Role of intestinal microbiome in the pathogenesis of age-related macular degeneration

Background: The microbiome is strongly linked to many extra-intestinal disorders. Gut commensal microbiota, in particular, plays an active role in human immune and intestinal homeostasis. Complex interactions of the microbiota with host genetics and other underlying factors lead to intestinal dysbiosis, which is thought to be linked to ocular inflammatory diseases. Thus, the aim of this review is to analyze the role of intestinal microbiome in age-related macular degeneration (AMD). Methods: A thorough literature search was performed using PubMed/MEDLINE, limited to English language publications, from January 2004 to March 2020. An additional search was made employing Google Scholar to complete the collected data as per the above-mentioned time-line and language limitations. The main keywords used included age-related macular degeneration, microbiome, dysbiosis, autoimmunity, gut microbiota, epigenetics, immune-mediated inflammatory diseases, and gut-retina axis. Results: Recent studies have proposed the role of intestinal microbiota in the pathogenesis of AMD. Changes in the microbiome have been shown to trigger several ocular inflammatory processes. There is increasing evidence demonstrating that intestinal microbial imbalance may play an important role in the pathogenesis of AMD. Conclusions: This review summarizes how alterations in the intestinal microbiota can be associated with the pathogenesis of AMD and how new therapeutic modalities can be designed to target this microbiome to limit the severe nature of this disease. Future advances in microbiome research may unveil a new era in understanding and managing AMD

The regulation of host defences to infection by the microbiota

The skin and mucosal epithelia of humans and other mammals are permanently colonised by large microbial communities (the microbiota). Due to this life-long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota, or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps protect the host against intestinal and extra-intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra-intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions which need to be answered. This article is protected by copyright. All rights reserved

Disruption of Intestinal Th17 Signaling & the Microbiome Exacerbates Extra-Intestinal Pathologies

IL-17 signaling to the intestinal epithelium is a critical regulator of the intestinal microbiome. There is a growing body of research linking alterations in both Th17 cells and the intestinal microbiome to extra-intestinal pathologies including hepatitis and neuroinflammation. For example, many patients with autoimmune, fulminant, and viral hepatitis exhibit increased systemic IL-17, and Il17ra-\- mice are protected in concanavalin A (Con A)-induced hepatitis, a murine model of immune-mediated hepatitis. In Multiple Sclerosis (MS), elevated IL-17 was found in CNS lesions, and disrupted Th17 differentiation in mice ameliorates disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. In addition, many patients with hepatitis and MS display an altered intestinal microbiome, and germ-free mice as well antibiotic-treated mice have decreased disease in Con A hepatitis and EAE. Despite these data, few studies have investigated how the relationship between enteric Th17 cells and the microbiome influences extra-intestinal pathologies. Based on these reported links, we hypothesized that intestinal IL-17R signaling plays a critical role in mitigating hepatic and neuroinflammation. To test this, we generated intestinal epithelial specific IL-17RA knockout mice (Il17rafl/fl x villin cre+ mice). Because enteric Th17 signaling regulates the commensal microbiota, these mice exhibited an altered intestinal microbiome along with a subsequent expansion of intestinal Th17 cells. We then tested these mice in the Con A hepatitis model and EAE neuroinflammation model. Our results showed that perturbation of intestinal IL-17RA signaling was sufficient to exacerbate both liver and neuroinflammation in a microbiome-dependent manner. Abrogation of intestinal IL-17RA disrupted the intestinal microbiota and promoted translocation of bacterial products to the liver. Together, this induced IL-18 production and subsequent lymphocyte activation and cell death to worsen hepatitis. In EAE, intestinal IL-17RA deficiency induced intestinal dysbiosis and increased intestinal Il17 and Csf2 and systemic responses in both cytokines. Preliminary data suggested a potential increase of inflammatory monocyte infiltration into the CNS, together exacerbating disease. These dissertation studies elucidate the differential role of enteric Th17 cells and the microbiome in extra-intestinal pathologies and more broadly in mucosal immunology. Moreover, it provides insight into novel therapeutic strategies that target the gut-liver and gut-brain axes

Microbiota and chronic inflammatory arthritis. an interwoven link

Background: Only recently, the scientific community gained insights on the importance of the intestinal resident flora for the host's health and disease. Gut microbiota in fact plays a crucial role in modulating innate and acquired immune responses and thus interferes with the fragile balance inflammation versus tolerance. Main body: Correlations between gut bacteria composition and the severity of inflammation have been studied in inflammatory bowel diseases. More recently similar alterations in the gut microbiota have been reported in patients with spondyloarthritis, whereas in rheumatoid arthritis an accumulating body of evidence evokes a pathogenic role for the altered oral microbiota in disease development and course. In the context of dysbiosis it is also important to remember that different environmental factors like stress, smoke and dietary components can induce strong bacterial changes and consequent exposure of the intestinal epithelium to a variety of different metabolites, many of which have an unknown function. In this perspective, and in complex disorders like autoimmune diseases, not only the genetic makeup, sex and immunologic context of the individual but also the structure of his microbial community should be taken into account. Conclusions: Here we provide a review of the role of the microbiota in the onset, severity and progression of chronic inflammatory arthritis as well as its impact on the therapeutic management of these patients. Furthermore we point-out the complex interwoven link between gut-joint-brain and immune system by reviewing the most recent data on the literature on the importance of environmental factors such as diet, smoke and stress

Immunoglobulin A and liver diseases.

Immunoglobulin A (IgA) is a major immunoglobulin isotype in the gut and plays a role in maintenance of gut homeostasis. Secretory IgA (SIgA) has multiple functions in the gut, such as to regulate microbiota composition, to protect intestinal epithelium from pathogenic microorganisms, and to help for immune-system development. The liver is the front-line organ that receives gut-derived products through the portal vein, implying that the liver could be severely affected by a disrupted intestinal homeostasis. Indeed, some liver diseases like alcoholic liver disease are associated with an altered composition of gut microbiota and increased blood endotoxin levels. Therefore, deficiency of SIgA function appears as a significant factor for the pathogenesis of liver diseases associated with altered gut microbiome. In this review, we describe SIgA functions on the gut microbiome and discuss the role of IgA for liver diseases, especially alcoholic liver disease and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

Research gaps in diet and nutrition in inflammatory bowel disease. A topical review by D-ECCO Working Group (Dietitians of ECCO)

Although the current doctrine of IBD pathogenesis proposes an interaction between environmental factors with gut microbiota in genetically-susceptible individuals, dietary exposures have attracted recent interest and are, at least in part, likely to explain the rapid rise in disease incidence and prevalence. The D-ECCO working group along with other ECCO experts with expertise in nutrition, microbiology, physiology and medicine reviewed the evidence investigating the role of diet and nutritional therapy in the onset, perpetuation and management of IBD. A narrative topical review is presented where evidence pertinent to the topic is summarized collectively under three main thematic domains: i) the role of diet as an environmental factor in IBD aetiology; ii) the role of diet as induction and maintenance therapy in IBD; and iii) assessment of nutritional status and supportive nutritional therapy in IBD. A summary of research gaps for each of these thematic domains is proposed which is anticipated to be agenda setting for future research in the area of diet and nutrition in IBD

Histopathology of the gut in rheumatic diseases

The gastrointestinal tract regulates the trafficking of macromolecules between the environment and the host through an epithelial barrier mechanism and is an important part of the immune system controlling the equilibrium between tolerance and immunity to non-self-antigens. Various evidence indicates that intestinal inflammation occurs in patients with rheumatic diseases. In many rheumatic diseases intestinal inflammation appears to be linked to dysbiosis and possibly represents the common denominator in the pathogenesis of different rheumatic diseases. The continuative interaction between dysbiosis and the intestinal immune system may lead to the aberrant activation of immune cells that can re-circulate from the gut to the sites of extraintestinal inflammation as observed in patients with ankylosing spondylitis. The exact contribution of genetic factors in the development of intestinal inflammation in rheumatic diseases needs to be clarified

Characterization of the fecal microbiome in cats with inflammatory bowel disease or alimentary small cell lymphoma.

Feline chronic enteropathy (CE) is a common gastrointestinal disorder in cats and mainly comprises inflammatory bowel disease (IBD) and small cell lymphoma (SCL). Both IBD and SCL in cats share features with chronic enteropathies such as IBD and monomorphic epitheliotropic intestinal T-cell lymphoma in humans. The aim of this study was to characterize the fecal microbiome of 38 healthy cats and 27 cats with CE (13 cats with IBD and 14 cats with SCL). Alpha diversity indices were significantly decreased in cats with CE (OTU p = 0.003, Shannon Index p = 0.008, Phylogenetic Diversity p = 0.019). ANOSIM showed a significant difference in bacterial communities, albeit with a small effect size (P = 0.023, R = 0.073). Univariate analysis and LEfSE showed a lower abundance of facultative anaerobic taxa of the phyla Firmicutes (families Ruminococcaceae and Turicibacteraceae), Actinobacteria (genus Bifidobacterium) and Bacteroidetes (i.a. Bacteroides plebeius) in cats with CE. The facultative anaerobic taxa Enterobacteriaceae and Streptococcaceae were increased in cats with CE. No significant difference between the microbiome of cats with IBD and those with SCL was found. Cats with CE showed patterns of dysbiosis similar to those in found people with IBD

Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players?

Introduction: Non-alcoholic fatty liver disease (NAFLD), considered the leading cause of chronic liver disease in children, can often progress from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It is clear that obesity is one of the main risk factors involved in NAFLD pathogenesis, even if specific mechanisms have yet to be elucidated. We investigated the distribution of intestinal bifidobacteria and lactobacilli in the stools of four groups of children: obese, obese with NAFL, obese with NASH, and healthy, age-matched controls (CTRLs). Material and methods: Sixty-one obese, NAFL and NASH children and 54 CTRLs were enrolled in the study. Anthropometric and metabolic parameters were measured for all subjects. All children with suspected NASH underwent liver biopsy. Bifidobacteria and lactobacilli were analysed in children’s faecal samples, during a broader, 16S rRNA-based pyrosequencing analysis of the gut microbiome. Results: Three Bifidobacterium spp. (Bifidobacterium longum, Bifidobacterium bifidum, and Bifidobacterium adolescentis) and five Lactobacillus spp. (L. zeae, L. vaginalis, L. brevis, L. ruminis, and L. mucosae) frequently recurred in metagenomic analyses. Lactobacillus spp. increased in NAFL, NASH, or obese children compared to CTRLs. Particularly, L. mucosae was significantly higher in obese (p = 0.02426), NAFLD (p = 0.01313) and NASH (p = 0.01079) than in CTRLs. In contrast, Bifidobacterium spp. were more abundant in CTRLs, suggesting a protective and beneficial role of these microorganisms against the aforementioned diseases. Conclusions: Bifidobacteria seem to have a protective role against the development of NAFLD and obesity, highlighting their possible use in developing novel, targeted and effective probiotics

Lymphoma caused by intestinal microbiota.

The intestinal microbiota and gut immune system must constantly communicate to maintain a balance between tolerance and activation: on the one hand, our immune system should protect us from pathogenic microbes and on the other hand, most of the millions of microbes in and on our body are innocuous symbionts and some can even be beneficial. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been shown to be caused by the presence of certain bacteria. Animal models played an important role in establishing causation and mechanism of bacteria-induced MALT lymphoma. In this review we discuss different ways that animal models have been applied to establish a link between the gut microbiota and lymphoma and how animal models have helped to elucidate mechanisms of microbiota-induced lymphoma. While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma