Gut bacterial ClpB-like gene function is associated with decreased body weight and a characteristic microbiota profile

Abstract

Background: The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans.

Results: Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10-2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10^-7), Rikenellaceae (r = 0.702, p = 3.9 × 10^-4), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = - 0.445, p = 0.038) and Prevotellaceae RA (r = - 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function.

Conclusions: In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. Video Abstract.

Keywords: Bacterial gene function; Body weight regulation; Microbiome; Obesity.

Fig. 1

Gut bacterial ClpB-like gene function is associated with decreased body weight in humans. a Box plot showing the differences of gut bacterial ClpB-like gene function (K03695, KEGG annotation) between subjects without (body mass index, BMI 18.5–30 kg/m²) and with obesity (BMI ≥ 30 kg/m²). b Scatterplot displaying the relationship between BMI and gut bacterial ClpB-like gene function. c Scatterplot of the relationship between waist circumference and gut bacterial ClpB-like gene function. d Scatterplot of the relationship between the percentage of total fat mass assessed by DEXA and gut bacterial ClpB-like gene function

Fig. 2

Gut bacterial ClpB-like gene function and microbiota metabolites. a Significant O-PLS correlations coefficients for the model between gut bacterial ClpB-like gene function (K03695, KEGG annotation) and metabolites in feces (data in feces was previously normalized using the probabilistic quotient normalization (PQN)). b Significant O-PLS correlation coefficients for the model between gut bacterial ClpB-like gene function (K03695, KEGG annotation) and metabolites in plasma. c Heatmap showing the Spearman correlation coefficients and associated p values adjusting by FDR between significant metabolites in plasma and feces and bacterial families. Hierarchical clustering analysis was performed using Ward linkage and Euclidean distance. A cluster with the strongest correlations is highlighted with a black square

Fig. 3

Gut bacterial ClpB-like gene function and metagenomics. a Top bacterial taxa at the family level contributing reads to the gut bacterial ClpB-like gene function, in total relative figures per sample (uncultured, uc; not assigned, na). b–d Box plots showing the differences of some of the top ten bacterial families (relative abundance, RA) contributing to the gut bacterial ClpB-like gene function in subjects with and without obesity. e Mice body weights after gut microbiota transplantation. Controls (mouse, M; control, c) are shown in yellow (n = 11) and mice which received microbiota from human donors (transplant, t) are shown in blue (n = 22). f Bar chart showing mean and standard deviation mice body weights, regarding the median of the gut bacterial ClpB-like gene function detected in mice, K03695 (arbitrary units, AU). g Scatterplot showing the relationship between percent weight gain in mice (calculated as (body weight final (g)—body weight initial (g))/body weight initial (g)*100) and gut bacterial ClpB-like gene function, K03695 (AU), in mice. h Scatterplot showing the relationship between percent weight gain in mice and Prevotellaceae RA in humans. i Scatterplot showing the relationship between gut bacterial ClpB-like gene function (K03695, KEGG annotation) and Prevotellaceae absolute abundance (AA) in mice. j Scatterplot showing the relationship between the final weight (7th week) in mice and Prevotellaceae baroniae AA in humans. k Scatterplot showing the relationship between gut bacterial ClpB-like gene function (K03695, KEGG annotation) in mice and Prevotellaceae baroniae AA in human donors