Blood-borne immune cells carry low biomass DNA remnants of microbes in patients with colorectal cancer or inflammatory bowel disease

Abstract The involvement of the human intestinal microbiome in the regulation of immune cell homeostasis, as well as in the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC), are well-established1–4. Bacteria interact with immune cells at the sites of intestinal inflammation, but also in the CRC tumor microenvironment1–6. Indeed, bacterial remnants have recently been detected in human intestinal tissue in patients with IBD, at primary tumor sites and in the metastases of patients with CRC, and in whole blood3,7,8. A defective intestinal epithelial barrier is thought to promote bacterial remnant translocation and disease progression6. However, it is unknown, how bacterial remnants translocate from the intestine to sites of metastasis or into the circulation. We hypothesized that bacterial remnants translocate within peripheral blood immune cells into the circulation. Here, we thus explored the composition of the detectable microbiome in peripheral blood mononuclear cells (PBMCs) of patients with CRC or IBD compared to healthy controls. The PBMC microbiome profiles partially align with the tumor- and metastasis-derived or intestinal tissue-derived microbiome signatures obtained from the same patients with CRC or IBD, respectively. Our metagenomics data, supported by 16S-rRNA-FISH-Flow, imaging flow cytometry and species-specific qPCR, reveal the presence of translocated bacterial genetic sequences in the patients with CRC and IBD, likely due to an intestinal barrier defect. Pathway and serum metabolomics analysis connected to the metabolic potential of the PBMC-derived microbiome sequences support the onset of microbial translocation in such patients. Thus, our data suggest that in patients with intestinal barrier leakage, such as those with CRC or IBD, there is the potential for the translocation of bacterial remnants into the circulation via peripheral immune cells. Competing Interest Statement MS has shares and is co-founder of Recolony AG, Zurich, CH and has shares in PharmaBiome AG, Zurich, CH. MS served as Advisor for Abbvie, Gilead, Fresenius, Topadur, Takeda, Roche, Astra Zeneca and Celltrion. MS received speakers honoraria from Janssen, Falk Pharma, Vifor Pharma, Pileje and Bromatech. MS received research grants from Abbvie, Takeda, Gilead, Gnubiotics, Roche, Axalbion, Pharmabiome, Topadur, Basilea, MBiomics, Storm Therapeutics, LimmatTech, Zealand Pharma, NodThera, Calypso Biotech, Menarini. Pileje, Herbodee, Vifor. GR has shares and is cofounder and head of the scientific advisory board of PharmaBiome. GR has consulted to Abbvie, Arena, Augurix, BMS, Boehringer, Calypso, Celgene, FALK, Ferring, Fisher, Genentech, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller. GR received speakers honoraria from Abbvie, Astra Zeneca, BMS, Celgene, FALK, Janssen, MSD, Pfizer, Phadia, Takeda, Tillots, UCB, Vifor and Zeller. GR received educational grants and research grants from Abbvie, Ardeypharm, Augurix, Calypso, FALK, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB and Zeller. MT served as advisor for Topadur and Takeda. MT received speakers honoraria from Janssen, Takeda and Intuitive Surgical. RF has served as an Advisor or speaker for Roche, Pierre Fabre Pharma, Servier, Bristol Myers Squibb, Merck Sharp&Dome, Astra Zeneca. LB has served as advisor for Abbvie, Amgen, BMS, Falk, Janssen, Pfizer, Lilly, Takeda, Sanofi, Esocap, Aquilion and received speaker fees from Takeda, Sanofi, Abbvie, Janssen, Lilly, Falk, BMS, Pfizer. The additional authors declare that they have no competing interests relevant to this work.