Butyrate Improves Skin/Lung Fibrosis and Intestinal Dysbiosis in Bleomycin-Induced Mouse Models

Abstract

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.

Sodium Butyrate as Adjuvant Therapy with Mycophenolate Mofetil for Amelioration of Skin Fibrosis in Bleomycin-induced Scleroderma in Mice via Immunomodulatory, Antioxidant, Antiapoptotic and Antifibrotic Mechanisms

“…Even though NaB modulates apoptosis via alteration of the balance between pro-and antiapoptotic proteins and thus interferes with the maintenance of a good balance between DNA damage and apoptosis, caspase-3 expression increased in our work, for further investigation [40]. These findings were reflected histopathologically as a mild reduction of dermal fibrosis and dermal thickness when compared to the untreated scleroderma group which agrees with the recent study by Park et al [36].…”

“…There is a lack of reports studying the effect of NaB against dermal fibroblasts, a recent study conducted by Park et al [36] reported that suppressed TGF-β1 with their associated profibrotic and proinflammatory mediators against dermal fibroblasts during fibrosis and consequently can exhibit antifibrotic effects by inhibiting gene transcription involved in fibrogenesis. That effect on TGF-β1 is reflected consequently on dermal fibrosis and myofibroblast which is expressed by α-SMA which is in line with our results that reported that NaB leads to reduction of TGF-β1, α-SMA, and dermal thickness.…”

Gut microbiome and metabolites: The potential key roles in pulmonary fibrosis

“…Zhu’s team, in a mouse model of pulmonary fibrosis induced by lipopolysaccharide (LPS), demonstrated that butyrate pretreatment could inhibit ThY-1 gene expression and pulmonary fibrosis by inhibiting histone deacetylase (HDAC) activation and histone H4 deacetylation ( Zhu et al, 2016 ). Park et al (2021) observed that sodium butyrate treatment attenuated BLM-induced skin and lung fibrosis in a BLM-induced mouse model. They found that sodium butyrate modulates macrophage differentiation in mesenteric lymph nodes and bronchoalveolar lavage cells of model mice, and inhibits TGF-β reactive proinflammatory expression by increasing histone 3 acetylation, thereby showing indirect and direct antifibrotic effects on fibroblasts ( Park et al, 2021 ).…”

“…For example, 10% to 30% of patients with lung or breast cancer who receive radiation therapy will develop radiation-induced pneumonitis, and they are likely to develop radiation-induced lung fibrosis (Fleckenstein et al, 2007;Chao et al, 2017). In mice with local chest irradiation, Chen et al (2021) found that Akkermansia, Desulfovibrio and Parasutterella increased and Rikenella decreased at the genus level and that Distasonis, Goldsteinii, and Rodentium decreased at the species level. These changes were ameliorated after FMT (Chen et al, 2021).…”

Evaluation of biomarkers in the studies of keloid tissue after laser therapy

“…Для проведения доклинических исследований на лабораторных животных разработано несколько экспериментальных моделей, которые позволяют проследить за изменениями внешних признаков и особенностями протекания фиброза кожи. В одном из таких случаев проводят курс интердермальных инъекций цитотоксичного вещества -блеомицина (см., напр., [18,19]). Далее после того как во внешнем облике кожных покровов появятся необходимые изменения, делают паузу, чтобы дать затихнуть воспалительному процессу и затем начинают экспериментальные процедуры.…”