Gut Bacteria Products Prevent AKI Induced by Ischemia-Reperfusion

Abstract

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.

Microbiota and the control of blood-tissue barriers

“…Furthermore, butyrate can enhance histone acetylation in the BBB in vivo 71 as well as in dendritic cells in vitro. 74 However, butyrate acts not only on the cells that form the barrier. In the case of the testis, recolonization of GF mice with Clositridium Tyrobutyricum also restored testosterone levels to that of control mice without altering the levels of gonadotrophins, suggesting an effect on the Leydig cells.…”

Impact of environmental factors on alloimmunity and transplant fate

“…A reduction in SCFA butyrate was observed after bone marrow transplantation (BMT), and its administration, or that of butyrate-producing Clostridia, improved intestinal epithelial cell junctional integrity and reduced GVHD (150). Moreover, SCFA administration reduced kidney injury in a mouse model of IRI, an outcome associated with decreased DC maturation and T cell proliferation (151). Whether these properties of select bacterial metabolites can be co-opted to improve graft outcomes should be investigated.…”

Gut Feeling in AKI

“…4 The mechanism by which the gut microbiome confers protection against IRI is the focus of the study by AndradeOliveira et al, 5 which appears in this issue of JASN. In this exciting study, Andrade-Oliveira et al 5 have expanded the role of SCFAs beyond their well known role as nutrient for colonic epithelium and regulators of intracellular pH, ion transport, and cell proliferation to explain the gut-kidney connection in IRI. In a series of well designed in vivo and in vitro experiments, Andrade-Oliveira et al 5 show that treatment with SCFAs reduces IRI-induced kidney injury.…”

“…In this exciting study, Andrade-Oliveira et al 5 have expanded the role of SCFAs beyond their well known role as nutrient for colonic epithelium and regulators of intracellular pH, ion transport, and cell proliferation to explain the gut-kidney connection in IRI. In a series of well designed in vivo and in vitro experiments, Andrade-Oliveira et al 5 show that treatment with SCFAs reduces IRI-induced kidney injury. Among the SCFAs, acetate treatment offered the best protection.…”

“…Andrade-Oliveira et al 5 believe that the key mechanism that confers protection against AKI is reduction in inflammation mediated by an epigenetic mechanism. Andrade-Oliveira et al 5 also noticed an increase in autophagy, a reduction in apoptosis, and an improvement in mitochondrial biogenesis in response to treatment with SCFA. Furthermore, treatment with acetate-producing bacteria protected the mice kidneys from IRI.…”