RESUMEN
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing health problem for which no therapy exists to date. The modulation of the gut microbiome may have treatment potential for MASLD. Here, we investigated Anaerobutyricum soehngenii, a butyrate-producing anaerobic bacterium with beneficial effects in metabolic syndrome, in a diet-induced MASLD mouse model. Male C57BL/6J mice received a Western-type high-fat diet and water with 15% fructose (WDF) to induce MASLD and were gavaged with A. soehngenii (108 or 109 colony-forming units (CFU) 3 times per week) or a placebo for 6 weeks. The A. soehngenii gavage increased the cecal butyrate concentrations. Although there was no effect on histological MASLD scores, A. soehngenii improved the glycemic response to insulin. In the liver, the WDF-associated altered expression of three genes relevant to the MASLD pathophysiology was reversed upon treatment with A. soehngenii: Lipin-1 (Lpin1), insulin-like growth factor binding protein 1 (Igfbp1) and Interleukin 1 Receptor Type 1 (Il1r1). A. soehngenii administration also increased the intestinal expression of gluconeogenesis and fructolysis genes. Although these effects did not translate into significant histological improvements in MASLD, these results provide a basis for combined gut microbial approaches to induce histological improvements in MASLD.
Asunto(s)
Clostridiales , Hígado Graso , Enfermedades Metabólicas , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Composición de Base , Gluconeogénesis , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Hígado Graso/etiología , Hígado Graso/genética , Butiratos , Expresión Génica , Fosfatidato FosfatasaRESUMEN
Individuals with type 2 diabetes (T2D) show signs of low-grade inflammation, which is related to the development of insulin resistance and beta-cell dysfunction. However, the underlying triggers remain unknown. The gut microbiota is a plausible source as it comprises pro-inflammatory bacteria, bacterial metabolites and viruses, including (bacterio)phages. These prokaryotic viruses have been shown to mediate inflammatory responses in gastrointestinal disease. Given the differences in phage populations in healthy individuals versus those with cardiometabolic diseases such as T2D, we here questioned whether phages from T2D individuals would have increased immunogenic potential. To address this, we isolated intestinal phages from a fresh stool sample of healthy controls and individuals with newly diagnosed, treatment-naive T2D. Phages were purified using cesium chloride ultracentrifugation and incubated with healthy donor dendritic cells (DCs) and autologous T cells. Donors with T2D had slightly higher free viral particle numbers compared to healthy controls (p = .1972), which has been previously associated with disease states. Further, phages from T2D induced a higher inflammatory response in DCs and T cells than phages from HC. For example, the expression of the co-stimulatory molecule CD86 on DCs (p < .001) and interferon-y secretion from T cells (p < .01) were increased when comparing the two groups. These results suggest that phages might play a role in low-grade inflammation in T2D individuals.
Asunto(s)
Bacteriófagos , Técnicas de Cocultivo , Células Dendríticas , Diabetes Mellitus Tipo 2 , Inflamación , Humanos , Diabetes Mellitus Tipo 2/inmunología , Células Dendríticas/inmunología , Bacteriófagos/aislamiento & purificación , Bacteriófagos/fisiología , Masculino , Persona de Mediana Edad , Inflamación/inmunología , Inflamación/virología , Femenino , Heces/virología , Heces/microbiología , Adulto , Microbioma Gastrointestinal , Linfocitos T/inmunología , Anciano , Antígeno B7-2/metabolismoRESUMEN
Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.
Asunto(s)
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Histidina , Células T Invariantes Asociadas a Mucosa , Humanos , Histidina/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Persona de Mediana Edad , Masculino , Femenino , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Control Glucémico , Suplementos Dietéticos , Estudios de Casos y Controles , Heces/microbiología , Glucemia/metabolismo , Anciano , Adulto , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/genética , Administración Oral , Metilación de ADNRESUMEN
Obesity and type 2 diabetes (T2D) are growing burdens for individuals and the health-care system. Bariatric surgery is an efficient, but drastic treatment to reduce body weight, normalize glucose values, and reduce low-grade inflammation. The gut microbiome, which is in part controlled by intestinal antibodies, such as IgA, is involved in the development of both conditions. Knowledge of the effect of bariatric surgery on systemic and intestinal antibody response is limited. Here, we determined the fecal antibody and gut microbiome response in 40 T2D and non-diabetic (ND) obese individuals that underwent bariatric surgery (N = 40). Body weight, fasting glucose concentrations and inflammatory parameters decreased after bariatric surgery, whereas pro-inflammatory bacterial species such as lipopolysaccharide (LPS), and flagellin increased in the feces. Simultaneously, concentrations of LPS- and flagellin-specific intestinal IgA levels increased with the majority of pro-inflammatory bacteria coated with IgA after surgery. Finally, serum antibodies decreased in both groups, along with a lower inflammatory tone. We conclude that intestinal rearrangement by bariatric surgery leads to expansion of typical pro-inflammatory bacteria, which may be compensated by an improved antibody response. Although further evidence and mechanistic insights are needed, we postulate that this apparent compensatory antibody response might help to reduce systemic inflammation by neutralizing intestinal immunogenic components and thereby enhance intestinal barrier function after bariatric surgery.