Fungi and bacteria play a role in therapeutic response in pediatric inflammatory bowel disease

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Pediatric inflammatory bowel diseases (PIBD), including Crohn’s disease and ulcerative colitis, are increasing globally at a rapid pace. Current hypothesis for the pathogenesis of IBD is that the combination of genetic, environmental, and microbial factors leads to prolonged inflammation and increased gut permeability, with intestinal microbiota developing towards state sustaining inflammation. The composition of gut microbiota and mycobiota (the fungal gut microbiota) are altered in IBD. Yet, the complex interactions between gut fungi and bacteria are less researched.

Previously the gut microbiota in IBD was characterized with a reduction in the diversity of the commensal bacteria. Additionally, when comparing IBD patients to healthy controls, previous studies reported a reduction of potentially anti-inflammatory bacteria such as Roseburia, Bifidobacterium and Faecalibacterium. However, the methodology of different studies is variable, which hampers comparisons between studies.

There are multiple therapies to IBD, with more severe cases generally treated with anti-TNFa blockers. However, up to half of patients do not respond to treatment and loss of response is frequent. To this day, there are no clinical methods to predict responsiveness. Therefore, we conducted a study to examine the relation of response to anti-TNFa and fecal mycobiota and microbiota. We aimed to find biomarkers to predict response at an early phase of the therapy.

We recruited 30 patients with PIBD introduced to anti-TNFa blocker infliximab in Children’s hospital, Helsinki University. The participants provided stool samples at baseline and at two and six weeks after the start of treatment. We measured response to treatment using fecal calprotectin, which is a marker of intestinal inflammation. The cut off value for remission was <100 µg/g at week 6, which has specificity of 0.92 and negative prediction value of 95% to predict deep healing in the gut. The samples were analyzed by MiSeq sequencing targeting 16S and ITS regions.

As expected, there were substantial differences in the gut microbiota between treatment response groups. The responsive group had an increased abundance of several butyrate producing bacteria considered anti-inflammatory prior to treatment. Also, the response was predictable at baseline by genus Ruminococcus alone (AUC 0.790) and when combined with the fecal calprotectin (AUC 0.892).

Surprisingly, we noticed no significant differences in gut mycobiota between treatment response groups at baseline. However, at week six the responders showed an increase in Saccharomyces while the abundance of Candida was increased in non-responders.

Interestingly, the associations between gut myco- and microbiota varied between treatment response groups and were characterized by bacteria considered to play beneficial roles in IBD and Saccharomyces in responders, while bacteria that belong to altered bacterial composition in IBD were linked to Candida in non-responders.

What do our findings mean? Well, previously gut mycobiota and response to these drugs in PIBD has been studied in a single study using a metagenomic approach and comparing the studies with different methodologies is difficult. The finding that Saccharomyces was increased in responders hints towards the change of gut mycobiota towards healthy controls, while increase in Candida in non-responders reflects disease progression in PIBD.

Regarding the bacteria, our results of increased abundance of several butyrate producers in responders are supported by previous studies on response to anti-TNFa. Butyrate is a short-chain fatty acid that has an anti-inflammatory effect by upregulating the secretion of IL-10, an anti-inflammatory cytokine, and strengthening the intestinal barrier. These results highlight the role of intestinal microbiota prior to treatment in reaching remission. This was further strengthened by the fact, that after the start of anti-TNFa,  the microbiota composition changed in a comparable manner in responders and non-responders.

Our findings, together with previously published studies open a way for new research in this understudied field. Perhaps a purposeful modification of intestinal microbiota to reach remission could be a valid treatment in the future. That could help patients reach remission and perhaps to sustain the achieved remission. However, modification of gut microbiota requires further knowledge over the complex interactions between the bacteria and the fungi of the intestine. To help you get better knowledge of these complex interaction, please visit our article here https://www.nature.com/articles/s41598-022-10548-7.

Miikka Höyhtyä

Medical doctor, Tampereen Yliopisto