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Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects - PubMed

  • ️Mon Jan 01 2018

Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects

Johanna Sundin et al. Sci Rep. 2018.

Abstract

Altered fecal levels of chromogranins (Cg) and secretogranins (Sg) are demonstrated in irritable bowel syndrome (IBS), but their role in IBS pathophysiology remains unknown. This study aimed to determine if granins are associated with bacterial composition, immune activation and IBS symptoms. Protein levels of fecal granins (CgA, CgB, SgII and SgIII) were analysed with immunoassays. Mucosal mRNA expression of granins, TPH1 and immune markers were evaluated with RT-qPCR. 16S rRNA gene sequencing was performed on fecal and mucosal bacteria. The intestinal granin profile, based on fecal protein levels and mucosal mRNA expression, could not discriminate between IBS patients (n = 88) and healthy subjects (HS, n = 33). IBS patients dominated by high fecal or mucosal granin levels, respectively, did not differ in symptom or immune profiles. Fecal-dominated and mucosal-dominated granin clusters of IBS patients and HS, demonstrated separate fecal and mucosal bacterial profiles and high fecal abundance of granins were associated with a less diverse bacterial composition and the Bacteroides enterotype. The intestinal granin profiles of IBS patients and HS are linked to the intestinal bacterial composition, diversity and enterotypes. These findings suggest that granins may be one of several host-produced factors regulating the microbiota composition of the intestine.

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Conflict of interest statement

Magnus Simrén: Received unrestricted research grants from Danone, Glycom and Ferring Pharmaceuticals, and served as a Consultant/Advisory Board member for AstraZeneca, Danone, Nestlé, Almirall, Allergan, Albireo, Glycom, Menarini and Shire, and as a speaker for Tillotts, Menarini, Takeda, Shire, Allergan, and Almirall. Lena Öhman: Has received a financial support for research by Danone Research and AstraZeneca and served as an advisory board member for Genetic Analyses and as speaker for Abbvie, Takeda, Janssen and Tillots.

Figures

Figure 1
Figure 1

Granin profiles of IBS patients and healthy subjects. Intestinal profiles of fecal protein levels (nmol/L) and mucosal mRNA expression of chromogranins (CgA and CgB) and secretogranins (SgII and SgIII) of irritable bowel syndrome (IBS, n = 88, blue circle) and healthy subjects (n = 33, green square). (a) Multivariate orthogonal partial least squares-discriminant analysis (OPLS-DA) scatter plot of IBS patients compared to healthy subjects. (b) OPLS-DA loading scatter plot depicting the association between IBS patients and healthy subjects, respectively, and fecal protein levels and mucosal mRNA expression of granins. Multivariate analysis was performed with granins as X-variables and IBS patients and healthy patients, respectively, as Y-variables. (c) Dendrogram of the unsupervised bottom-up performed hierarchical clustering analysis (HCA) based on fecal protein levels and mucosal mRNA expression of granins in IBS patients. (d) OPLS-DA loading scatter plot depicting the association between granin clusters in IBS (fecal-dominated and mucosal-dominated) and fecal protein levels and mucosal mRNA expression of granins. (e) Dendrogram of the unsupervised bottom-up performed hierarchical clustering analysis (HCA) based on fecal protein levels and mucosal mRNA expression of granins in IBS patients. (f) OPLS-DA loading scatter plot depicting the association between granin clusters in healthy (fecal-dominated and mucosal-dominated) and fecal protein levels and mucosal mRNA expression of granins.

Figure 2
Figure 2

Gastrointestinal and psycological profiles clinical of the fecal-dominated and mucosal-dominated granin clusters of IBS patients. The clinical profiles based on the patients scores on severity of IBS symptoms (IBS-SSS items: pain frequency, pain intensity, abdominal distension, bowel habit dissatisfaction and life interference), non-GI symptoms (PHQ12), anxiety and depression (HADS), and GI-specific anxiety (VSI) were compared between fecal-dominated (red circle, n = 59) and mucosal-dominated (blue square, n = 19) granin clusters of IBS patients (VIP > 0.7). (a) Multivariate orthogonal partial least squares-discriminant analysis (OPLS-DA) scatter plot of fecal-dominated and mucosal-dominated granin clusters of IBS patients. (b) OPLS-DA loading plot of the clinical symptom profile of the fecal-dominated and mucosal-dominated clusters in IBS patients.

Figure 3
Figure 3

The bacterial composition profiles of IBS patients and healthy subjects based on fecal-dominated and mucosal-dominated granin clusters. The compositions of fecal bacterial genera were compared between of the fecal-dominated and mucosal-dominated clusters of granins in IBS patients and healthy subjects (VIP = 1.35). (a) Multivariate orthogonal partial least squares-discriminant analysis (OPLS-DA) scatter plot of the fecal bacterial composition of fecal-dominated (red circle, n = 62) and the mucosal-dominated (blue square, n = 20) clusters of IBS patients. (b) Multivariate orthogonal partial least squares-discriminant analysis (OPLS-DA) scatter plot of the fecal bacterial composition of fecal-dominated (red circle, n = 27), and mucosal-dominated granin (blue square, n = 4) clusters of healthy subjects. (c) OPLS-DA loadings column plot depicting the fecal bacterial genera that are of most importance for the separation between the fecal-dominated and mucosal-dominated granin clusters of IBS patients. The height of the bar reflects the contribution of each bacterial genus to the separation between the fecal-dominated and mucosal-dominated granin clusters of IBS patients. (d) OPLS-DA loadings column plot depicting the fecal bacterial genera that are of most importance for the separation between the fecal-dominated and mucosal-dominated granin clusters of healthy subjects. The height of the bar reflects the contribution of each bacterial genus to the separation between the fecal-dominated and mucosal-dominated granin clusters.

Figure 4
Figure 4

Mucosal bacterial composition profiles of IBS patients clustered into fecal-dominated and mucosal-dominated granin clusters. The composition of the mucosal bacterial genera of fecal-dominated (red circle, IBS n = 25, HS n = 10) and mucosal-dominated clusters of granins (blue square, IBS n = 5, HS n = 4) was compared between IBS patients and healthy subjects (VIP = 1.35). (a) OPLS-DA scatter plot of the mucosal bacterial composition of fecal-dominated (red circle, n = 25) and mucosal-dominated (blue square, n = 5) granin clusters of IBS patients. (b) OPLS-DA loading plot of the discriminatory bacterial genera separating the mucosal bacterial composition profile of the fecal-dominated (right) and mucosal-dominated (left) clusters of IBS. (c) OPLS-DA loadings column plot depicting the mucosal bacterial genera that are of most importance for the model of the mucosal bacterial profile of fecal-dominated and mucosal-dominated granin clusters of IBS. The height of the bar reflects each bacterial genus contribution to the separation between the fecal-dominated and mucosal-dominated granin clusters. (d) OPLS-DA scatter plot of the mucosal bacterial composition of fecal-dominated (red circle, n = 10) and mucosal-dominated (blue square, n = 4) granin clusters of healthy subjects). (e) OPLS-DA loading plot of the discriminatory bacterial genera separating the mucosal bacterial composition profile of fecal-dominated (right) and mucosal-dominated (left) granin clusters of healthy subjects. (f) OPLS-DA loadings column plot depicting the mucosal bacterial genera that are of most importance for the model of fecal-dominated and mucosal-dominated granin of healthy subjects. The height of the bar reflects each bacterial genus contribution to the separation between the fecal-dominated and mucosal-dominated granin clusters.

Figure 5
Figure 5

The association between fecal granin levels with fecal bacterial diversity and enterotypes of IBS patients (n = 86) and healthy subjects (n = 32). (a) Principal coordinate plot of co-inertia analysis between fecal granins (CgA, CgB, SgII and SgIII) with bacterial beta diversity in faeces of IBS patients and healthy subjects (JSD distance) coloured according to enterotype (Bacteroides n = 19, blue, Clostridiales n = 84, red and Prevotella n = 15, green). Each dot represents one individual. Grey arrows indicate the association direction and size of CgA, CgB, SgII and SgIII, respectively. (b) Comparison of fecal protein levels of granins (CgA, CgB, SgII and SgIII) of IBS patients and healthy subjects subdivided according to their enterotypes. (c) Comparison of the bacterial alpha diversity in faeces between the Bacteroides, Clostridiales and Prevotella enterotypes of IBS patients and healthy subjects.

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