Table 1. Overview of the interplay between IBD therapeutics and gut microbiome and future possibilities/recommended actions.

Drug	Impact of gut microbiota on therapeutic	Impact of therapeutic on gut microbiota	Future possibilities/recommended actions
5-ASA	-Bacterial azoreductases release active moiety[18]	-Inhibits growth of certain species including Bacteroides sp., Clostridium sp.[32], Campylobacter concisus, and Escherichia coli[33]	-Increase the abundance of azo-reducing bacteria in the gut using specifically designed “azo-reducing” probiotic strains
	-Acetylates 5-ASA to ineffective acetyl-5-ASA[28,29]	-Exacerbates growth of certain C. concisus strains[33]	-Develop inhibitor molecules to microbial acetyltransferases
		-Downregulates Salmonella invasiveness[38] -Inhibits bacterial polyphosphate kinase[39] -Increases SCFA-producers, decreases Proteobacteria[43] -Alters Firmicutes: Bacteroidetes ratio[46] -Alters fungal microbiota diversity and composition, restores bacteria-fungi correlation patterns[48]	-Investigate the impact of 5-ASA on the gut resistome
Methotrexate	-Metabolise methotrexate to methotrexate- PG[57] -Reduce methotrexate-PG to inactive metabolite DAMPA[58,59]	-Inhibits bacterial growth[52,57,65,67] -Selects for antimicrobial resistance genes[70]	-Investigate the impact of methotrexate on the gut resistome -Develop methotrexate-specific probiotic strains, e.g., Bacteroides fragilis, that ameliorate undesirable changes to the gut epithelium
Glucocorticoids	-Metabolise the drug[78,79] -Convert the drug to androgens[83] -May convert the drug to a metabolite that causes proliferation of prostate cancer cells[86]	-Alters microbiome composition to a healthier profile[87,88,90,91]	-Investigate drug-metabolising capabilities of the microbiome using metabolomics and metatranscriptomics -Assess the safety of resulting metabolites -Identify microbial enzymes responsible for drug metabolism
Calcineurin inhibitors	-Metabolise drug to less potent metabolites[100]	-Alters microbiome composition and functionality[88,101–103]	-Investigate drug-metabolising capabilities of the microbiome using metabolomics and metatranscriptomics -Assess the safety of resulting metabolites -Identify microbial enzymes responsible for drug metabolism -Develop strategies to prevent drug metabolism
Tofacitinib	-	-Alters microbiome composition[113]	-Investigate the impact of gut microbiota on the drug
TNF inhibitors	-May bind to the drug™ -May cleave the drug[123]	-Alters microbiome composition and functionality to a healthier profile [127,128,130]	-Investigate the impact of gut microbiota on drug stability -Develop strategies to prevent drug cleavage Vedolizumab ustekinumab -Investigate the impact of gut microbiota on the drugs -Investigate the impact of the drugs on gut microbiota
Exclusive enteral nutrition		-Alters microbiome composition[160,163,166] -Can reduce microbial diversity [157,158,161,162] -Improves/normalises bile acid metabolism[161,163,165] -Alters SCFA levels[166]	-Administer Akkermansia muciniphila before treatment to improve remission maintenance
Hematopoietic stem cell transplantation		-Alters microbiome composition to a healthier profile[173,174]	-Investigate the impact of gut microbiota on therapy efficacy
Mesenchymal stem cell therapy		-Alters microbiome composition to a healthier profile[187–189] -Decreases sulphur metabolism[189] -Increases Cetobacterium relative abundance[190]	-Investigate the impact of gut microbiota on therapy efficacy

DAMPA: 4-amino-4-deoxy-N-methylpteroic acid; IBD: inflammatory bowel disease; methotrexate-PG: methotrexate-polyglutamate; SCFA: short chain fatty acid; TNF: tumour necrosis factor; 5-ASA: 5-aminosalicylic acid.