Depression and fatigue in active IBD from a microbiome perspective-a Bayesian approach to faecal metagenomics.

BACKGROUND: Extraintestinal symptoms are common in inflammatory bowel diseases (IBD) and include depression and fatigue. These are highly prevalent especially in active disease, potentially due to inflammation-mediated changes in the microbiota-gut-brain axis. The aim of this study was to investigate the associations between structural and functional microbiota characteristics and severity of fatigue and depressive symptoms in patients with active IBD. METHODS: We included clinical data of 62 prospectively enrolled patients with IBD in an active disease state. Patients supplied stool samples and completed the questionnaires regarding depression and fatigue symptoms. Based on taxonomic and functional metagenomic profiles of faecal gut microbiota, we used Bayesian statistics to investigate the associative networks and triangle motifs between bacterial genera, functional modules and symptom severity of self-reported fatigue and depression. RESULTS: Associations with moderate to strong evidence were found for 3 genera (Odoribacter, Anaerotruncus and Alistipes) and 3 functional modules (pectin, glycosaminoglycan and central carbohydrate metabolism) with regard to depression and for 4 genera (Intestinimonas, Anaerotruncus, Eubacterium and Clostridiales g.i.s) and 2 functional modules implicating amino acid and central carbohydrate metabolism with regard to fatigue. CONCLUSIONS: This study provides the first evidence of association triplets between microbiota composition, function and extraintestinal symptoms in active IBD. Depression and fatigue were associated with lower abundances of short-chain fatty acid producers and distinct pathways implicating glycan, carbohydrate and amino acid metabolism. Our results suggest that microbiota-directed therapeutic approaches may reduce fatigue and depression in IBD and should be investigated in future research.

Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors.

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8+ T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.