The gut–kidney axis in IgA nephropathy: role of microbiota and diet on genetic predisposition

Abstract

Recent data suggest that gut-associated lymphoid tissue (GALT) plays a major role in the development of immunoglobulin A (IgA) nephropathy (IgAN). A genome-wide association study showed that most loci associated with the risk of IgAN are also associated with immune-mediated inflammatory bowel diseases, maintenance of the intestinal barrier and regulation of response to gut pathogens. Studies involving experimental models have demonstrated a pivotal role of intestinal microbiota in the development of IgAN in mice producing high levels of IgA and in transgenic mice overexpressing BAFF, a B-cell factor crucial for IgA synthesis, indicating the role of genetic background, B-cell activity, GALT intestinal immunity and diet. The effect of diet was suggested by pilot studies carried out 30 years ago which showed that a gluten-rich diet induced IgAN in mice and that some patients benefited from a gluten-free diet. A recent experimental model in mice expressing human IgA1 and Fc alpha receptor CD89 reported clinical and histological improvement after a gluten-free diet. Clinical observations have elicited new interest in GALT hyper-reactivity in IgAN patients. In a pilot study, a reduction in proteinuria was attained using an enteric controlled-release formulation of the corticosteroid budesonide targeted to the Peyer's patches at the ileocecal junction. This formulation was tested in the placebo-controlled NEFIGAN phase 2b trial, with a reduction in proteinuria after 9 months of treatment together with stabilization of renal function in patients with persistent proteinuria. In conclusion, the gut-kidney axis modulated by microbiota and diet is a promising target for focused treatment of IgAN in genetically predisposed patients at risk of progression.

Current Perspectives and Mechanisms of Relationship between Intestinal Microbiota Dysfunction and Dementia: A Review

“…2 ). Toxic metabolites such as trimethylamine N-oxide, D-amino acids, hippurate, phenylacetylglutamine, polyamines including putrescine, cadaverine, agmatine, and tyramine, acrolein, p -cresol sulfate, indoxyl sulfate, indole-3 acetic, phenol- and sulfur-containing compounds, as well as ammonia produced by the intestinal microbes can destroy the junctional complexes of the intestinal epithelial lining, thereby increasing the leakiness of the gut [, 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ] (immune responses triggered by these microbial metabolites are integral to leaky gut [ 163 , 164 , 165 ]). This increases impairment in selective transport and paracellular shunt of substances between the gut and circulatory system, allowing for unregulated movement of biomolecules including toxins into the surrounding tissues and circulatory system from the luminal side of the gut (Fig.…”

The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy

“…The disease is characterized by deposition of IgA-based immune complexes in the glomerular mesangial areas which can be observed using immunofluorescence assays. At present, it is believed that loss of IgA glycosylation, genetic factors and mucosal immunity are all involved in the pathogenesis of IgAN [4,5]. The detailed pathogenesis of IgAN is still not fully understood.…”

The epipharynx-kidney axis triggers glomerular vasculitis in immunoglobulin A nephropathy

“…Immunoglobulin A (IgA) deposition in the glomerular mesangium is the histological hallmark of IgA nephropathy (IgAN) and has led to extensive research on mucosaassociated lymphoid tissue (MALT) since the initial recognition of this disease approximately 50 years ago. MALT governs mucosal immunity and, in particular, the palatine tonsils (organized MALT) [1][2][3][4][5][6][7][8][9][10] and the gut-associated lymphatic tissue [11][12][13][14][15][16][17][18][19] have drawn significant interest.…”