In silico analysis of changes in predicted metabolic capabilities of intestinal microbiota after fecal microbial transplantation for treatment of recurrent Clostridioides difficile infection

Abstract

Importance: Fecal microbial transplantation (FMT) is effective in treating recurrent Clostridioides difficile (RCDI) infection. The therapeutic efficacy of FMT is thought to be related to restoration of intestinal microbial composition and diversity and key microbially derived compounds, such as short-chain fatty acids (SCFAs) and bile acids. However, it is unknown if other microbially derived metabolites or processes contribute to FMT efficacy. Aim: To identify changes in KEGG orthology (KO) groups pre-FMT versus post-FMT to explore other potential microbial derived products that may be important for the therapeutic benefits of FMT in treatment of RCDI. Methods: In-silico analyses of shotgun metagenomics sequencing data was used to examine the change in KO groups comparing pre-FMT to post-FMT stool samples in patients with RCDI. Statistical significance was determined using univariate linear mixed models analyses to estimate changes in KOs pre-FMT and at week 1, 4, and 12 post-FMT, with time (weeks) as the main variable. A literature review was completed to propose biological relevance. Results: Of the 59,987 KO groups identified by shotgun metagenomics sequencing, only 27 demonstrated a statistically significant change after FMT. These KO groups are involved in many cellular processes including metabolism (10/27), DNA synthesis/replication/repair (8/27), cellular signaling (2/27), substrate transport (6/27), and other miscellaneous functions (1/27). Of interest, KO groups involved in iron homeostasis, glycerol metabolism, and arginine regulation, have been implicated to play an important role bacterial growth and virulence, in addition to modulating the intestinal microbial composition. Conclusion: Our analyses demonstrate several biologically plausible KO groups that are potentially important in mediating the efficacy of FMT in RCDI, beyond microbial diversity, SCFAs, and bile acids.