The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We ...characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.
Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual ...relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the capacity of these cells to induce CD4(+) and CD8(+) T cell proliferation. Furthermore, SCFAs ameliorated the effects of hypoxia in kidney epithelial cells by improving mitochondrial biogenesis. Notably, mice treated with acetate-producing bacteria also had better outcomes after AKI. Thus, we demonstrate that SCFAs improve organ function and viability after an injury through modulation of the inflammatory process, most likely via epigenetic modification.
Butyrate is a short‐chain fatty acid derived from the metabolism of indigestible carbohydrates by the gut microbiota. Butyrate contributes to gut homeostasis, but it may also control inflammatory ...responses and host physiology in other tissues. Butyrate inhibits histone deacetylases, thereby affecting gene transcription, and also signals through the metabolite‐sensing G protein receptor (GPR)109a. We produced an mAb to mouse GPR109a and found high expression on podocytes in the kidney. Wild‐type and Gpr109a–/– mice were induced to develop nephropathy by a single injection of Adriamycin and treated with sodium butyrate or high butyrate‐releasing high‐amylose maize starch diet. Butyrate improved proteinuria by preserving podocyte at glomerular basement membrane and attenuated glomerulosclerosis and tissue inflammation. This protective phenotype was associated with increased podocyte‐related proteins and a normalized pattern of acetylation and methylation at promoter sites of genes essential for podocyte function. We found that GPR109a is expressed by podocytes, and the use of Gpr109a–/– mice showed that the protective effects of butyrate depended on GPR109a expression. A prebiotic diet that releases high amounts of butyrate also proved highly effective for protection against kidney disease. Butyrate and GPR109a play a role in the pathogenesis of kidney disease and provide one of the important molecular connections between diet, the gut microbiota, and kidney disease.—Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade‐Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic‐ and GPR109a‐mediated mechanisms. FASEB J. 33, 11894–11908 (2019). www.fasebj.org
Asthma is a chronic inflammatory disease that affects more females than males after puberty, and its symptoms and severity in women change during menstruation and menopause. Recently, evidence has ...demonstrated that interactions among the microbiota, female sex hormones, and immunity are associated with the development of autoimmune diseases. However, no studies have investigated if therapeutic gut microbiota modulation strategies could affect asthma exacerbation during menstruation and menopause. Here we aimed to examine the preventive effects of a probiotic,
Bifidobacterium longum
5
1A
, on airway inflammation exacerbation in allergic ovariectomized mice. We first evaluated the gut microbiota composition and diversity in mice 10 days after ovariectomy. Next, we examined whether re-exposure of ovariectomized allergic mice to antigen (ovalbumin) would lead to exacerbation of lung inflammation. Finally, we evaluated the preventive and treatment effect of
B. longum
5
1A
on lung inflammation and airway hyperresponsiveness. Our results showed that whereas ovariectomy caused no alterations in the gut microbiota composition and diversity in this animal model, 10 days after ovariectomy, preventive use administration of
B. longum
5
1A
, rather than its use after surgery was capable of attenuate the exacerbated lung inflammation and hyperresponsiveness in ovariectomized allergic mice. This prophylactic effect of
B. longum
5
1A
involves acetate production, which led to increased fecal acetate levels and, consequently, increased Treg cells in ovariectomized allergic mice.
Allergic contact dermatitis (ACD) is an inflammatory skin reaction whose incidence has increased and has been associated with a dietary pattern rich in saturated fats and refined sugars. Considering ...the increased incidence of ACD and the lack of research about the influence of a short-term high-sugar diet on dermatitis, our aim is to improve understanding of the influence of a high-sugar diet on ACD. We introduced a diet rich in sugar fifteen days before inducing contact dermatitis with oxazolone, in mice, and maintained it until the end of the experiment, which lasted three weeks in total. The dermatitis model increased cholesterol and triglycerides in the liver, and the combination of diet and dermatitis increased weight and worsened liver cholesterol measurements. Furthermore, the high-sugar diet increased the production of IL-6, IFN-γ and TNF-α in the skin, which may be involved in the increase in epithelial skin thickness observed in experimental ACD.
The phenotypes of allergic airway diseases are influenced by the interplay between host genetics and the gut microbiota, which may be modulated by probiotics. We investigated the probiotic effects on ...allergic inflammation in A/J and C57BL/6 mice. C57BL/6 mice had increased gut microbiota diversity compared to A/J mice at baseline. Acetate producer probiotics differentially modulated and altered the genus abundance of specific bacteria, such as Akkermansia and Allistipes, in mouse strains. We induced airway inflammation followed by probiotic treatment and found that only A/J mice exhibited decreased inflammation, and the beneficial effects of probiotics in A/J mice were partially due to acetate production. To understand the relevance of microbial composition colonization in the development of allergic diseases, we implanted female C57BL/6 mice with A/J embryos to naturally modulate the microbial composition of A/J mice, which increased gut microbiota diversity and reduced eosinophilic inflammation in A/J. These data demonstrate the central importance of microbiota to allergic phenotype severity. Video Abstract.
RAW_REF_TEXT Correction /RAW_REF_TEXT RAW_REF_TEXT Open Access /RAW_REF_TEXT RAW_REF_TEXT Published:14 July 2021 /RAW_REF_TEXT Correction to: A probiotic has differential effects on allergic airway ...inflammation in A/J and C57BL/6 mice and is correlated with the gut microbiome RAW_REF_TEXT Mateus B. Casaro1, /RAW_REF_TEXT RAW_REF_TEXT Andrew M. Thomas2,3,4, /RAW_REF_TEXT RAW_REF_TEXT Eduardo Mendes1, /RAW_REF_TEXT RAW_REF_TEXT Claudio Fukumori1, /RAW_REF_TEXT RAW_REF_TEXT Willian R. Ribeiro1, /RAW_REF_TEXT RAW_REF_TEXT Fernando A. Oliveira5, /RAW_REF_TEXT RAW_REF_TEXT Amanda R. Crisma6, /RAW_REF_TEXT RAW_REF_TEXT Gilson M. Murata7, /RAW_REF_TEXT RAW_REF_TEXT Bruna Bizzarro8, /RAW_REF_TEXT RAW_REF_TEXT Anderson Sá-Nunes8, /RAW_REF_TEXT RAW_REF_TEXT Joao C. Setubal4, /RAW_REF_TEXT RAW_REF_TEXT Marcia P. A. Mayer9, /RAW_REF_TEXT RAW_REF_TEXT Flaviano S. Martins10, /RAW_REF_TEXT RAW_REF_TEXT Angélica T. Vieira11, /RAW_REF_TEXT RAW_REF_TEXT Ana T. F. B. Antiorio12, /RAW_REF_TEXT RAW_REF_TEXT Wothan Tavares-de-Lima13, /RAW_REF_TEXT RAW_REF_TEXT Niels O. S. Camara8, /RAW_REF_TEXT RAW_REF_TEXT Rui Curi14, /RAW_REF_TEXT RAW_REF_TEXT Emmanuel Dias-Neto3,15 & /RAW_REF_TEXT RAW_REF_TEXT Caroline M. Ferreira 1 /RAW_REF_TEXT Microbiome volume 9, Article number: 159 (2021) Cite this article RAW_REF_TEXT 89 Accesses /RAW_REF_TEXT RAW_REF_TEXT 1 Altmetric /RAW_REF_TEXT RAW_REF_TEXT Metrics details /RAW_REF_TEXT The Original Article was published on 10 June 2021 Correction to: Fig. 4 figure1 A/J embryo implantation in C57BL/6 mothers resulted in experimental allergic airway inflammation similar to C57BL/6 offspring. a Schematic representation of the embryo transfer and OVA-inducing airway inflammation protocol. b Phylogenetic diversity in mice. All values were calculated using Adonis with 999 permutations on unweighted UniFrac distances. d Total and differential (Eos, eosinophils; Neut, neutrophils; Mono, mononuclear) number of cells in the bronchoalveolar lavage (BALF) of the A/J, C57BL/6, and A/J transplanted OVA groups (n = 3–5). e Levels of (pg/ml) of interleukin (IL)-4 and interferon (INF)-γ in the BALF of the A/J, C57BL/6, and A/J transplanted OVA groups (n = 3–5). Correction Open Access Published:14 July 2021 /RAW_REF_TEXT Correction to: A probiotic has differential effects on allergic airway inflammation in A/J and C57BL/6 mice and is correlated with the gut microbiome RAW_REF_TEXT Mateus B. Casaro1, Andrew M. Thomas2,3,4, Eduardo Mendes1, Claudio Fukumori1, Willian R. Ribeiro1, Fernando A. Oliveira5, Amanda R. Crisma6, Gilson M. Murata7, Bruna Bizzarro8, Anderson Sá-Nunes8, Joao C. Setubal4, Marcia P. A. Mayer9, Flaviano S. Martins10, Angélica T. Vieira11, Ana T. F. B. Antiorio12, Wothan Tavares-de-Lima13, Niels O. S. Camara8, Rui Curi14, Emmanuel Dias-Neto3,15 & Caroline M. Ferreira 1 /RAW_REF_TEXT Microbiome volume 9, Article number: 159 (2021) Cite this article RAW_REF_TEXT 89 Accesses 1 Altmetric Metrics details
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•Maternal synbiotics modulate gut microbiota depending on host genetics.•Maternal synbiotics affect allergic outcomes in A/J and B6 offspring differently.•Microbiota diversity was not ...enough to regulate airway eosinophilia in allergic A/J mice.
Emerging evidence has shown that the maternal diet influences the microbiota. Our objective was to elucidate whether synbiotic consumption during the perinatal period equally modulates offspring gut microbiota in the A/J and C57BL/6 and affects airway inflammatory cell infiltration. We administered the synbiotic to the dam throughout the whole perinatal period. To analyze the influence of gut microbiota changes on offspring health, we induced allergic airway inflammation on offspring. Twenty-four hours after the last ovalbumin challenge, pulmonary inflammation was analyzed. Perinatal synbiotic supplementation reduced eosinophilic inflammation and mucus production only in the C57BL/6 offspring. Synbiotic supplementation during the perinatal period increased the Lactobacillus genera, which could be associated with the immune regulatory effects observed in the C57BL/6 offspring. Interestingly, synbiotic supplementation increased the diversity of gut microbiota in the A/J offspring without improving airway inflammation, indicating that diversity itself was not sufficient to regulate experimental lung inflammation.
Asthma is a chronic inflammatory disease that affects more females than males after puberty, and its symptoms and severity in women change during menstruation and menopause. Recently, evidence has ...demonstrated that interactions among the microbiota, female sex hormones, and immunity are associated with the development of autoimmune diseases. However, no studies have investigated if therapeutic gut microbiota modulation strategies could affect asthma exacerbation during menstruation and menopause. Here we aimed to examine the preventive effects of a probiotic,
5
, on airway inflammation exacerbation in allergic ovariectomized mice. We first evaluated the gut microbiota composition and diversity in mice 10 days after ovariectomy. Next, we examined whether re-exposure of ovariectomized allergic mice to antigen (ovalbumin) would lead to exacerbation of lung inflammation. Finally, we evaluated the preventive and treatment effect of
5
on lung inflammation and airway hyperresponsiveness. Our results showed that whereas ovariectomy caused no alterations in the gut microbiota composition and diversity in this animal model, 10 days after ovariectomy, preventive use administration of
5
, rather than its use after surgery was capable of attenuate the exacerbated lung inflammation and hyperresponsiveness in ovariectomized allergic mice. This prophylactic effect of
5
involves acetate production, which led to increased fecal acetate levels and, consequently, increased Treg cells in ovariectomized allergic mice.
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