MicrobiotaMi Comment 27_21  by Federica Spaggiari

Related Journal Article:  Clostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota

This article was published in the: Nat Commun. 2021 Jan 19;12(1):462. doi: 10.1038/s41467-020-20746-4.

Clostridioides difficile behaviour in the inflamed gut: a transcriptional and microbial composition alteration

Clostridioides difficile is a Gram positive, spore-forming and ubiquitous anaerobe that can be easily found in the soil. C. difficile is a member of the normal human gut flora even if its growth and activity are suppressed by more dominant anaerobes in healthy conditions. The rate of gut colonization varies among age groups. In particular, it is abundant during infancy, when the gut microbiota is still immature.

Treatment with broad-spectrum antibiotics promotes dysbiosis, C. difficile survival over other bacteria and favours its activity. These bacteria perform their pathogenic action through the production of two toxins (TcdA and TcdB) that have a role in the impairment and loss of integrity of the gut epithelial barrier. Since C. difficile is auxotrophic but thrives in the inflamed gut, Fletcher et Al. hypothesised that the toxin-mediated inflammation in the gut induces alterations in the canonical transcriptional patterns of both bacterial and host genes, promoting C. difficile persistence.

Two groups of antibiotic-treated mice were infected with spores from two C. difficile strains, 630Δerm and 630Δerm tcdR::ermB respectively, with the latter unable to produce high levels of toxins. As expected, tcdR mutant mice showed a minor inflammatory damage in the cecal epithelium. Interestingly, the in vivo transcriptomes of the two different strains were extremely different while the in vitro analysis did not highlight such distinction. These data suggest a primary effect of the environmental inflammation on bacteria transcriptional activity.

In particular, in wild type C. difficile infected mice, an enrichment in carbohydrate metabolism associated genes and PTS was detected. These gene products allow the bacterial population to access different nutritional sources. Conversely, the transcription of genes involved in the biosynthesis of some amino acids, such as isoleucine and valine, are downregulated while the respective amino acids’ transporters are specifically overexpressed. These results lead to the hypothesis that the inflamed environment provides C. difficile with the needed substrates for its survival and that the bacterial population modifies its transcriptome in order to take advantage of the provided molecules.

Transcriptional activity alteration could be observed in the host gut tissue as well. The observed transcriptional profile includes an upregulation in the expression of inflammatory and proteolytic genes, among which MMPs and TIMPSs transcripts were the most abundant. The overexpression of MMPs leads to collagen remodelling both in vitro and in vivo. Thus,  Fletcher et Al. speculate that C. difficile utilizes the products of collagen degradation as a source of peptides and amino acids.

Further experiments were focused on the effects of toxin-mediated inflammation on gut microbiota composition. 16S rRNA amplicon sequencing on cecal DNA from all the groups showed a reduction in Akkermansaceae and Bacteroidaceae in the microbiota of mice infected with C. difficile wild-type strain. Since Bacteroidaceae are proline and hydroxyproline utilizer, as C. difficile is, their limited presence could be the result of nutrients competition.

This study extensively analyzed the effects that C. difficile colonization has on host gene expression as well as the role that the inflamed gut has in the promotion of these bacterial population survival. Moreover, a comprehensive investigation on the gut microbiota alteration highlighted the occurrence of a competition for nutrients among diverse commensal species. These observations shed light on the mechanism that C. difficile exploit to prosper in the inflamed environment and identified new potential targets for the treatment of CDIs that are still a major cause of morbidity and mortality worldwide.

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<a href="https://microbiotami.com/author/federica/" target="_self">Federica Spaggari</a>

Federica Spaggari

Federica Spaggiari, after graduating in Biotechnology from the University of Modena and Reggio Emilia, Federica is pursuing a Master’s in Translational Cancer Medicine at King’s College London. During the first part of the program, she spent six months in the Invasion and Metastasis research group led by Professor Claire Wells and studied the molecular mechanisms underlying oesophageal cancer. She is currently working in the Tumour Immunology lab supervised by Dr James Arnold where she is focusing on the optimization of CAR T-cell therapy for solid tumours. In September 2022 she will join the Cancer Biomarker Centre at CRUK Manchester Institute as a PhD student.