Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

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Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment.

Type 2 diabetes is the fastest-growing metabolic disease in the world. Many clinical studies have found that type 2 diabetes patients have metabolic disorders and chronic inflammatory states accompanied by disturbances in the gut microbiota. The gut microbiota plays an important role in body metabolism and immune regulation, and disturbances in the gut microbiota in conjunction with destruction of the intestinal barrier in type 2 diabetes patients causes damage to multiple organs. Therefore, the gut microbiota may be a new therapeutic target for treating type 2 diabetes and related diseases. In this review, we introduce the characteristics of the gut microbiota in type 2 diabetes and related diseases, as well as highlight the potential molecular mechanisms of their effects on intestinal barrier disruption, metabolic disorders, and chronic inflammation. Finally, we summarize an intestinal microecological therapeutic strategy, with a focus on shaping the intestinal bacteria, to improve the malignant progress of type 2 diabetes and related diseases. AUTHOR SUMMARY: Type 2 diabetes (T2D) is the fastest-growing metabolic disease in the world. Many clinical studies have found that T2D patients have metabolic disorders and chronic inflammatory states, accompanied by disturbances of the gut microbiota and increased intestinal permeability. The number of human gut microbiota is more than 10 times of human cells, and they play an important role in the body's metabolism and immune regulation. The abnormal intestinal metabolites and intestinal barrier disruption caused by the gut microbiota dysbiosis in the T2D facilitate intestinal bacteria and their harmful metabolites entering the circulatory system. The abnormal entering will cause the damage to multiple organs through disturbing insulin sensitivity, glucose metabolism, and immune homeostasis. Therefore, the gut microbiota may be a new therapeutic target for improving T2D and its related diseases. In this review, we introduce the compositional characteristics of the gut microbiota in T2D, and highlight some new molecular mechanisms of their effects on intestinal barrier disruption, metabolic disorders and chronic inflammation in T2D and its related diseases. Finally, we summarize an intestinal microecological therapeutic strategy, with a focus on shaping the intestinal bacteria, to improve the malignant progress of T2D and related diseases.

Role of the gut microbiota in type 2 diabetes and related diseases.

Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.

The Impact of CKD on Uremic Toxins and Gut Microbiota.

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failure results in disturbed renal metabolic activities with reduced renin, erythropoietin, and vitamin D production, which adversely affects the immune system. Decreased kidney function also leads to reduced glomerular filtration and the retention of uremic toxins. A large number of uremic toxins with detrimental effects on immune cells have been identified. Besides small water-soluble and protein-bound compounds originating from the intestinal microbiome, several molecules in the middle molecular range, e.g., immunoglobulin light chains, retinol-binding protein, the neuropeptides Met-enkephalin and neuropeptide Y, endothelin-1, and the adipokines leptin and resistin, adversely affect immune cells. Posttranslational modifications such as carbamoylation, advanced glycation products, and oxidative modifications contribute to uremic toxicity. Furthermore, high-density lipoprotein from uremic patients has an altered protein profile and thereby loses its anti-inflammatory properties.

Immune Dysfunction in Uremia 2020

The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease

Objective Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD). Design Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity. Results A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats. Conclusion Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients. Trial registration number This study was registered at ClinicalTrials.gov (NCT03010696).

https://gut.bmj.com/content/gutjnl/69/12/2131.full.pdf

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

Palatine tonsils are important lymphoid organs featuring constant cross-talks between the commensal microorganisms and immune system, and have been implicated as critical autoimmunity origins for immune-related diseases, including rheumatoid arthritis (RA), a common autoimmune disorder. However, there was no evidence to show link between tonsillar microbiota and RA. Here, we identified a significant dysbiosis of RA tonsillar microbiota, with loss of Streptococcus salivarius and its functional molecules salivaricins (a type of antibacterial peptides). Consistent with the niche-preference, S. salivarius and salivaricins administrated intranasally or intraorally conferred prophylactic and therapeutic efficacies against experimental arthritis. Moreover, we demonstrated, for the first time, that S. salivarius and salivaricins exerted immunosuppressive capacities via inhibiting CD4+ effector T cell subsets and autoantibody production in mice and human. These results uncover a communication between tonsillar microbiota and host autoimmunity, and identify the active components from tonsillar microbes in modulating immune homeostasis.

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Yuanjie Zhou

Papers

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

Mining the human tonsillar microbiota as autoimmune modulator