Although the etiology of IBD remains exclusive, the complex interaction of the gut microbial communities with immune cells can influence the disease severity and susceptibility to immune therapy in IBD patients [
2]. The relationship between the gut microbiome and anti-TNF therapy is complex and not fully understood, however, research on the role of the microbiome in the context of anti-TNF-alpha therapy is continuously evolving. The gut microbiome, which consists of trillions of microorganisms residing in the gastrointestinal tract, plays a crucial role in immune modulation [
55‐
58], intestinal inflammation [
59], and response to immunomodulatory therapies [
2,
60,
61], including anti-TNF-alpha drugs [
62]. Emerging studies have suggested that certain microbial markers may be associated with treatment outcomes and response to anti-TNF-alpha therapy [
62,
63]. For example; diverse microbes are generally associated with a healthier gut and patients with a more diverse gut microbiome respond better to anti-TNF-alpha therapy, while the presence of certain microbial species or groups of bacteria are associated with either a positive or negative response to anti-TNF-alpha therapy [
63]. For example, a higher abundance of
Faecalibacterium prausnitzii, Ruminococcus bromii, Bifidobacterium ssp., Clostridium colinum,
Eubacterium rectale, and lower levels of
Streptococcus mitis have have been linked to a better treatment response to anti-TNF therapy in IBD patients [
64‐
66]. Moreover, increased levels of butyrate‐producing species (such as
Roseburia inulinivorans and
Burkholderiales) and a higher level of branched-chain amino acids are shown to be positively correlated with the clinical response to Vedolizumab [
67]. In contrast, short-chain fatty acids producing bacteria such as
Lachnospiraceae and
Ruminococcaceae families, have been found to be associated with primary non-responders to the anti-TNF-α therapies [
68]. In addition, the patients with gut microbial dysbiosis [
69] or with additional fibrostenotic disease often exhibit no-response or poor response to anti-TNF therapy [
70‐
73]. The balance between the two dominant microbial groups mainly
Prevotella and
Bacteroides in the gut has also been explored in relation to anti-TNF therapeutic response in patients [
74,
75]. Higher levels of
Prevotella relative to Bacteroides have been associated with better response to biologics [
76]. Interestingly, a recent study by Caenepeel et al. (2024) investigated various combinations of clinical and microbial data to predict the efficacy of TNF-alpha (infliximab, adalimumab, and golimumab) in patients with both CD and UC [
77]. Their model, integrating clinical parameters, stool features (moisture and calprotectin), and identification of microbial dysbiosis, achieved a 73.9% accuracy rate in predicting treatment outcomes with different biologicals. Notably, the study unveiled the significant microbiota-modulating effect of anti-TNF-α therapy, while vedolizumab appeared less effective in patients with dysbiotic microbiota. In addition, abundance of Fusobacterium also correlated with fecal calprotectin concentrations and postoperative relapse in patients with CD [
78].
In addition to changes in the bacteriome, dysbiosis in the mycobiome also plays a crucial role in the pathophysiology of IBD and may influences responses to therapy. For instance, an increase in Basidiomycota and a decrease in Ascomycota, especially Saccharomyces cerevisiae, are associated with disease activity and biologic response [
79]. Shifting Basidiomycota to Ascomycota ratios are observed during remission, hence indicating a potential marker for fungal dysbiosis [
80]. Notably, the abundance of
Candida albicans in IBD is reduced in patients who are primary responders to anti-TNF-alpha therapies [
80]. While viruses are more abundant in the microbiome compared to bacteria, there is limited exploration of the inflammatory bowel disease (IBD) virome. Despite the bacteriome being a more accurate reflection of IBD activity, specific viruses such as those from the Retroviridae family are associated with CD [
81]. However, their precise connection to the response to anti-TNF-alpha therapies remains unclear [
82]. Although finding microbial biomarkers for clinical response to biological therapies seems to be a promising target, considering the diversity of changes in different populations and lack of statistical power among studies, it is important to note that research in this area is ongoing, and findings may not yet have fully translated into routine clinical practice.