Patients with chronic kidney disease (CKD) have a higher cardiovascular risk compared to the average population, and this is partially due to the plasma accumulation of solutes known as uremic toxins. The binding of some solutes to plasma proteins complicates their removal via conventional therapies, e.g., hemodialysis. Protein-bound uremic toxins originate either from endogenous production, diet, microbial metabolism, or the environment. Although the impact of diet on uremic toxicity in CKD is difficult to quantify, nutrient intake plays an important role. Indeed, most uremic toxins are gut-derived compounds. They include Maillard reaction products, hippurates, indoles, phenols, and polyamines, among others. In this review, we summarize the findings concerning foods and dietary components as sources of uremic toxins or their precursors. We then discuss their endogenous metabolism via human enzyme reactions or gut microbial fermentation. Lastly, we present potential dietary strategies found to be efficacious or promising in lowering uremic toxins plasma levels. Aligned with current nutritional guidelines for CKD, a low-protein diet with increased fiber consumption and limited processed foods seems to be an effective treatment against uremic toxins accumulation.

A critical role for host-microbe interactions and establishment of vaccine responses has been postulated. Human milk oligosaccharides, of which 2′-fucosyllactose (2′FL) is the most prevalent, are known to alter host-associated microbial communities and play a critical role in the immunologic development of breastfed infants. Dietary supplementation with a combination of 2′FL and prebiotic short-chain (sc) galacto-oligosaccharides (GOS) and long-chain (lc) fructo-oligosaccharides (FOS) was employed to examine human milk oligosaccharide effects on immune responsiveness, within a murine influenza vaccination model. Female mice (6 wk old, C57Bl/6JOlaHsd) were fed either control diet (CON) or scGOS/lcFOS/2′FL-containing diet (GF2F) for 45 d. After starting dietary intervention (day 14), mice received a primary influenza vaccination (day 0) followed by a booster vaccination (day 21), after which ear challenges were conducted to measure vaccine-specific delayed type hypersensitivity (DTH). Serum immunoglobulin (Ig) levels, fecal and cecal microbial community structure, short-chain fatty acids, host intestinal gene expression and cellular responses in the mesenteric lymph nodes (MLNs) were also measured. Relative to CON, mice fed the GF2F diet had increased influenza vaccine–specific DTH responses (79.3%; P < 0.01), higher levels of both IgG1 (3.2-fold; P < 0.05) and IgG2a (1.2-fold; P < 0.05) in serum, and greater percentages of activated B cells (0.3%; P < 0.05), regulatory T cells (1.64%; P < 0.05), and T-helper 1 cells (2.2%; P < 0.05) in their MLNs. GF2F-fed mice had elevated cecal butyric (P < 0.05) and propionic (P < 0.05) acid levels relative to CON, which correlated to DTH responses (R² = 0.22; P = 0.05 and R² = 0.39; P < 0.01, respectively). Specific fecal microbial taxa altered in GF2F diet fed mice relative to CON were significantly correlated with the DTH response and IgG2a level increases. Dietary GF2F improved influenza vaccine–specific T-helper 1 responses and B cell activation in MLNs and enhanced systemic IgG1 and IgG2a concentrations in mice. These immunologic changes are correlated with microbial community structure and metabolites.

Background. Short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) and CpG-ODN affect intestinal epithelial cells (IEC). Epithelial IL1α may contribute to allergic sensitization via autocrine mediator release affecting dendritic cells (DC). We studied whether IL1α contributes to Th2-associated mediator release by activated IEC and IEC/DC cocultures and possible modulation by scGOS/lcFOS±CpG-ODN. Methods. Solid phase or transwell cultured IEC were preincubated with IL1α and/or IFNγ/TNFα for 6 h. The transwell IEC were also apically exposed to scGOS/lcFOS±CpG-ODN for 6 h, washed, and re-exposed, while cocultured with immature moDC (ccDC) for 48 h. These ccDC were subsequently added to allogeneic naïve T cells (MLR). IEC- and/or DC-derived mediators and T cell cytokines were measured. Results. IL1α tended to enhance IL25 and enhanced IL33 and CCL20 release by IEC, while IL1α or TNFα or IFNγ enhanced CCL22. These were all further increased upon combined exposure of IFNγ/TNFα±IL1α coinciding with increased IL33 secretion in the solid phase culture. In the transwell, IL25 and IL33 remained under detection, while CCL20 and CCL22 were induced by IL1α or IFNγ/TNFα, respectively, and a synergistic increase was observed upon combined exposure of IFNγ/TNFα and IL1α. Furthermore, IFNγ was found to enhance galectin-9 secretion, which was more pronounced in IFNγ/TNFα±IL1α-exposed IEC and coincided with TGFβ increase. Epithelial CpG-ODN exposure further increased CCL20, while reducing CCL22 release by IFNγ/TNFα/IL1α-activated IEC; however, scGOS/lcFOS suppressed both. Combined scGOS/lcFOS and CpG-ODN reduced CCL22, while CCL20 and regulatory galectin-9 and TGFβ remained high in the supernatant of IFNγ/TNFα/IL1α-activated IEC and the following IEC/DC coculture. ccDC of scGOS/lcFOS- and CpG-ODN-exposed IFNγ/TNFα/IL1α-activated IEC increased IFNγ, IL10, TGFβ, and galectin-9 secretion in the MLR compared to ccDC exposed to control-activated IEC. Conclusion. IL1α enhanced CCL20 and Th2-associated CCL22 release by IFNγ/TNFα-activated IEC. Combined scGOS/lcFOS and CpG-ODN exposure suppressed CCL22, while maintaining high CCL20, TGFβ, and galectin-9 concentrations. In addition, ccDC derived from this IEC/DC coculture enhanced Th1 and regulatory mediator secretion mimicking known in vivo effects.

Early-life nutrition significantly impacts vaccination efficacy in infants, whose immune response to vaccines is weaker compared to adults. This study investigated vaccination efficacy in female C57Bl/6JOlaHsd mice (6 weeks old) fed diets with 0.7% galacto-oligosaccharides (GOS)/long-chain fructo-oligosaccharides (lcFOS) (9:1), 0.3% human milk oligosaccharides (HMOS), or a combination (GFH) for 14 days prior to and during vaccination. Delayed-type hypersensitivity (DTH) was measured by assessing ear swelling following an intradermal challenge. Influvac-specific IgG1 and IgG2a levels were assessed using ELISAs, while splenic T and B lymphocytes were analyzed for frequency and activation via flow cytometry. Additionally, cytokine production was evaluated using murine splenocytes co-cultured with influenza-loaded dendritic cells. Mice on the GFH diet showed a significantly enhanced DTH response (p < 0.05), increased serological IgG1 levels, and a significant rise in memory B lymphocytes (CD27+ B220+ CD19+). GFH-fed mice also exhibited more activated splenic Th1 cells (CD69+ CXCR3+ CD4+) and higher IFN-γ production after ex vivo restimulation (p < 0.05). These findings suggest that GOS/lcFOS and HMOS, particularly in combination, enhance vaccine responses by improving memory B cells, IgG production, and Th1 cell activation, supporting the potential use of these prebiotics in infant formula for better early-life immune development.

Chronic kidney disease (CKD) is increasingly linked to intestinal barrier dysfunction, which contributes to systemic inflammation and disease progression. We investigated whether 2′-fucosyllactose (2′-FL), a human milk oligosaccharide, could modulate intestinal epithelial barrier function under uremic toxin exposure and examined the role of the aryl hydrocarbon receptor (AhR). Using wild-type (WT) and AhR knockout (AhR KO) Caco-2 cell lines, we assessed barrier function and cellular responses through transepithelial electrical resistance (TEER), paracellular permeability (Papp), tight junction (TJ) gene expression, AhR target gene activation, and metabolic assays. AhR deficiency impaired epithelial maturation, confirming its role in barrier development. Short-term exposure to uremic toxins (UTs) did not significantly affect TEER or paracellular permeability under the conditions tested. However, 2′-FL reduced paracellular permeability in both WT and AhR KO cells in the presence of FCS. These effects occurred without changes in TJ gene expression, indicating mechanisms beyond transcriptional regulation. AhR target genes were not induced by UTs, suggesting limited receptor activation, and metabolic activity was unaffected. Overall, 2′-FL reduced paracellular permeability under selected experimental conditions, while the impaired barrier development observed in AhR-deficient cells supports a role for AhR in intestinal epithelial barrier development.