Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis

Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis

Exploring the role of gut microbiota in advancing personalized medicine

Ongoing extensive research in the field of gut microbiota (GM) has highlighted the crucial role of gut-dwelling microbes in human health. These microbes possess 100 times more genes than the human genome and offer significant biochemical advantages to the host in nutrient and drug absorption, metabolism, and excretion. It is increasingly clear that GM modulates the efficacy and toxicity of drugs, especially those taken orally. In addition, intra-individual variability of GM has been shown to contribute to drug response biases for certain therapeutics. For instance, the efficacy of cyclophosphamide depends on the presence of Enterococcus hirae and Barnesiella intestinihominis in the host intestine. Conversely, the presence of inappropriate or unwanted gut bacteria can inactivate a drug. For example, dehydroxylase of Enterococcus faecalis and Eggerthella lenta A2 can metabolize L-dopa before it converts into the active form (dopamine) and crosses the blood–brain barrier to treat Parkinson’s disease patients. Moreover, GM is emerging as a new player in personalized medicine, and various methods are being developed to treat diseases by remodeling patients’ GM composition, such as prebiotic and probiotic interventions, microbiota transplants, and the introduction of synthetic GM. This review aims to highlight how the host’s GM can improve drug efficacy and discuss how an unwanted bug can cause the inactivation of medicine

The role of the microbiome in rheumatoid arthritis

The human microbiome plays a vital role in both health and disease. The evolution of molecular techniques to characterise entire microbiome communities has renewed interest in the involvement of microorganisms in the pathogenesis of Rheumatoid arthritis (RA). In this thesis, 16S and ITS amplicon sequencing were used to characterise bacterial and fungal DNA present in a range of human and mouse samples. Firstly, characterisation of the microbiome present in blood samples obtained from human RA, ankylosing spondylitis, and psoriatic arthritis patients was carried out, relative to healthy controls. Results revealed that the bacterial population in the serum of RA patients was distinct from the healthy state. Through the analysis of paired RA patient blood taken before and three months after treatment, partial microbiome normalisation was identified and was particularly evident in seronegative arthritis patients. Next, the presence and identity of bacterial and fungal communities were investigated in samples of synovial fluid obtained from human RA patients and healthy controls. Our findings revealed that the synovial fluid microbiome of RA could be distinguished from control. Further, IL6, IL71A, IL22, IL23 were elevated in the blood and synovial fluid of RA subjects. The association of IL6 with bacteria and fungi microbiome was observed in the RA synovial fluid. Finally, a characterisation of the bacterial community members presents in the stool, urine, synovial fluid, blood, and serum from collagen-induced arthritis (CIA) and control mouse samples were undertaken. Here, we demonstrated that the bacterial community in CIA stool samples was distinct from the control. These data propose that the human blood and synovial fluid microbiome and gut microbiome of the mice is modulated by disease status (RA) and therefore have the potential to serve as a novel biomarker in RA pathogenesis and treatment response. Further, studies are required to investigate these initial findings

Perspectives in melanoma: meeting report from the Melanoma Bridge (December 5th-7th, 2019, Naples, Italy).

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report

Osteoarthritis: genetics and phenotypes in all their complexity

The genetic epidemiology of ostheoarthritis, using genome-wide association studies and other omics to elucidate teh pathology of this common joint disorder

The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis