Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice

Authors: CROSSLAND, NICHOLAS - Boston University; BECK, SAMUEL - Boston University; TAN, WEI - Boston University; LO, MING - Boston University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ZHANG, CHAO - Boston University; CROTT, JIMMY - Boston University

Submitted to: Gut Microbes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/22/2023
Publication Date: 12/5/2023
Citation: Crossland, N.A., Beck, S., Tan, W.Y., Lo, M., Mason, J., Zhang, C., Crott, J. 2023. Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice. Gut Microbes. https://doi.org/10.1080/19490976.2023.2288187.
DOI: https://doi.org/10.1080/19490976.2023.2288187

Interpretive Summary: Older age is the single most important risk factor for developing colorectal cancer (CRC). The profile of microbes that inhabit the colon are also known to change with age and there is increasing evidence that the totality of colonic microbes harbored by a person-the gut microbiome-plays a large role in the evolution of CRC. To examine the potentially causal role of the gut microbiome in mediating the development of this cancer, we performed fecal transplants into young recipient mice who possessed an underlying predisposition to developing CRC with the gut microbiome of either young or old mice and repeated the transplants monthly thereafter. Changes in the profile of fecal organisms, and the organic biochemicals contained in the feces were evident between the two groups of recipients, and consistent with increased inflammation and micro-organisms previously associated with tumor risk in the recipients of old microbiome. These findings support a causal role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.

Technical Abstract: Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the composition of the gut microbial community changes with age and is reported to become more pro-inflammatory, it is unclear whether such changes are also pro-tumorigenic for the colon. To address this gap, we conducted fecal material transplants (FMT) from young (DY, ~6 wk) and old (DO, ~72 wk) donor mice into young (8 wk) recipient mice that were pre-treated with antibiotics. After initiating tumorigenesis with azoxymethane, recipients were maintained for 19 weeks during which time they received monthly FMT boosters. Compared to recipients of young donors (RY), recipients of old donors (RO) had an approximately 3-fold higher prevalence of histologically confirmed colon tumors (15.8 vs 50%, Chi2 32 P=0.03), approximately 2-fold higher proliferating colonocytes and approximately 23% higher colonic IL-6. Transcriptomics analysis of the colonic mucosa revealed a striking upregulation of mitochondria-related genes in the RO mice, a finding corroborated by increased mitochondrial abundance. Amongst the differences in fecal microbiome observed between DY and DO mice, the genera Ruminoclostridium, Lachnoclostridium and Marvinbryantia were more abundant in DY mice while the genera Bacteroides and Akkermansia were more abundant in DO mice. Amongst recipients Ruminoclostridium and Lachnoclostridium were higher in RY mice while Bacteroides was higher in RO mice. Differences in fecal microbiota were observed between young and old mice, some of which persisted upon transplant into recipient mice. Recipients of old donors displayed significantly higher colonic proliferation, inflammation and tumor abundance compared to recipients of young donors. These findings support an etiological role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.