Transplantation of bacteriophages from ulcerative colitis patients shifts the gut bacteriome and exacerbates severity of DSS-colitis

Abstract

Inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC) are characterized by chronic and debilitating gut inflammation. Altered bacterial communities of the intestine are strongly associated with IBD initiation and progression. The gut virome, which is primarily composed of bacterial viruses (bacteriophages, phages) is thought to be an important factor regulating and shaping microbial communities in the gut. While alterations in the gut virome have been observed in IBD patients, the contribution of these viruses to alterations in the bacterial community and heightened inflammatory responses associated with IBD patients remains largely unknown. Here, we performed in vivo microbial cross-infection experiments to follow the effects of fecal virus-like particles (VLPs) isolated from UC patients and healthy controls on bacterial diversity and severity of experimental colitis in human microbiota-associated (HMA) mice. Shotgun metagenomics confirmed that several phages were transferred to HMA mice, resulting in treatment-specific alterations in the gut virome. VLPs from healthy and UC patients also shifted gut bacterial diversity of these mice, an effect that was amplified during experimental colitis. VLPs isolated from UC patients specifically altered the relative abundance of several bacterial taxa previously implicated in IBD progression. Additionally, UC VLP administration heightened colitis severity in HMA mice, as indicated by shortened colon length and increased pro-inflammatory cytokine production. Importantly, this effect was dependent on intact VLPs. Our findings build on recent literature indicating that phages are dynamic regulators of bacterial communities in the gut and implicate the intestinal virome in modulating intestinal inflammation and disease.

The gut virome: A new microbiome component in health and disease

“… 84 A recent preprint study observed that transplantation of VLPs from UC patient faeces to human-microbiota-associated (HMA) mice significantly aggravated colitis in mice and changed the bacterial taxa associated with IBD pathogenesis. 8 In another murine study, several phage taxa belonging to Caudovirales were shown to mediate TLR9-dependent activation of CD4 + T cells to exacerbate intestinal inflammation, by enhancing the TLR-dependent production of IFN-γ. 71 Together, these results emphasised the potential central role of phages in activating the gut mucosal immune responses and exacerbating colitis.…”

“… 6 The human virome is composed of eukaryotic and prokaryotic viruses, including viruses that infect human cells, viruses that infect microbes (such as bacteria, fungi, and archaea), and plant viruses that are primarily derived from environment and diet. 7 Akin to the bacterial microbiome (bacteriome), the gut virome also plays an important role in the pathogenesis of disease, including inflammatory bowel disease (IBD), 8 Clostridioides difficile infection (CDI), 9 obesity, 10 diabetes, SARS-CoV-2 infection, 11 , 12 liver diseases, 13 colorectal cancer (CRC), 14 as well as malnutrition. 15 Gut virome rectification has shown great potential as disease therapeutics through faecal microbiota transplantation (FMT), faecal virome transplantation (FVT), and phage therapy.…”