With rapidly accumulating knowledge on the impact of the microbiome on mammalian host in the past decade, gut dysbiosis, which is defined as a status of microbial imbalance, is believed to be an important contributing factor of many diseases [1]. Studies continue to establish the potential of gut microbiome, constitutes or metabolites as a source of disease diagnostic biomarkers of diseases or alternative targets for therapy of diseases [2]. The use of fecal medicine in folk healing practice could date back to 1500 years ago, the Eastern Jin Dynasty of ancient China, when the Yellow-Dragon Decoction was recorded by Hong Ge in Zhou-Hou-Bei-Ji-Fang (肘後備急方, a. k.a the Handbook of Prescription for Emergency) for alleviating gastrointestinal disorder. Nowadays, Feces Trogopterori (Wu-Ling-Zhi, 五靈脂) is still commonly prescribed for blood circulation-promoting and stasis-removing effects. Recent advances in this field are promoting microbiome-based therapeutics progressing from transplanting the whole microbial community (fecal microbiota transplantation, FMT) to the administration of precisely defined and clinically validated symbiotic microbial consortia or even directly providing microbiota-derived products such as proteins and metabolites [3]. Approaches such as dietary intervention, prebiotics supplementation and/or engineered symbiotic bacteria that aim to promote a desired gut microbial changes or production of desired metabolites are also under investigation to selectively restore or promote the beneficial functions of the microbiota [3].

FMT has demonstrated to be a promising solution of Clostridium difficile infection (CDI) which can achieve ∼96% remission for recurrent CDI [4]. Clinical application of FMT has been expanded to over 80 other diseases in eight categories which show the promising future of FMT for dysbiosis-related diseases, in particularly, inflammatory bowel disease (IBD). IBD is characterized by chronic inflammation of the gastrointestinal tract (GI) and includes two main subtypes, namely ulcerative colitis (UC) and Crohn's disease (CD). CD is characterized by inflammation spanning over the entire GI with healthy parts of the intestine mixed in between inflamed areas and ileum as the most commonly affected area, while UC is mainly limited in colon and rectum and causes continuous inflammation [5]. The epidemiology of IBD shows dramatically rising incidence and the younger age of onset [6]. Although the etiology is not fully understood, many studies point to the presence of genetic predisposition, immune dysfunction and microbial imbalance and a complex interaction between the genetic, environmental or microbial factors and the immune responses in the occurrence and progression of IBD [5]. Current treatments include 5-aminosalicylate agents, corticosteroids, antibiotics, nonsteroidal anti-inflammatory drugs, immunomodulators, and anti-TNF therapies and aim to induce and maintain a state of remission.

IBD patients display distinct gut microbial signatures when compared with healthy individuals, including a general reduction in species richness together with decreases of a number of the commensal and beneficial bacteria such as Firmicutes and Bacteroidetes and an increase or bloom of Proteobacteria [7]. Manipulation of the gut microbiome and its interactions with the gut immune system seems to be a safer and more sustainable approach for improving patient symptoms and FMT is currently one of the most researched topics in the field of IBD [8]. An increasing number of clinical trials have demonstrated that FMT is moderately effective in both subtypes of IBD [9,10]. However, the measurement of therapeutic outcomes usually uses clinical endpoints, mainly clinical remission together with endoscopic remission and/or histologic remission. The factors driving clinical response or nonresponse remain unknown [11].

It is widely believed that the effective element of FMT is microbes and their functions [12]. Many commensal bacteria and their metabolites or co-metabolites with human host have demonstrated to be crucial in promoting gut integrity and immune health [13]. A large body of studies have established the associations of some gut microbes and metabolites with IBD [14,15]. Despite an increasing clinical application of FMT in IBD, most studies are still at the exploratory stage and deal with confounding factors such as sample preparation and FMT protocol (such as delivery mode, dosing frequency), disease patterns, detection methods, concomitant special diet or prior-antibiotics use etc, significantly hindering a reasonable analysis of the outcomes and the inconsistency. In addition to clinical endpoints, it is imperative to characterize the key microbial/metabolic signatures in donors and patients in FMT therapy and identify the species and/or molecules that could differentiate responders and nonresponders and highly correlate with immune signatures and outcomes (efficacy or safety). Such information will definitely shed lights on therapeutic mechanisms of FMT, provide the rationale for protocol optimization to fine tuning the microbiome-metabolome-host immunity axis, and offer crucial candidate set of microbes/metabolites for biomarker selection and targets for precision FMT. For this purpose, this review summarized the existing knowledge on typical gut microbial and metabolic alterations in IBD patients and the experimental evidence on their regulatory roles in immune function. Then, the outcomes of the clinical trials of FMT in both UC and CD patients that have been registered on ClinicalTrials.gov with results retrievable from PubMed using a combination of the keywords “FMT”, “clinical trials” and “IBD” within the past 10 years were reviewed. Finally, the data on gut microbial and metabolic shifts and immune response available for these clinical trials were first summarized for discussion.