Role of the gut microbiome in chronic diseases
The gut microbiome, i.e., the community of bacteria and other microorganisms living in the human gut, has been implicated both directly and indirectly (mediating the effects of diet) on human health. The associations between gut microbiome composition and disease status have been widely reported, while recent studies have demonstrated the role of the gut microbiome in influencing remote organs, mucosal, and immune function.
Differences in gut microbiome composition and function have been associated with a variety of chronic diseases ranging from gastrointestinal inflammatory and metabolic conditions to neurological, cardiovascular, and respiratory illnesses.
Gut microbiome and autoimmune disease
The pathogenesis of autoimmune diseases (AIDs) is not only attributed to genetic susceptibilities but also environmental factors, among which, the disturbed gut microbiota has attracted increasing attention. Compositional and functional changes in gut microbiota have been reported in various autoimmune diseases, and increasing evidence suggests that disturbed gut microbiota contributes to their immunopathogenesis.
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory condition that manifests in joint damage. It was recently demonstrated that different environmental factors are involved in the development of both intestinal/oral dysbiosis and arthritis onset and outcome, among which the most relevant are diet, smoking, and infections.
The observation that germ-free mice are protected from the development of experimental arthritis suggests a possible role for the microbiome in the pathogenesis of this disease. The composition of the gut microbiota in RA patients free of therapy is severely altered compared to healthy controls. Investigators reported that compared with healthy controls, patients with RA show decreased gut microbial diversity, which correlates with autoantibody levels and disease duration. In addition, at the compositional level, patients with RA show an increased abundance of Prevotella species, including Prevotella copri
Type 1 diabetes
In humans, intestinal microbiota alterations, including loss of bacterial diversity, preceded the onset of metabolic symptoms associated with type 1 diabetes (T1D).
Various human-based studies have also reported altered intestinal microbiota in connection to T1D from several ethnic groups. The common findings from these studies include increased numbers of Bacteroides species and deficiency of bacteria that produce SCFAs in cases of T1D. Specifically, the butyrate producer Faecalibacterium prausnitzii has been found to be decreased in abundance in children with diabetes-related autoantibodies. In addition, increased intestinal permeability and decreased microbial diversity before T1D diagnosis have been reported.
Atopic dermatitis (eczema)
Atopic eczema, a chronic inflammatory skin disorder, is most prevalent in early childhood. The pathogenesis of eczema has been attributed to skin-barrier dysfunctions, immune dysregulation as well as environmental–host-microbial interactions. Environmental factors and modern lifestyle trends have been shown to indirectly contribute to the pathogenesis of the disease through modulation of the gut microbiome.
It is evident that the compositional and proportional differences in the gut microbiome are associated with the development of AID via an immunomodulatory effect of the gut microbiome. The gut microbiome may contribute to the development, persistence, and severity of AID via immunologic, metabolic, and neuroendocrine pathways.
The rapid increase in asthma prevalence in industrialized nations over the past several decades cannot be explained by genetic risk factors alone and is thought to be related to altered environmental exposures associated with modern Western lifestyles. Early life is the most important period during which microbiota dysbiosis in the gut may lead to the development of many respiratory diseases, as the gut microbiota has a significant influence on immune-cell maturation and resistance to pathogens. Several validated epidemiological observations have implicated early-life environmental exposures in increased risk for childhood asthma. Many of these exposures are known to shape the nascent gut microbiome, including cesarean birth, antibiotic use, formula feeding, and other environmental factors including airborne toxins.
Gut microbiome and bowel disorders
Irritable bowel syndrome (IBS)
IBS is generally characterized by abdominal pain, discomfort, and altered bowel habits. Although the etiology is multifactorial, a recent understanding of the pathophysiology of IBS has revealed that variations in the normal gut microbiota may have a role to play in the low-grade intestinal inflammation associated with the syndrome. Microbial dysbiosis in the gut is thought to be involved in IBS pathogenesis and a recent study revealed a clear separation between the gut microbiota of patients with IBS and that of the controls. IBS was characterized by an increase in Firmicutes and, more specifically, in the numbers of Ruminococcus, Clostridium, and Dorea, in addition to a marked reduction of beneficial microbes such as Bifidobacterium and Faecalibacterium spp. Furthermore, systematic reviews have demonstrated the potentially harmful microbiota in patients with IBS, including phylum Proteobacteria, family Enterobacteriaceae (phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides (phylum Bacteroidetes). The Enterobacteriaceae family contains several pathogenic bacteria; for instance, Escherichia, Shigella, Campylobacter, and Salmonella.
Inflammatory bowel disease (IBD)
Long-lasting inflammation and ulceration of the colon are predominantly the main characteristics of IBD, which are features of Crohn’s disease and ulcerative colitis. IBD, encompassing both ulcerative colitis and Crohn’s disease, is characterized by chronic and relapsing inflammation of the GI tract. The onset of both conditions is, in general, not thought to be due to a single causal organism but to a general microbial dysbiosis in the gut. A role for gut microbes in the manifestation of IBD has been indicated by several studies and the gut microbiota are thought to be essential components in the development of mucosal lesions. The alterations in the composition and functionality of the gut microbiota in IBD compared with non-IBD controls have been shown previously. In general, microbial dysbiosis in IBD is characterized by a decrease in the diversity and stability of the microbiota. Specifically, a decrease in Firmicutes and an increase in Proteobacteria taxa are the most consistent outcome of IBD microbiome studies.
Gut microbiome composition and cardiometabolic diseases
The alterations in gut microbiota composition and the metabolic potential of gut microbiota have been identified as contributing factors in cardiovascular disease (CVD) development. Recently, mechanistic links between the gut microbiota and the severity of myocardial infarction have been reported in rats. Hypertension is the most prevalent modifiable risk factor for CVD.
Type 2 diabetes
Adults with type 2 diabetes (T2D) have an altered gut microbiota composition compared to healthy controls. Among the commonly reported findings, the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia, and Roseburia were negatively associated with T2D, while the genera of Ruminococcus, Fusobacterium, and Blautia were positively associated with T2D.
Non-alcoholic fatty liver disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) and the more advanced stage non-alcoholic steatohepatitis (NASH) are common comorbidities of obesity and T2D with an increasing burden on society. There is an increasing body of evidence linking the gut-liver axis to the development of NAFLD. Gut dysbiosis is directly related to increased intestinal permeability as a consequence of epithelial barrier deterioration, tight junction alteration, and bacterial translocation causing endotoxemia, which might reach and damage the liver through the portal vein. Several studies have revealed alterations in the gut microbiome in people with NAFLD compared with healthy controls.
Chronic kidney disease (CKD)
There has been a growing interest in studying the composition of the gut microbiota in patients with CKD as well as the mechanisms by which gut dysbiosis contributes to CKD progression. The influence of the gut microbiota on the gut–kidney axis acts in a reciprocal way with either CKD significantly modifying the composition and functions of the gut microbiota. Alternatively, the gut microbiota can manipulate the processes leading to CKD onset and progression through inflammatory, endocrine, and neurologic pathways. Therefore, understanding the complex interaction between these two organs may provide novel interventions to prevent the progression of CKD by targeting the gut microbiota.
The existence of intestinal microbiota alterations such as a decrease in microbial richness, diversity, and uniformity has been related to CKD. Patients with CDK show lower colonization of Bifidobacterium sp, Lactobacillaceae, Bacteroidaceae, Akkermansia, and Prevotellaceae genera, and higher intestinal levels of Enterobacteriaceae, particularly Enterobacter, Klebsiella, and Escherichia, and also increased levels of Enterococci and Clostridium perfringes. The decrease in the abundance of Akkermansia muciniphilla, an important probiotic, in patients with CKD negatively correlated with plasma IL-10 levels, suggesting that an altered microbiota in CKD may promote chronic systemic inflammation. This chronic systemic inflammation state represents a major risk factor for CKD progression.
CDK patients are characterized by decreased consumption of dietary fibers that are required for SCFA production. A lack of dietary fibers leads to increased amino nitrogen, which can be transformed into uremic toxins by the gut microbiota.
Mental health disorders
Gut microbes have been shown to also influence neurological functions and these links have been termed the “gut−brain axis”. The gut microbiota communicates with the brain through three major pathways—the neural pathway (vagus nerve, enteric nervous system), the immune pathway (cytokines), and the endocrine pathway (HPA axis, gut hormones). Impaired functioning of this connection can lead to the manifestation of mental disorders. Common gut microbial species belonging to the phylum Firmicutes and Actinobacteria, and the genera Bacteroides and Bifidobacterium, may be contributing to mental health disorders.
Gut microbiota modulates the gut−brain axis in numerous direct and indirect ways. This includes maintaining gut permeability by modulating the integrity of tight junctions in the gut epithelium, producing a wide variety of metabolites including neurotransmitters, SCFAs, and amino acids. These gut-derived metabolites can affect the central nervous system by acting locally on the enteric nervous system or enter circulation and affect the brain. Furthermore, alteration in the levels of gut microbial metabolites, such as SCFAs, ammonia, tryptophan, and histamine have shown to be associated, directly or by breaking down into neuroactive catabolites with various neurological conditions like Parkinson’s disease (PD), anorexia nervosa (AN), Alzheimer’s disease (AD), autism spectrum disorder (ASD), and chronic stress and depression.
Effects of a healthy diet are mediated via the gut microbiome
The most obvious way of targeting the gut microbiome is through dietary modifications. Already, several controlled clinical dietary intervention studies targeting the human gut microbiota have been reported. For example, diets rich in fiber were shown to significantly improve glucose control and promote a healthier metabolic profile in T2DM patients as well as reduce the risk of coronary heart disease.
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