Abstract:Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propion… Show more
“…In RA, propionate is believed to induce systemic effects on adaptive immune cells and modulate the functional phenotype of arthritogenic synovial fibroblasts ( 39 ). Supplementation of propionate in the drinking water in mice with collagen induced arthritis (a preclinical RA model) has been shown to result in reduced frequency of bone marrow megakaryocyte erythrocyte progenitor population ( 40 ), which may support inflammatory arthritis attenuating effects ( 41 ). Finally, in a prospective observational study, a high‐fiber low‐meat diet (providing the fuel for SCFA biosynthesis) was associated with better odds for responding to biological treatment in RA ( 42 ).…”
ObjectiveWe investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate‐treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT).MethodsThis exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate‐to‐high peripheral PsA disease activity, despite at least 3 months of methotrexate‐treatment, were included in a 26‐week, double‐blind, 1:1 randomized, sham‐controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose‐to‐mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1H Nuclear Magnetic Resonance.ResultsTrial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017‐0.33]) vs. 0.012 [0‐0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N‐acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02).ConclusionIntestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.
“…In RA, propionate is believed to induce systemic effects on adaptive immune cells and modulate the functional phenotype of arthritogenic synovial fibroblasts ( 39 ). Supplementation of propionate in the drinking water in mice with collagen induced arthritis (a preclinical RA model) has been shown to result in reduced frequency of bone marrow megakaryocyte erythrocyte progenitor population ( 40 ), which may support inflammatory arthritis attenuating effects ( 41 ). Finally, in a prospective observational study, a high‐fiber low‐meat diet (providing the fuel for SCFA biosynthesis) was associated with better odds for responding to biological treatment in RA ( 42 ).…”
ObjectiveWe investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate‐treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT).MethodsThis exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate‐to‐high peripheral PsA disease activity, despite at least 3 months of methotrexate‐treatment, were included in a 26‐week, double‐blind, 1:1 randomized, sham‐controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose‐to‐mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1H Nuclear Magnetic Resonance.ResultsTrial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017‐0.33]) vs. 0.012 [0‐0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N‐acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02).ConclusionIntestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.
“…However, these gut microbiota metabolites can induce an increase in megakaryocyte maturation and platelet production. 85 Research on the role of the gut microbiota in megakaryocytic lineage development remains lacking, requiring further in-depth exploration in future studies. Figure 2.…”
Section: Gut Microbiota and Hematopoiesismentioning
The gut microbiota constitutes a vast ecological system within the human body, forming a mutually interdependent entity with the host. In recent years, advancements in molecular biology technologies have provided a clearer understanding of the role of the gut microbiota. They not only influence the local immune status and metabolic functions of the host’s intestinal tract but also impact the functional transformation of hematopoietic stem cells (HSCs) through the gut-blood axis. In this review, we will discuss the role of the gut microbiota in influencing hematopoiesis. We analyze the interactions between HSCs and other cellular components, with a particular emphasis on the direct functional regulation of HSCs by the gut microbiota and their indirect influence through cellular components in the bone marrow microenvironment. Additionally, we propose potential control targets for signaling pathways triggered by the gut microbiota to regulate hematopoietic function, filling crucial knowledge gaps in the development of this research field.
“…The altered microbiome in SS patients may also activate the immune system via molecular mimicry and metabolite changes, leading to chronic inflammation and damage to the exocrine glands [ 46 , 121 ]. Gut metabolites alterations are also observed in other autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis [ 122 – 124 ]. These findings can be used to discover novel metabolites, in addition to the classical short chain fatty acids [ 125 , 126 ], that can be used as therapeutic molecules.…”
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by inflammatory cell infiltration of the salivary and lacrimal glands, resulting in acinar epithelial cell atrophy, cell death, and loss of exocrine function. At least half of SS patients develop extraglandular inflammatory disease and have a wide range of systemic clinical manifestations that can affect any organ system, including connective tissues. As many as 3.1 million people in the U.S. suffer from SS, a disease that causes severe impairment. Women are nine times more likely than men to be affected by this condition. Unfortunately, there is currently no effective treatment for SS, and the available options only provide partial relief. Treatment involves using replacement therapies such as artificial saliva and eye lubricants, or immunosuppressive agents that have limited efficacy. The medical community recognizes that there is a significant need for more effective treatments for SS. Increasing evidence demonstrates the links between the dysfunction of the human microbial community and the onset and development of many human diseases, signifying the potential use of microorganisms as an alternative strategy to conquer these issues. The role of the microbiome in controlling immune function of the human host in the context of autoimmune diseases like SS is now becoming better understood and may help to enable new drug development strategies. Natural probiotics and synthetic biology applications hold promise for novel treatment approaches to solve the encryption of many complex and multifactorial immune disorders, like SS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
