We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively.

Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides.

Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.     

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

ABSTRACT

Early dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigella was observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.     

Significance of the Gut Microbiome for Viral Diarrheal and Extra-Intestinal Diseases

The composition of the mammalian gut microbiome is very important for the health and disease of the host. Significant correlations of particular gut microbiota with host immune responsiveness and various infectious and noninfectious host conditions, such as chronic enteric infections, type 2 diabetes, obesity, asthma, and neurological diseases, have been uncovered. Recently, research has moved on to exploring the causalities of such relationships. The metabolites of gut microbiota and those of the host are considered in a ‘holobiontic’ way. It turns out that the host’s diet is a major determinant of the composition of the gut microbiome and its metabolites. Animal models of bacterial and viral intestinal infections have been developed to explore the interrelationships of diet, gut microbiome, and health/disease phenotypes of the host. Dietary fibers can act as prebiotics, and certain bacterial species support the host’s wellbeing as probiotics. In cases of Clostridioides difficile-associated antibiotic-resistant chronic diarrhea, transplantation of fecal microbiomes has sometimes cured the disease. Future research will concentrate on the definition of microbial/host/diet interrelationships which will inform rationales for improving host conditions, in particular in relation to optimization of immune responses to childhood vaccines.     

Indonesian children fecal microbiome from birth until weaning was different from microbiomes of their mothers

ABSTRACT

Gastrointestinal (GI) microbiota play an important role in human health and wellbeing and the first wave of gut microbes arrives mostly through vertical transmission from mother to child. This study has undertaken to understand the microbiota profile of healthy Southeast Asian mother-infant pairs. Here, we examined the fecal, vaginal and breast milk microbiota of Indonesian mothers and the fecal microbiota of their children from less than 1 month to 48 months old. To determine the immune status of children and the effect of diet at different ages, we examined the level of cytokines, bile acids in the fecal water and weaning food frequency. The fecal microbiota of the children before weaning contained mainly Bacteroides and Bifidobacterium, which presented at low abundance in the samples of mothers. After weaning, the fecal microbiome of children was mainly of the Prevotella type, with decreasing levels of Bifidobacterium, thus becoming more like the fecal microbiome of the mother. The abundance of infant fecal commensals generally correlated inversely with potential pathogens before weaning. The fecal Bifidobacterium in children correlated inversely with the consumption of complex carbohydrates and fruits after weaning. The specific cytokines related to the proliferation and maturation of immunity were found to increase after weaning. A decreasing level of primary bile acids and an increase of secondary bile acids were observed after weaning. This study highlights the change in the GI microbiota of infants to adult-type microbiota after weaning and identifies diet as a major contributing factor.     

Gut microbiome in primary sclerosing cholangitis: A review

Primary sclerosing cholangitis(PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease(IBD) and the "gut-liver" axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSCIBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites,including bile acids(BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.     

益生菌对大肠癌的防治作用及机制研究进展

大肠癌(colorectal cancer,CRC)是目前最常见的恶性肿瘤之一,CRC的发生及发展与肠道微生态有密切的关系。肠道菌群对于肠道功能的维持及内环境的平衡具有重要作用。肠道菌群失调可通过多种途径促进CRC的发生。益生菌是调节肠道微生态的主要方法,并可通过多种机制发挥抗肿瘤作用。本文综合目前研究进展,从调节肠道代谢产物、保护肠道黏膜屏障完整性、抑制肠道炎症、调节宿主免疫反应、促进凋亡和细胞分化、抑制细胞增殖等方面总结益生菌对癌前病变及CRC的防治作用及机制,为临床肠道微生态的调节及CRC的防治提供指导。     

Gut Microbiota as a Modulator of Cardiometabolic Risk: Mechanisms and Therapeutic Implications

Obesity-related disorders result from the combination of genetic susceptibility and environmental factors, including gut microbiota. Evidence from animal models provides insight into several mechanisms underlying the interaction between microbiome and host metabolic and inflammatory responses, such as increased energy harvest from the diet, regulation of intestinal transit rate and mucosal barrier function, modulation of fatty acid metabolism, and lipopolysaccharide-induced activation of Toll-like receptor-4 inflammatory pathway. In humans, gut microbiota alterations could link high energy intake and obesity-related cardiometabolic disorders; the composition of intestinal microflora of obese patients differs from that of lean subjects and microbiota manipulation through prebiotic/probiotics or microbial transplantation can affect post-prandial endotoxinemia levels and glucose metabolism. We discuss mechanisms connecting gut microbiota to obesity-related diseases and potential therapeutic applications.     

Gut Microbiome in Obesity,Metabolic Syndrome,and Diabetes

Purpose of Review

Obesity and diabetes are worldwide epidemics. There is also a growing body of evidence relating the gut microbiome composition to insulin resistance. The purpose of this review is to delineate the studies linking gut microbiota to obesity, metabolic syndrome, and diabetes.

Recent findings

Animal studies as well as proof of concept studies using fecal transplantation demonstrate the pivotal role of the gut microbiota in regulating insulin resistance states and inflammation.

Summary

While we still need to standardize methodologies to study the microbiome, there is an abundance of evidence pointing to the link between gut microbiome, inflammation, and insulin resistance, and future studies should be aimed at identifying unifying mechanisms.

     

Alcoholic Liver Disease: The Gut Microbiome and Liver Cross Talk

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut‐derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota.     

Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment

Gut microbiota constitute the largest reservoir of the human microbiome and are an abundant and stable ecosystem—based on its diversity, complexity, redundancy, and host interactions This ecosystem is indispensable for human development and health. The integrity of the intestinal mucosal barrier depends on its interactions with gut microbiota. The commensal bacterial community is implicated in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC). The dysbiosis of microbes is characterized by reduced biodiversity, abnormal composition of gut microbiota, altered spatial distribution, as well as interactions among microbiota, between different strains of microbiota, and with the host. The defects in microecology, with the related metabolic pathways and molecular mechanisms, play a critical role in the innate immunity of the intestinal mucosa in UC. Fecal microbiota transplantation (FMT) has been used to treat many diseases related to gut microbiota, with the most promising outcome reported in antibiotic‐associated diarrhea, followed by IBD. This review evaluated the results of various reports of FMT in UC. The efficacy of FMT remains highly controversial, and needs to be regularized by integrated management, standardization of procedures, and individualization of treatment.     

Role of gut microbiota in cardiovascular diseases

The human gut is colonized by a community of microbiota, primarily bacteria,that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology.Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease(CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites,including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.     

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.     

Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis

Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.