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.     

The gut microbial influence on cholestatic liver disease

Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut‐liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host‐microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment‐stratifiers. In this way, gut microbiome‐based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.     

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.     

Alternations of gut microbiota composition in neonates conceived by assisted reproductive technology and its relation to infant growth

ABSTRACT

The gut microbiome in newborns may be strongly influenced by their intrinsic host microenvironmental factors (e.g., the gestational age) and has been linked to their short-term growth and potentially future health. It is yet unclear whether early microbiota composition is significantly different in newborns conceived by assisted reproductive technology (ART) when compared with those who were conceived spontaneously. Additionally, little is known about the effect of gut microbiota composition on weight gain in early infancy. We aimed to characterize the features and the determinants of the gut microbiome in ART newborns and to assess the impact of early microbiota composition on their weight gain in early infancy in mother-infant dyads enrolled in the China National Birth Cohort (CNBC). Among 118 neonates born by ART and 91 neonates born following spontaneous conception, we observed significantly reduced gut microbiota α-diversity and declined Bacteroidetes relative abundance in ART neonates. The microbiota composition of ART neonates was largely driven by specific ART treatments, hinting the importance of fetus intrinsic host microenvironment on the early microbial colonization. Following up these neonates for six months after their births, we observed the effects of gut microbiome composition on infant rapid weight gaining. Collectively, we identified features and determinants of the gut microbiota composition in ART neonates, and provided evidence for the importance of microbiota composition in neonatal growth.     

Hypogonadism alters cecal and fecal microbiota in male mice

Low testosterone levels increase the risk for cardiovascular disease in men and lead to shorter life spans. Our recent study showed that androgen deprivation via castration altered fecal microbiota and exacerbated risk factors for cardiovascular disease, including obesity, impaired fasting glucose, excess hepatic triglyceride accumulation, and thigh muscle weight loss only in high-fat diet (HFD)-fed male mice. However, when mice were administered antibiotics that disrupted the gut microbiota, castration did not increase cardiovascular risks or decrease the ratio of dried feces to food intake. Here, we show that changes in cecal microbiota (e.g., an increased Firmicutes/Bacteroidetes ratio and number of Lactobacillus species) were consistent with changes in feces and that there was a decreased cecal content secondary to castration in HFD mice. Castration increased rectal body temperature and plasma adiponectin, irrespective of diet. Changes in the gut microbiome may provide novel insight into hypogonadism-induced cardiovascular diseases.     

Longitudinal gut microbiome changes in alcohol use disorder are influenced by abstinence and drinking quantity

ABSTRACT

Many patients with alcohol use disorder (AUD) consume alcohol chronically and in large amounts that alter intestinal microbiota, damage the gastrointestinal tract, and thereby injure other organs via malabsorption and intestinal inflammation. We hypothesized that alcohol consumption and subsequent abstinence would change the gut microbiome in adults admitted to a treatment program. Stool and oral specimens, diet data, gastrointestinal assessment scores, anxiety, depression measures and drinking amounts were collected longitudinally for up to 4 weeks in 22 newly abstinent inpatients with AUD who were dichotomized as less heavy drinkers (LHD, <10 drinks/d) and very heavy drinkers (VHD, 10 or more drinks/d). Next-generation 16 S rRNA gene sequencing was performed to measure the gut and oral microbiome at up to ten time points/subject and LHD and VHD were compared for change in principal components, Shannon diversity index and specific genera. The first three principal components explained 46.7% of the variance in gut microbiome diversity across time and all study subjects, indicating the change in gut microbiome following abstinence. The first time point was an outlier in three-dimensional principal component space versus all other time points. The gut microbiota in LHD and VHD were significantly dissimilar in change from day 1 to day 5 (p = .03) and from day 1 to week 3 (p = .02). The VHD drinking group displayed greater change from baseline. The Shannon diversity index of the gut microbiome changed significantly during abstinence in five participants. In both groups, the Shannon diversity was lower in the oral microbiome than gut. Ten total genera were shared between oral and stool in the AUD participants. These data were compared with healthy controls from the Human Microbiome Project to investigate the concept of a core microbiome. Rapid changes in gut microbiome following abstinence from alcohol suggest resilience of the gut microbiome in AUD and reflects the benefits of refraining from the highest levels of alcohol and potential benefits of abstinence.     

Characterization of the human gut microbiome during travelers' diarrhea

Alterations in the gut microbiota are correlated with ailments such as obesity, inflammatory bowel disease, and diarrhea. Up to 60% of individuals traveling from industrialized to developing countries acquire a form of secretory diarrhea known as travelers' diarrhea (TD), and enterotoxigenic Escherichia coli (ETEC) and norovirus (NoV) are the leading causative pathogens. Presumably, TD alters the gut microbiome, however the effect of TD on gut communities has not been studied. We report the first analysis of bacterial gut populations associated with TD. We examined and compared the gut microbiomes of individuals who developed TD associated with ETEC, NoV, or mixed pathogens, and TD with no pathogen identified, to healthy travelers. We observed a signature dysbiotic gut microbiome profile of high Firmicutes:Bacteroidetes ratios in the travelers who developed diarrhea, regardless of etiologic agent or presence of a pathogen. There was no significant difference in α-diversity among travelers. The bacterial composition of the microbiota of the healthy travelers was similar to the diarrheal groups, however the β-diversity of the healthy travelers was significantly different than any pathogen-associated TD group. Further comparison of the healthy traveler microbiota to those from healthy subjects who were part of the Human Microbiome Project also revealed a significantly higher Firmicutes:Bacteriodetes ratio in the healthy travelers and significantly different β-diversity. Thus, the composition of the gut microbiome in healthy, diarrhea-free travelers has characteristics of a dysbiotic gut, suggesting that these alterations could be associated with factors such as travel.     

Gut microbiota imbalance and colorectal cancer

The gut microbiota acts as a real organ. The symbiotic interactions between resident micro-organisms and the digestive tract highly contribute to maintain the gut homeostasis. However, alterations to the microbiome caused by environmental changes(e.g., infection, diet and/or lifestyle) can disturb this symbiotic relationship and promote disease, such as inflammatory bowel diseases and cancer. Colorectal cancer is a complex association of tumoral cells, non-neoplastic cells and a large amount of micro-organisms, and the involvement of the microbiota in colorectal carcinogenesis is becoming increasingly clear. Indeed, many changes in the bacterial composition of the gut microbiota have been reported in colorectal cancer, suggesting a major role of dysbiosis in colorectal carcinogenesis. Some bacterial species have been identified and suspected to play a role in colorectal carcinogenesis, such as Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis, Enterococcus faecalis, Clostridium septicum, Fusobacterium spp. and Escherichia coli. The potential pro-carcinogenic effects of these bacteria are now better understood. In this review, we discuss the possible links between the bacterial microbiota and colorectal carcinogenesis, focusing on dysbiosis and the potential pro-carcinogenic properties of bacteria, such as genotoxicity and other virulence factors, inflammation, host defenses modulation, bacterial derived metabolism, oxidative stress and anti-oxidative defenses modulation. We lastly describe how bacterial microbiota modifications could represent novel prognosis markers and/or targets for innovative therapeutic strategies.     

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.     

Composition and richness of the serum microbiome differ by age and link to systemic inflammation

Advanced age has been associated with alterations to the microbiome within the intestinal tract as well as intestinal permeability (i.e., “leaky gut”). Prior studies suggest that intestinal permeability may contribute to increases in systemic inflammation—an aging hallmark—possibly via microorganisms entering the circulation. Yet, no studies exist describing the state of the circulating microbiome among older persons. To compare microbiota profiles in serum between healthy young (20–35 years, n?=?24) and older adults (60–75 years, n?=?24) as well as associations between differential microbial populations and prominent indices of age-related inflammation. Unweighted Unifrac analysis, a measure of β-diversity, revealed that microbial communities clustered differently between young and older adults. Several measures of α-diversity, including chao1 (p?=?0.001), observed species (p?=?0.001), and phylogenetic diversity (p?=?0.002) differed between young and older adults. After correction for false discovery rate (FDR), age groups differed (all p values ≤?0.016) in the relative abundance of the phyla Bacteroidetes, SR1, Spirochaetes, Bacteria_Other, TM7, and Tenericutes. Significant positive correlations (p values ≤?0.017 after FDR correction) were observed between IGF1 and Bacteroidetes (ρ?=?0.380), Spirochaetes (ρ?=?0.528), SR1 (ρ?=?0.410), and TM7 (ρ?=?0.399). Significant inverse correlations were observed for IL6 with Bacteroidetes (ρ?=???0.398) and TM7 (ρ?=???0.423), as well as for TNFα with Bacteroidetes (ρ?=???0.344). Similar findings were observed at the class taxon. These data are the first to demonstrate that the richness and composition of the serum microbiome differ between young and older adults and that these factors are linked to indices of age-related inflammation.     

Dietary pulses as a means to improve the gut microbiome,inflammation, and appetite control in obesity

A dysbiotic intestinal microbiome has been linked to chronic diseases such as obesity, which may suggest that interventions that target the microbiome may be useful in treating obesity and its complications. Appetite dysregulation and chronic systemic low-grade inflammation, such as that observed in obesity, are possibly linked with the intestinal microbiome and are potential therapeutic targets for the treatment of obesity via the microbiome. Dietary pulses (e.g., common beans) are composed of nutrients and compounds that possess the potential to modulate the gut microbiota composition and function which can in turn improve appetite regulation and chronic inflammation in obesity. This narrative review summarizes the current state of knowledge regarding the connection between the gut microbiome and obesity, appetite regulation, and systemic and adipose tissue inflammation. More specifically, it highlights the efficacy of interventions employing dietary common beans as a means to improve gut microbiota composition and/or function, appetite regulation, and inflammation in both rodent obesity and in humans. Collectively, results presented and discussed herein provide insight on the gaps in knowledge necessary for a comprehensive understanding of the potential of beans as a treatment for obesity while highlighting what further research is required to gain this understanding.     

Assessing gut microbiota perturbations during the early phase of infectious diarrhea in Vietnamese children

Diarrheal diseases remain the second most common cause of mortality in young children in developing countries. Efforts have been made to explore the impact of diarrhea on bacterial communities in the human gut, but a thorough understanding has been impeded by inadequate resolution in bacterial identification and the examination of only few etiological agents. Here, by profiling an extended region of the 16S rRNA gene in the fecal microbiome, we aimed to elucidate the nature of gut microbiome perturbations during the early phase of infectious diarrhea caused by various etiological agents in Vietnamese children. Fecal samples from 145 diarrheal cases with a confirmed infectious etiology before antimicrobial therapy and 54 control subjects were analyzed. We found that the diarrheal fecal microbiota could be robustly categorized into 4 microbial configurations that either generally resembled or were highly divergent from a healthy state. Factors such as age, nutritional status, breastfeeding, and the etiology of the infection were significantly associated with these microbial community structures. We observed a consistent elevation of Fusobacterium mortiferum, Escherichia, and oral microorganisms in all diarrheal fecal microbiome configurations, proposing similar mechanistic interactions, even in the absence of global dysbiosis. We additionally found that Bifidobacterium pseudocatenulatum was significantly depleted during dysenteric diarrhea regardless of the etiological agent, suggesting that further investigations into the use of this species as a dysentery-orientated probiotic therapy are warranted. Our findings contribute to the understanding of the complex influence of infectious diarrhea on gut microbiome and identify new opportunities for therapeutic interventions.     

Diet and Gut Microbial Function in Metabolic and Cardiovascular Disease Risk

Over the past decade, the gut microbiome has emerged as a novel and largely unexplored source of variability for metabolic and cardiovascular disease risk, including diabetes. Animal and human studies support several possible pathways through which the gut microbiome may impact health, including the production of health-related metabolites from dietary sources. Diet is considered important to shaping the gut microbiota; in addition, gut microbiota influence the metabolism of many dietary components. In the present paper, we address the distinction between compositional and functional analysis of the gut microbiota. We focus on literature that highlights the value of moving beyond surveys of microbial composition to measuring gut microbial functioning to delineate mechanisms related to the interplay between diet and gut microbiota in cardiometabolic health.     

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.     

Development of the human gastrointestinal microbiota and insights from high-throughput sequencing

Little was known about the development of the gastrointestinal (GI) tract microbiota, until recently, because of difficulties in obtaining sufficient sequence information from enough people or time points. Now, with decreased costs of DNA sequencing and improved bioinformatic tools, we can compare GI tract bacterial communities among individuals, of all ages from infancy to adulthood. Some key recent findings are that the initial bacterial community, even in the GI tract, depends strongly on delivery mode; that the process of early development of the microbiota is highly unstable and idiosyncratic; that the microbiota differs considerably among children from different countries; and that older adults have substantially different GI tract communities than younger adults, indicating that the GI tract microbiota can change throughout life. We relate these observations to different models of evolution including the evolution of senescence and suggest that probiotics be selected based on patient age. Studies of the microbiota in older people might tell us which probiotics could increase longevity. Drug metabolism varies among individuals with different microbial communities, so age- and region-specific clinical trials are required to ensure safety and efficacy.     

Improving healthspan via changes in gut microbiota and fermentation

Dietary resistant starch impact on intestinal microbiome and improving healthspan is the topic of this review. In the elderly population, dietary fiber intake is lower than recommended. Dietary resistant starch as a source of fiber produces a profound change in gut microbiota and fermentation in animal models of aging. Dietary resistant starch has the potential for improving healthspan in the elderly through multiple mechanisms as follows: (1) enhancing gut microbiota profile and production of short-chain fatty acids, (2) improving gut barrier function, (3) increasing gut peptides that are important in glucose homeostasis and lipid metabolism, and (4) mimicking many of the effects of caloric restriction including upregulation of genes involved in xenobiotic metabolism.     

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

ABSTRACT

The gastrointestinal microbiome plays a pivotal role in physiological homeostasis of the intestine as well as in the pathophysiology of diseases including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Emerging evidence suggests that gut microbiota signal to the mitochondria of mucosal cells, including epithelial cells and immune cells. Gut microbiota signaling to mitochondria has been shown to alter mitochondrial metabolism, activate immune cells, induce inflammasome signaling, and alter epithelial barrier function. Both dysbiosis of the gut microbiota and mitochondrial dysfunction are associated with chronic intestinal inflammation and CRC. This review discusses mitochondrial metabolism of gut mucosal cells, mitochondrial dysfunction, and known gut microbiota-mediated mitochondrial alterations during IBD and CRC.     

Weight‐loss interventions and gut microbiota changes in overweight and obese patients: a systematic review

Imbalances in the gut microbiota, the bacteria that inhabit the intestines, are central to the pathogenesis of obesity. This systematic review assesses the association between the gut microbiota and weight loss in overweight/obese adults and its potential manipulation as a target for treating obesity. This review identified 43 studies using the keywords ‘overweight’ or ‘obesity’ and ‘microbiota’ and related terms; among these studies, 17 used dietary interventions, 11 used bariatric surgery and 15 used microbiota manipulation. The studies differed in their methodologies as well as their intervention lengths. Restrictive diets decreased the microbiota abundance, correlated with nutrient deficiency rather than weight loss and generally reduced the butyrate producers Firmicutes, Lactobacillus sp. and Bifidobacterium sp. The impact of surgical intervention depended on the given technique and showed a similar effect on butyrate producers, in addition to increasing the presence of the Proteobacteria phylum, which is related to changes in the intestinal absorptive surface, pH and digestion time. Probiotics differed in strain and duration with diverse effects on the microbiota, and they tended to reduce body fat. Prebiotics had a bifidogenic effect and increased butyrate producers, likely due to cross‐feeding interactions, contributing to the gut barrier and improving metabolic outcomes. All of the interventions under consideration had impacts on the gut microbiota, although they did not always correlate with weight loss. These results show that restrictive diets and bariatric surgery reduce microbial abundance and promote changes in microbial composition that could have long‐term detrimental effects on the colon. In contrast, prebiotics might restore a healthy microbiome and reduce body fat.     

Microbiome changes associated with acute and chronic pancreatitis: A systematic review

BackgroundAltered intestinal microbiota has been reported in pancreatic disorders, however, it remains unclear whether these changes alter the course of disease in patients with acute (AP) and chronic pancreatitis (CP), or whether these disease states alter the environment to enable pathogenic microbial composition changes to occur. We undertook a systematic review to characterize the gut microbiome in pancreatitis patients.MethodsMEDLINE and EMBASE were searched for studies on microbiota in pancreatitis published from January 1, 2000 to June 5, 2020. Animal studies, reviews, case reports, and non-English articles were excluded. A frequency analysis was performed for outcomes reported in ≥2 studies and studies were analyzed for risk of bias and quality of evidence.Results22 papers met inclusion criteria; 15 included AP, 7 included CP. No studies were appropriately designed to assess whether alterations in the gut microbiome exacerbate pancreatitis or develop as a result of pancreatitis. We did identify several patterns of microbiome changes that are associated with pancreatitis. The gut microbiome demonstrated decreased alpha diversity in 3/3 A P studies and 3/3 C P studies. Beta diversity analysis revealed differences in bacterial community composition in the gut microbiome in 2/2 A P studies and 3/3 C P studies. Functionally, gut microbiome changes were associated with infectious pathways in AP and CP. Several studies suffered from high risk of bias and inadequate quality.ConclusionsDetecting differences in microbial composition associated with AP and CP may represent a diagnostic tool. Appropriately controlled longitudinal studies are needed to determine whether microbiome changes are causative or reactive in pancreatitis.