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.

Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed “adipokines.” Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled “low-grade inflammatory state” of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.

Leptin is an adipose‐secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1‐cell polarization and inhibit Th2‐cell responses. Additionally, leptin induces Th17‐cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg‐cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL‐12, TNF‐α, and IL‐6, (iii) increased DC production of TGF‐β, and (iv) limited the capacity of DCs to induce syngeneic CD4⁺ T‐cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin‐free conditions induced Treg or T_H17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.

Recent findings regarding the influence of the microbiota in many inflammatory processes have provided a new way to treat diseases. Now, one may hypothesize that the origin of a plethora of diseases is related to the health of the gut microbiota and its delicate, although complex, interface with the epithelial and immune systems. The ‘westernization’ of diets, for example, is associated with alterations in the gut microbiota. Such alterations have been found to correlate directly with the increased incidence of diabetes and hypertension, the main causes of chronic kidney diseases (CKDs), which, in turn, have a high estimated prevalence. Indeed, data have arisen showing that the progression of kidney diseases is strictly related to the composition of the microbiota. Alterations in the gut microbiota diversity during CKDs do not only have the potential to exacerbate renal injury but may also contribute to the development of associated comorbidities, such as cardiovascular diseases and insulin resistance. In this review, we discuss how dysbiosis through alterations in the gut barrier and the consequent activation of immune system could intensify the progression of CKD and vice versa, how CKDs can modify the gut microbiota diversity and abundance.