Bifidobacterium longum RAPO Attenuates Dermal and Pulmonary Fibrosis in a Mouse Model of Systemic Sclerosis through Macrophage Modulation and Growth of Short-Chain Fatty Acid Producers
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Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro, B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc.
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro, B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc.
참고문헌 (62)
- Jeong JE, "Clinical characteristics of juvenile systemic sclerosis in Korea : 31-year single-center study", J Rheum Dis, 31, pp.25~32 (2024)
- Tsou PS, "Advances in epigenetics in systemic sclerosis : molecular mechanisms and therapeutic potential", Nat Rev Rheumatol, 17, pp.596~607 (2021)
- Bukiri H, "Current advances in the treatment of systemic sclerosis", Curr Opin Pharmacol, 64, pp.102211~ (2022)
- Lee SG, "Epidemiology and treatment of systemic sclerosis in Korea", J Rheum Dis, 29, pp.200~214 (2022)
- Volkmann ER, "Is there a role for the microbiome in systemic sclerosis?", Expert Rev Clin Immunol, 19, pp.237~240 (2023)
- Volkmann ER, "Association of systemic sclerosis with a unique colonic microbial consortium", Arthritis Rheumatol, 68, pp.1483~1492 (2016)
- Plichta DR, "Congruent microbiome signatures in fibrosis-prone autoimmune diseases : IgG4-related disease and systemic sclerosis", Genome Med, 13, pp.35~ (2021)
- Mehta H, "Early-life antibiotic exposure causes intestinal dysbiosis and exacerbates skin and lung pathology in experimental systemic sclerosis", J Invest Dermatol, 137, pp.2316~2325 (2017)
- Park HJ, "Butyrate improves skin", lung fibrosis and intestinal dysbiosis in bleomycin-induced mouse models, 2021, pp.22, 2765~
- Strahm N, "Effects of faecal microbiota transplantation on the small intestinal mucosa in systemic sclerosis", Rheumatology(Oxford), 62, pp.2918~2929 (2023)
- Marighela TF, "Effect of probiotics on gastrointestinal symptoms and immune parameters in systemic sclerosis : a randomized placebo-controlled trial", Rheumatology(Oxford), 58, pp.1985~1990 (2019)
- Hoffmann-Vold AM, "Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome(ACHIM)in patients with systemic sclerosis : study protocol for the randomised controlled phase II ReSScue trial", BMJ Open, 11, pp.e048541~ (2021)
- Balakrishnan B, "Prevotella histicola protects from arthritis by expansion of Allobaculum and augmenting butyrate production in humanized mice", Front Immunol, 12, pp.609644~ (2021)
- Scher JU, "Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis", Elife, 2, pp.e01202~ (2013)
- Wensel CR, "Next-generation sequencing : insights to advance clinical investigations of the microbiome", J Clin Invest, 132, pp.e154944~ (2022)
- Li J, "Development of a bacterial macroarray for the rapid screening of targeted antibody-secreted hybridomas", SLAS Discov, 24, pp.190~198 (2019)
- Campanero-Rhodes MA, "Development and evaluation of a microarray platform for detection of serum antibodies against Streptococcus pneumoniae capsular polysaccharides", Anal Chem, 92, pp.7437~7443 (2020)
- Lee SH, "Anti-microbial antibody response is associated with future onset of Crohn’s disease independent of biomarkers of altered gut barrier function, subclinical inflammation, and genetic risk", Gastroenterology, 161, pp.1540~1551 (2021)
- Thirumalapura NR, "Bacterial cell microarrays for the detection and characterization of antibodies against surface antigens", J Immunol Methods, 309, pp.48~54 (2006)
- Campanero-Rhodes MA, "Microarray strategies for exploring bacterial surface glycans and their interactions with glycan-binding proteins", Front Microbiol, 10, pp.2909~ (2020)
- Kim S, "Peptoniphilus gorbachii alleviates collagen-induced arthritis in mice by improving intestinal homeostasis and immune regulation", Front Immunol, 14, pp.1286387~ (2024)
- Hübner RH, "Standardized quantification of pulmonary fibrosis in histological samples", Biotechniques, 44, pp.507~517 (2008)
- Rivière A, "Bifidobacteria and butyrate-producing colon bacteria : importance and strategies for their stimulation in the human gut", Front Microbiol, 7, pp.979~ (2016)
- Mysore V, "Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2", J Exp Med, 219, pp.e20210562~ (2022)
- Vujkovic-Cvijin I, "The systemic anti-microbiota IgG repertoire can identify gut bacteria that translocate across gut barrier surfaces", Sci Transl Med, 14, pp.eabl3927~ (2022)
- Papp M, "Presence of anti-microbial antibodies in liver cirrhosis--a tell-tale sign of compromised immunity?", PLoS One, 5, pp.e12957~ (2010)
- Watanabe D, "Contribution of the gut microbiota to intestinal fibrosis in Crohn’s disease", Front Med(Lausanne), 9, pp.826240~ (2022)
- Rieder F, "The gut microbiome in intestinal fibrosis : environmental protector or provocateur?", Sci Transl Med, 5, pp.190~ (2013)
- Christmann BS, "Human seroreactivity to gut microbiota antigens", J Allergy Clin Immunol, 136, pp.1378~1386 (2015)
- Zeng MY, "Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens", Immunity, 44, pp.647~658 (2016)
- Fretheim H, "Fecal microbiota transplantation in systemic sclerosis : a double-blind, placebo-controlled randomized pilot trial", PLoS One, 15, pp.e0232739~ (2020)
- Volkmann ER, "Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts", BMJ Open Gastroenterol, 4, pp.e000134~ (2017)
- Natalello G, "Gut microbiota analysis in systemic sclerosis according to disease characteristics and nutritional status", Clin Exp Rheumatol, 38(Suppl 125), pp.73~84 (2020)
- Arron ST, "High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis", J Invest Dermatol, 134, pp.2138~2145 (2014)
- Johnson ME, "Microbiome dysbiosis is associated with disease duration and increased inflammatory gene expression in systemic sclerosis skin", Arthritis Res Ther, 21, pp.49~ (2019)
- Takahashi Y, "Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis", Respir Res, 19, pp.34~ (2018)
- Nakajima A, "IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria", J Exp Med, 215, pp.2019~2034 (2018)
- Magri G, "Human secretory IgM emerges from plasma cells clonally related to gut memory B cells and targets highly diverse commensals", Immunity, 47, pp.118~134 (2017)
- Boonstra M, "Association of anti–topoisomerase I antibodies of the IgM isotype with disease progression in anti–topoisomerase I–positive systemic sclerosis", Arthritis Rheumatol, 72, pp.1897~1904 (2020)
- Jones K, "Immunoglobulin M in health and diseases : how far have we come and what next?", Front Immunol, 11, pp.595535~ (2020)
- Sterlin D, "The antibody", microbiota interface in health and disease, 2020, pp.13, 3~11
- Fang Z, "Bifidobacterium longum mediated tryptophan metabolism to improve atopic dermatitis via the gut-skin axis", Gut Microbes, 14, pp.2044723~ (2022)
- MacSharry J, "Immunomodulatory effects of feeding with Bifidobacterium longum on allergen-induced lung inflammation in the mouse", Pulm Pharmacol Ther, 25, pp.325~334 (2012)
- Derrien M, "Insights into endogenous Bifidobacterium species in the human gut microbiota during adulthood", Trends Microbiol, 30, pp.940~947 (2022)
- Devika NT, "Deciphering the metabolic capabilities of Bifidobacteria using genome-scale metabolic models", Sci Rep, 9, pp.18222~ (2019)
- Oh DK, "Bifidobacterium longum BORI inhibits pain behavior and chondrocyte death, and attenuates osteoarthritis progression", PLoS One, 18, pp.e0286456~ (2023)
- Jeong Y, "Therapeutic potential of a novel Bifidobacterium identified through microbiome profiling of RA patients with different RF levels", Front Immunol, 12, pp.736196~ (2021)
- Ruiz L, "Bifidobacteria and their molecular communication with the immune system", Front Microbiol, 8, pp.2345~ (2017)
- Gong P, "Mesenchymal stem cells alleviate systemic sclerosis by inhibiting the recruitment of pathogenic macrophages", Cell Death Dis, 8, pp.466~ (2022)
- Toledo DM, "Macrophages in systemic sclerosis : novel insights and therapeutic implications", Curr Rheumatol Rep, 21, pp.31~ (2019)
- Al-Adwi Y, "Macrophages as determinants and regulators of fibrosis in systemic sclerosis", Rheumatology(Oxford), 62, pp.535~545 (2023)
- Mathes AL, "Global chemokine expression in systemic sclerosis(SSc) : CCL19 expression correlates with vascular inflammation in SSc skin", Ann Rheum Dis, 73, pp.1864~1872 (2014)
- Wu M, "Ccl2 in the circulation predicts long-term progression of interstitial lung disease in patients with early systemic sclerosis : data from two independent cohorts", Arthritis Rheumatol, 69, pp.1871~1878 (2017)
- Bhandari R, "Profibrotic activation of human macrophages in systemic sclerosis", Arthritis Rheumatol, 72, pp.1160~1169 (2020)
- Flint HJ, "Links between diet, gut microbiota composition and gut metabolism", Proc Nutr Soc, 74, pp.13~22 (2015)
- Lee C, "Microbial components and effector molecules in T helper cell differentiation and function", Immune Netw, 23, pp.e7~ (2023)
- Li M, "Pro-and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells", Eur J Pharmacol, 831, pp.52~59 (2018)
- He M, "Gut microbiota as a potential target of metabolic syndrome : the role of probiotics and prebiotics", Cell Biosci, 7, pp.54~ (2017)
- Kou R, "Ameliorating Effects of Bifidobacterium longum subsp. infantis FB3-14 against high-fat-diet-induced obesity and gut microbiota disorder", Nutrients, 15, pp.4104~ (2023)
- Trompette A, "Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis", Nat Med, 20, pp.159~166 (2014)
- Bermudez-Brito M, "Cell-free culture supernatant of Bifidobacterium breve CNCM I-4035 decreases pro-inflammatory cytokines in human dendritic cells challenged with Salmonella typhi through TLR activation", PLoS One, 8, pp.e59370~ (2013)
- Yang KM, "Lactobacillus reuteri AN417 cell-free culture supernatant as a novel antibacterial agent targeting oral pathogenic bacteria", Sci Rep, 11, pp.1631~ (2021)
