Ulcerative colitis (UC) is an inflammatory disease that affects the colon and rectum. It is believed that genetic factors, host immune system disorders, intestinal microbiota dysbiosis, and environmental factors contribute to the pathogenesis of UC. Previous studies have linked missing microbes to ulcerative colitis. These microbes make metabolites that help keep the gut healthy. Now a new study by researchers at the University of Chicago (UChicago) demonstrates that restoring a single microbial species, Bacteroides sp. CL1-UC (Bc), to the gut microbiome at a key developmental timepoint can prevent antibiotic-induced colitis in a mouse model of the condition.
Their study, “Early-life microbial restitution reduces colitis risk promoted by antibiotic-induced gut dysbiosis in IL-10-/- mice,” was published in the journal Gastroenterology.
“We previously showed maternal antibiotic-induced gut dysbiosis vertically transmitted to offspring increases experimental colitis risk in IL-10 gene deficient (IL-10-/-) mice, a finding that may result from the loss/lack of essential microbes needed for appropriate immunological education early in life,” wrote the researchers. “Here, we aimed to identify key microbes required for proper development of the early life gut microbiome that decreases colitis risk in genetically susceptible animals.”
The researchers used metagenomic sequencing, which provides access to a larger reservoir of genomic and transcriptomic data, followed by reconstruction of metagenome-assembled genomes (MAGs) on fecal samples of IL-10-/- mice with and without antibiotic-induced dysbiosis. This led them to the bacterial phylum Bacteroides.
“We know that the kinds of microbes that you’re exposed to early in life actually determine how your immune system develops,” said senior author Eugene Chang, MD, the Martin Boyer professor of medicine at UChicago. “Our immune system learns to recognize our own selves, and the trillions of microbes in our gut—they’re ‘us’ as well, so our immune system has to learn to tolerate these organisms, just as it tolerates our own cells. Early exposure to antibiotics can eradicate some of the organisms that are essential for educating the immune system to develop immune tolerance.”
Mice that lack a gene known as IL-10 (IL-10-/-) were studied to overcome the challenges of studying human patients. “This mouse model has been established as being genetically susceptible to IBD, and we know that the gut microbiome plays a crucial role in the development of colitis in this model,” explained first author Jun Miyoshi, MD, PhD, a senior assistant professor in the department of gastroenterology and hepatology at Kyorin University School of Medicine, and a former postdoctoral scholar at UChicago.
The researchers observed that Bacteroides was very abundant in the microbiomes of untreated mice, but not found in the mice that had been exposed to antibiotics. They also noted that they did not find Bacteroides in the treated mice that did not go on to develop colitis, but they often found Bacteroides in mice that did end up with the condition.
“These bacteria were eradicated by early exposure to antibiotics and were essential for educating the immune system in developing immune tolerance,” added Chang. “When those mice later acquired the bacteria, their immune system had never seen it. It was viewed as foreign, not as self, and their immune systems reacted to it.”
The researchers observed the differences between adding Bc back to the microbiomes of the mice with dysbiosis at two time points: around infancy (three weeks of age) and adulthood (11 weeks of age).
Engrafting Bc into the younger mice corrected their dysbiosis and prevented colitis. However, dysbiosis was not corrected in adulthood and unfortunately worsened their colitis.
“This shows that you can’t just restore the missing bacteria at any time point, it has to be at a specific time early in life to have a beneficial effect,” stated Chang. “In young animals, we know that the immune system is developing, it’s naïve, it has to be taught, and it’s taught by being exposed to certain kinds of microbes. In some ways, it’s similar to a peanut allergy—early exposure to the antigen can tolerize the immune system to help avoid a peanut allergy, but it has to happen within a very finite window.”
Their findings demonstrate how relatively small changes can have a dramatic impact on a system. “It’s like the tall trees of the Amazon rainforest,” said Chang. “You need the tall trees, because if you don’t have them, the ecosystem below cannot develop properly. But if you have those trees in place, the rest of the ecosystem will flourish.”
“Restitution of a keystone microbial strain missing in the early life antibiotic-induced gut dysbiosis results in recovery of the microbiome, proper development of immune tolerance, and reduced risk for colitis in genetically prone hosts,” concluded the researchers.
Further studies are needed before work is seen in human studies. However, their findings may lead to new approaches and strategies for treating complex immune disorders. Chang concluded that we need to shift our thinking to not what immediately precedes these diseases but what happens early in life to intervene for these patients affected.
