Elevated fecal calprotectin is associated with gut microbial dysbiosis, altered serum markers and clinical outcomes in older individuals

Abstract

Fecal calprotectin is an established marker of gut inflammation in inflammatory bowel disease (IBD). Elevated levels of fecal calprotectin as well as gut microbial dysbiosis have also been observed in other clinical conditions. However, systemic and multi-omics alterations linked to elevated fecal calprotectin in older individuals remain unclear. This study comprehensively investigated the relationship between fecal calprotectin levels, gut microbiome composition, serum inflammation and targeted metabolomics markers, and relevant lifestyle and medical data in a large sample of older individuals (n = 735; mean age ± SD: 68.7 ± 6.3) from the TREND cohort study. Low (0-50 μg/g; n = 602), moderate (> 50-100 μg/g; n = 64) and high (> 100 μg/g; n = 62) fecal calprotectin groups were stratified. Several pro-inflammatory gut microbial genera were significantly increased and short-chain fatty acid producing genera were decreased in high vs. low calprotectin groups. In serum, IL-17C, CCL19 and the toxic metabolite indoxyl sulfate were increased in high vs. low fecal calprotectin groups. These changes were partially mediated by the gut microbiota. Moreover, the high fecal calprotectin group showed increased BMI and a higher disease prevalence of heart attack and obesity. Our findings contribute to the understanding of fecal calprotectin as a marker of gut dysbiosis and its broader systemic and clinical implications in older individuals.

Keywords: Calprotectin; Cardiovascular disease; Gut microbiota; Inflammation; Metabolites; Neurological disease.

Figure 1

Distribution of fecal calprotectin for different concentration intervals in the study population of older individuals (n = 735).

Figure 2

Genus-level differential abundance analysis. (a) Group-wise boxplots of the relative abundance (log2) of genera that show significant differences in group contrasts. (b) Significant (FDR-corrected, covariate-adjusted) findings of differential abundance of gut microbial genera for comparisons between moderate (> 50–100 μg/g) or high (> 100 μg/g) vs. low (≤ 50 μg/g) fecal calprotectin groups. The size of the markers corresponds to the base mean value (the mean of normalized counts of all samples) and the markers are color-coded based on group comparison. Bars indicate the standard error of log2-fold change. The phylum of the genera is indicated in brackets. P Proteobacteria, F Firmicutes.

Figure 3

Serum markers with significant differences between fecal calprotectin groups. (a) IL-17C, (b) CCL19 and (c) indoxyl sulfate were identified through multiple regression with potential confounders of fecal calprotectin included as covariates. The p-values have been FDR corrected for the number of 92 inflammation markers and 135 metabolites. Serum marker values were normalized and reported with arbitrary units. Red points indicate median values.