New concept "bacterial constipation" proposed: Two types of gut bacteria act in concert

A research group led by Designated Lecturer Tomonari Hamaguchi from the Academic Research & Industry-Academia-Government Collaboration Office, Nagoya University and Professor Emeritus Kinji Ohno (currently a Professor at Nagoya University of Arts and Sciences) has demonstrated that two types of gut bacteria act together to cause treatment-resistant chronic idiopathic constipation (CIC). The group has proposed a new concept called "bacterial constipation." Their findings, which are expected to lead to the development of new treatments, were published in the February 18 issue of Gut Microbes.

Constipation is a common gastrointestinal disorder characterized by infrequent bowel movements and hard stools. It has long been thought to result from "slowed intestinal motility (peristalsis)." However, the mechanisms underlying CIC-which occurs independently of intestinal motility-and constipation associated with Parkinson's disease (PD) remained unknown. Constipation in CIC and PD is unlikely to respond to laxatives or prokinetic agents.

The research group therefore focused on "intestinal mucus," a substance that retains moisture in stool and lubricates the gut. They investigated the possibility that degradation of intestinal mucus by gut bacteria causes constipation.

Intestinal mucus is composed mainly of mucin, a high-molecular-weight glycoprotein. Mucin has a high water-retaining capacity and lines the inside of the gut, protecting the intestinal wall from bacteria while also serving as a lubricant that helps stool pass smoothly.

To identify the causative gut bacteria, the researchers performed 16S rRNA sequencing analysis and qPCR analysis on fecal samples collected from across Japan: 147 healthy controls, 231 patients with Parkinson's disease, and 54 CIC patients. The results showed that two bacterial species-Bacteroides thetaiotaomicron and Akkermansia muciniphila-were abnormally increased in the stool of patients.

To investigate the function of these bacteria, the researchers conducted transplantation experiments using germ-free mice. The results showed that transplanting either bacterium alone did not cause constipation, but co-transplanting both simultaneously caused the mice to develop constipation-characterized by harder stools (reduced fecal wet weight) and decreased defecation frequency. This demonstrated that the two bacterial species act cooperatively to cause constipation. Germ-free mice transplanted with a defined set of eight gut bacteria used as a control did not develop constipation.

Furthermore, intestinal permeability testing revealed that the presence of both bacterial species suppressed the intestinal barrier function, confirming the occurrence of leaky gut (increased intestinal permeability).

B. thetaiotaomicron is known to possess sulfatase activity-the ability to remove sulfate groups-while A. muciniphila lacks this ability but has been reported to specifically degrade mucin. Based on this, the researchers investigated the possibility that B. thetaiotaomicron strips away the protective sulfate groups from mucin, thereby enabling A. muciniphila to degrade it.

The researchers generated a strain of B. thetaiotaomicron that had lost its mucosal desulfation function through deletion of the anaerobic sulfatase-maturating enzyme (anSME) gene. When this ΔanSME strain was co-colonized with A. muciniphila in germ-free mice^*, alleviation of constipation was confirmed. Co-transplantation of this modified strain with A. muciniphila resulted in increased fecal pellet count and fecal wet weight, confirming suppression of constipation.

Hamaguchi commented: "I believe bacterial constipation develops because the bacteria themselves have acquired a markedly elevated capacity to degrade mucus. As a preliminary proposal for treatment, we are considering the development of drugs that block the activity of the 'key-unlocking enzyme' (sulfatase), as well as treatment using bacteriophages-viruses that specifically infect and eliminate bacteria without infecting humans. Going forward, we aim to develop fundamental treatments with fewer side effects that target bacteria rather than humans."

Ohno commented: "By proposing 'bacterial constipation' and clarifying its mechanism, I believe we can now pursue more precisely targeted treatments. While developing drugs that enhance enzyme activity is difficult, developing drugs that inhibit enzyme activity-though a relatively unexplored area of research-is comparatively more feasible."

Germ-free mice:
These are mice raised in a state completely free of microorganisms, both inside and on the surface of their bodies. They are bred inside special isolation equipment (isolators) and are provided with completely sterilized water and food. In this study, the group created gnotobiotic mice by introducing and colonizing only specific bacteria into them. Furthermore, the first professor of the laboratory where this research was conducted, Masasumi Miyagawa, succeeded in creating the world's first germ-free guinea pig in 1954. The research technique of "germ-free animals," pioneered by Professor Miyagawa, continues to be used in medical and biological research even decades later. This study was conducted as a collaborative project with the Central Institute for Experimental Medicine and Life Science (CIEA/CIEM), which has further developed germ-free animal experimentation, and technical guidance was received.

Journal Information
Publication: Gut Microbes
Title: Bacterial constipation: Mucin-degrading intestinal commensal bacteria cause constipation
DOI: 10.1080/19490976.2025.2596809