Early-life gut microbial dysbiosis exacerbates colitis

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder that causes intestinal inflammation. Although the precise cause of IBD is unknown, several factors that lead to this disease have been identified. These factors are linked to age, immune system, genetics, and environment. One of the key factors behind IBD manifestation is gut microbial dysbiosis.

Study: Early-Life Gut Microbiota Governs Susceptibility to Colitis via Microbial-Derived Ether Lipids. Image Credit: Design_Cells / Shutterstock

Background

A healthy gut comprises a rich diversity of obligate anaerobes and low oxygen levels. In contrast, individuals with IBD exhibited a high level of reactive oxygen species (ROS) and nitrogen. Intestinal inflammation triggers an increase in colonic oxygenation, which leads to bacterial population imbalance in both aerobic and anaerobic bacteria populations.

Prior research has shown how obligate anaerobes, such as Clostridium butyricum and Bifidobacterium, and their metabolites affect the colonic environment in IBD. As stated above, gut microbial imbalance is present in IBD patients, which has been associated with increased facultative anaerobes and decreased facultative anaerobes. 

Plasmalogens are a common form of ether lipids widely distributed in anaerobic bacteria and animals. These are involved with signaling and protection against ROS and membrane structure. Even though plasmalogen synthase (pls) has been linked to the majority of the members of the gut microbiome, there has been a dearth of information regarding plasmalogen-producing bacteria in gut microbiota. 

Recently, plasmalogens have been found in facultative anaerobic and aerobic bacteria. There is a need to better characterize bacterial communities of plasmalogen-positive species (pls [PlsA/R]-positive) and elucidate their function linked to gut inflammatory diseases to identify therapeutic targets. 

Ether-linked phospholipids have been found to influence ferroptosis, which is associated with the regulation of intestinal diseases. However, few studies have been conducted to understand the age-related changes in the gut microbiome, i.e., from young adulthood to the mature adult stage, which influences intestinal health. 

About the Study

A recent Research journal study investigated the role of microbiota linked to the anaerobic plasmalogen biosynthetic pathway in establishing intestinal homeostasis. The study hypothesized that the presence of pls [PlsA/R]-positive bacterial species and plasmalogen bestow valuable intestine homeostasis in early life. 

Feces samples from nineteen IBD patients and twelve healthy individuals were obtained. Both male and female individuals who had active ulcerative colitis were recruited. The age of the participants was between 10 and 30 years.

For animal experiments, mice models were used. The mice were subjected to 12 hours of light/dark cycle with free access to food and water. Colitis was induced in mice by dextran sulfate sodium (DSS). A group of mice without colitis was considered as a control.

Study Findings

The study predominantly focussed on bacteria-producing ether lipids because of their unique anaerobic biosynthesis pathways associated with the regulation of early-life gut microbiota alteration on colitis. The incidence of colitis was associated with high levels of ROS and decreased anaerobic bacteria population.

Prior studies have indicated that ether lipids, such as plasmalogens, function as ROS scavenger molecules and endogenous antioxidants to promote ferroptosis. The present study determined the association between changes in gut microbial structure, ferroptosis, and colitis development.

Ether lipids-producing anaerobic bacteria, found in the early stages of life of patients or mice with IBD, were characterized. It was observed that changes in ether-linked lipids, signaling due to gut anaerobic bacterial dysbiosis, enhanced the risk of ferroptosis and colitis.

Prior research has demonstrated that antibiotic therapy using neomycin, metronidazole, or ciprofloxacin, prevents the incidence of colitis. A reduction in colonic inflammation was observed in germ-free mice (control) and those who received antibiotic treatment at 18 weeks of age; however, impairment in barrier function occurred. Nevertheless, when 8 weeks old mice were subjected to similar antibiotic treatment, exacerbated colitis was observed. These contradictory observations occurred due to age-associated gut microbial dysbiosis, which induced the pathogenesis of gut inflammation.

Notably, the current study documented that an early-life microbiota depletion due to antibiotic cocktail treatment intensified DSS-induced colitis. In contrast, mid-life microbiota depletion led to a decreased clinical symptom of colitis upon DSS challenge. This finding is in line with previous reports that showed early-life microbial dysbiosis in pups increased the risk of colitis later in life. This occurrence could be due to various reasons. One explanation is the effect of early-life antibiotic treatment causing microbial dysbiosis, causing a decrease in the colonic epithelial cell cytoprotective properties of specific bacteria and their metabolites (e.g., secondary bile acids and short-chain fatty acids). 

Based on 16S rRNA sequencing, it was shown that young mice contained higher levels of plasmalogen-positive species in the colon compared to mature adult mice. A reduction in colonic plasmalogen-producing bacteria and plasmalogen levels was correlated with reduced dimethyl-acetal (DMA) derivatives in colon contents of DSS-induced colitis mice. Lower fecal plasmalogen levels and reduced ether-linked phospholipids levels were observed in microbiota-depleted mice.

Conclusions

The current study identified microbes essential for an early-life healthy gut microbiota that could reduce the risk of colitis in later life. Plasmalogens play a crucial role in the progression of colitis. They can attenuate inflammatory responses and revert the increased colitis susceptibility of mice lacking anaerobic bacteria. In the future, the underlying mechanism of plasmalogen-positive microbiota to maintain intestinal health must be elucidated.