A Shigella Species Variant is Causally Linked to Intractable Functional Constipation

Idiopathic functional constipation (IFC) is a relatively common, severe form of slow transit constipation that can be notoriously difficult to treat. Based on recent research demonstrating the role of the gut microbiome in gut transit, this study aimed to establish a causal relationship between peristalsis-inhibiting bacteria and idiopathic functional constipation.

This study used the colon segments of 4 patients (1 male and 3 female, aged 25–52) diagnosed with idiopathic functional constipation based on the Rome IV criteria, various clinical measures of slow colonic transit, and who failed conservative measures and thus elected to undergo colectomy. Subsequent to the murine experiments described below, 68 adults with IFC were tested with a polymerase chain reaction for inhibitory gut bacteria.

Supernatant from the fresh colon segments was plated and cultured. The individual bacterial colonies that subsequently grew were reinoculated into culture tubes and their inhibitory effect on peristalsis was tested. The colonies that had the most inhibitory effect (referred to as “peristaltic contraction-inhibiting bacteria”, or PIB) underwent 16s rNA genomic analysis. The bacterial supernatants underwent further analysis by high phase liquid chromatography and mass spectrometry to identify specific colonic transit inhibitory substances. In vivo testing of the PIBs effects on colonic contraction consisted of gavaging mice with PIB and measuring colonic transit, and then administering PIB-lysing bacteriophages to test if this reversed any prolongation of transit time.

Phylogenetic analysis showed the colonies with the most peristalsis-inhibiting effects to have a similar, but distinct 16S ribosome from Shigella dysenteriae. The specific substance produced by these bacteria with the most inhibitory effect on colonic contraction was docosapentenoic acid. Mice who were administered the PIB did have slower colonic transit times, which were subsequently reduced on the introduction of PIB-lysing bacteriophages. Furthermore, a PCR assay was established to detect PIB in human feces, with PIB being present in 56% (30 of 68) of patients with idiopathic functional constipation, compared with 0 of the non-IFC patients.

This study suggests a causal role of a novel strain of Shigella in the pathogenesis of severe idiopathic functional constipation.

Although it has long been thought that constipation is related to dysbiosis of the gut microbiome, this study does the important job of identifying a specific substance and novel bacterial strain that directly slows gut transit. This finding could be used to both diagnose and treat IFC in the future. Constipation is a significant burden for pediatric patients and pediatricians. Although additional studies are needed in children, this study has the potential to lead to treatments which would greatly improve quality of life.