Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy

Abstract

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.MethodsThe diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.ResultsIntestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.ConclusionsThe metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.

Recent advances of gut microbiota in chronic kidney disease patients

“…Of note, 5-hydroxyeicosatetraenoic acid and 5-hydroxy-6E,8Z,11Z-eicosatrienoic acid were related to glomerulosclerosis classification [119]. The latest study demonstrated that the levels of intestinal fatty acids, mostly unsaturated fatty acids, were significantly decreased in patients with IgA nephropathy [120]. Disorders of linoleic acid, arachidonic acid, anti-/pro-inflammatory fatty acid metabolites, and intestinal aryl hydrocarbon receptor signaling deficiency might indicate intestinal mucosal barrier injury in patients with IgA nephropathy [120].…”

“…The latest study demonstrated that the levels of intestinal fatty acids, mostly unsaturated fatty acids, were significantly decreased in patients with IgA nephropathy [120]. Disorders of linoleic acid, arachidonic acid, anti-/pro-inflammatory fatty acid metabolites, and intestinal aryl hydrocarbon receptor signaling deficiency might indicate intestinal mucosal barrier injury in patients with IgA nephropathy [120]. Moreover, high levels of galactose deficient IgA1, interleukin-22 and tumour necrosis factor α while lower level of 3-indolepropionic acid were related to kynurenine metabolic pathway from tryptophan metabolism, indicating tryptophan metabolites including 3-indolepropionic acid, kynurenine and indoleacrylic acid had synergistic effects on modulating immuno-inflammatory responses in patients with IgA nephropathy [120].…”

“…Disorders of linoleic acid, arachidonic acid, anti-/pro-inflammatory fatty acid metabolites, and intestinal aryl hydrocarbon receptor signaling deficiency might indicate intestinal mucosal barrier injury in patients with IgA nephropathy [120]. Moreover, high levels of galactose deficient IgA1, interleukin-22 and tumour necrosis factor α while lower level of 3-indolepropionic acid were related to kynurenine metabolic pathway from tryptophan metabolism, indicating tryptophan metabolites including 3-indolepropionic acid, kynurenine and indoleacrylic acid had synergistic effects on modulating immuno-inflammatory responses in patients with IgA nephropathy [120]. In addition, Chai and his colleague [121] demonstrated that α-diversity and β-diversity were remarkably different between patients with IgA nephropathy and healthy controls, which were accompanied by decreased levels of caproic acid, acetic acid, propionic acid, butyric acid and isobutyric acid in faeces of patients with IgA nephropathy compared to healthy controls.…”

Landscape of intestinal microbiota in patients with IgA nephropathy, IgA vasculitis and Kawasaki disease

“…The codifferent bacteria in IgAN and IgAV disease are Coprococcus, a genus of anaerobic cocci, an important genus of intestinal bacteria that ferment carbohydrates, and produce butyric and acetic acids and lactic acid. The relatively low abundance of Coprococcus in patients leads to relatively low production of butyric acid, allowing for disruption of intestinal barrier function, which may contribute to the development of the disease (Wu et al, 2022). In patients with IgAV, significant alterations in the intestinal flora of Coprococcus may indicate a preclinical stage of IgAN and vice versa.…”

Gut Microbes in Immunoglobulin A Nephropathy and Their Potential Therapeutic Applications

“…In addition, Zivkovic et al speculated that n-3 PUFA supplementation is associated with improved kidney function in IgAN ( 44 ). Increased levels of pro-inflammatory arachidonic acid metabolites, decreased levels of anti-inflammatory unsaturated fatty acids and fatty acid derivatives may play a role in persistent intestinal inflammatory and immune activation in IgAN patients, which might cause immune hyperactivation in IgAN patients ( 45 ).…”