and filtered to obtain stool slurry [165]. Fecal suspensions were given via oral capsules, through nasogastric and nasoduodenal tubes into the upper gastrointestinal tract (top), or through a colonoscope or a retention enema catheter into the colon (bottom).
Source: Based on Bakken [166].
CDI results from excessive use of antibiotics or gastrointestinal surgery, resulting in the loss of the local microbiota. Such local microbiota includes the loss of essential groups from the Lachnospiraceae and Enterobacteriaceae communities. These changes in the structure and functions of the resident microbiota reduce the resistance for intestinal pathogens, such as Clostridium difficile, to localize and propagate in the gut [169, 170]. While other pathogens can be treated with other antibiotic treatments, C. difficile can exist in three different lifestyles (planktonic, biofilm, and spore) that complicate the process of eliminating these pathogens from the gut. The ability of the microbe to evade antibiotic treatment by regulating its lifestyle often leads to recurrent CDI, where the intestinal microbiota fails to recover and thus establishing a new homeostatic balance within the host post‐initial insult. Left untreated, the pathogen can manifest in different forms including diarrhea, pseudomembranous colitis, toxic mega colon, and other symptoms, even rarely resulting in death [171, 172].
Tremendous amount of research links bacterial dysbiosis in both human and mice showed the depletion of Bacteroidetes and enrichment of Proteobacteria that are linked to a higher risk rate of acquiring CDI [173–176]. The use of FMT to treat CDI showed lower rates of recurrent CDI, leading to the recovery of the Bacteroidetes and Clostridium clusters IV and XIVa (Firmicutes) while showing depletion of the Proteobacteria populations [177, 178]. This is further proven by a study conducted on 317 patients showing 92% of patients showed complete recovery from CDI, out of which 89% exhibited full recovery after the first treatment. Only approximately 4% of patients experienced a relapse in symptoms after the FMT [177, 178]. It is mentioned from the studies above that FMT as adjunctive therapy to antibiotic treatment would be an avenue that merits further investigation.
Aside from typical colonoscopic lavage, there is increasing interest in oral delivery of encapsulated FMT. Compared to colonoscopy, oral FMT administration is considered non‐invasive, less resource intensive, easily administered, and more accessible to patients [179]. A meta‐analysis has identified that a single FMT capsule infusion has an average colonization efficiency of 80%, whereas multiple infusions showed 92% efficiency [180]. In a randomized clinical trial, orally administered FMT showed minimal difference compared to FMT lavage to prevent recurrent infection over 12 weeks [181]. Current studies are geared toward developing smart oral delivery methods to facilitate the targeted release of the microbes. Preliminary studies of FMT capsules with a targeted colonic release(FMTcr) showed better therapeutic effects compared to FMT capsules with the gastric release (FMTgr) [182].
1.3.1.2 Prebiotic‐, Diet‐, and Probiotic‐Mediated Prevention of Pathogenic Infections
As discussed in the earlier subchapter 1.2, a perturbation in the gut ecosystem increases the risk of microbiome dysbiosis, significantly increasing the hosts' vulnerability to infection [163, 183]. Thus, other measures have been taken to re‐establish homeostatic balance and restore the host health. In the following, we will discuss the use of prebiotics, diet, and probiotic means of balancing the gut microbiome.
The use of prebiotic fibers has been proven to increase the localization of Firmicutes and Bacteroidetes. Studies using a non‐Westernized diet (balanced fat, sugar, and dietary fiber) found that the microbiota stability was maintained better than those with a Western diet when challenged with antibiotic treatment, preventing the proliferation and colonization of opportunistic pathogens [184]. In a separate study, mice fed with microbiota‐accessible carbohydrates (MAC) were shown to mitigate CDI through promoting the growth of MAC‐utilizing taxa, resulting in the production of beneficial metabolites such as SCFA [185].
Adjusting the dietary consumption of lipids was further found to encourage the growth of certain microbial groups by altering hepatic lipid and bile metabolism, thus indirectly changing the microbiome and their corresponding metabolites [163]. Fatty acids can alter pathogen virulence, survival, and growth; thus, clinical applications of fatty acid in infection treatment are carried out [186]. Scientists studying various dietary lipid sources influence the host's pathological response to Citrobacter rodentium infection, where olive oil showed one of the best chemoprotective properties [187].
1.3.2 Inflammatory Disease
In the event of microbiome dysbiosis, inflammation occurs resulting from the immune system attempting to remedy the situation [188]. There are increasing evidences suggesting the link of diet, microbiota imbalance, and the pathogenesis of the inflammatory disease. The nutritional composition may trigger inflammation through direct interactions with the mucosal tissues and indirect interactions by altering the microbiota composition [164, 189–192]. We will discuss IBD as a case study on the effect of diet on IBD pathogenesis.
Patients suffering from IBD experience due to long‐term incidences of tissue inflammation on the dorsal end of the GI tract [193] that can be divided into Crohn's disease (CD) and UC. The dietary habits of individuals can either prevent or increase the risk of developing IBD [193]. A westernized diet abundant in fat and protein increases the risk of developing IBD [194], while fiber‐rich diet was found to lower the risk of developing IBD in rats [195, 196]. As discussed in Section 1.2, a fatty and protein‐rich diet was found to enrich Proteobacteria and deplete Firmicutes and Bacteroidetes involved in the biosynthesis of butyrate production [197–199]. These reduced levels of SCFAs in the large intestine are primarily attributed to preventing bowel inflammation [200, 201]. The use of FMT to enrich butyrate‐producing microbes was found to recover the microbiome balance and alleviate IBD symptoms.
There are various approaches to treat CD, where the use of exclusive enteral nutrition (EEN) [164, 191] has been used as first‐line therapy to treat pediatric patients in some countries and regions [202, 203]. A study involving 114 CD patients below the age of 12 showed an approximately 88% remission rate when subjected to EEN [204]. Another study compared oral and continuous enteral feeding of EEN to alleviate symptoms in both groups [205]. The mechanism of EEN‐induced CD remission is unclear where a variation of EEN showed that the composition does not play a direct role in the recovery process [164]. It is hypothesized that EEN triggers anti‐inflammatory molecule production, intestinal barrier restoration, and recovers microbiota perturbation [191, 206]. It was found that EEN decreases microbiome diversity, triggering enrichment of certain populations in the microbiota [207–209]. Despite variations in the enriched population, EEN does certainly affect the microbiota populations and in turn change the microbiome landscape.
Other nutritional elements such as amino acids, fibers, vitamins, and fatty acids can influence IBD pathogenesis. Some studies showed that glutamine‐ and arginine‐supplemented diet conferred improved protection against dextran sulfate sodium (DSS)‐induced colitis in a murine model [210, 211]. Prebiotic fibers can attenuate IBD symptoms in mice model [195, 212] through regulating intestinal bacterial composition and synthesis of anti‐inflammatory by‐products, such as SCFAs [193, 213, 214].
1.3.3 Cancer
Many studies concluded that the microbiota plays a role in cancer pathogenesis in humans. It is further demonstrated that the dietary nutritional content facilitates the behavior of the microbiome. Prebiotics‐containing fiber (soluble and insoluble) helps to move the bowel by bulking up the intestinal lumen and absorbing carcinogens such as nitrosamines, thus limiting the contact time of the carcinogens to the GI epithelium tissue. These fibers also house the SCFA‐producing
