Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease, ulcerative colitis, and pouchitis, are chronic, relapsing intestinal inflammatory disorders mediated by dysregulated immune responses to resident microbiota. Current standard therapies that block immune activation with oral immunosuppressives or biologic agents are generally effective, but each therapy induces a sustained remission in only a minority of patients. Furthermore, these approaches can have severe adverse events. Recent compelling evidence of a role of unbalanced microbiota (dysbiosis) driving immune dysfunction and inflammation in IBD supports the therapeutic rationale for manipulating the dysbiotic microbiota. Traditional approaches using currently available antibiotics, probiotics, prebiotics, and synbiotics have not produced optimal results, but promising outcomes with fecal microbiota transplant provide a proof of principle for targeting the resident microbiota. Rationally designed oral biotherapeutic products (LBPs) composed of mixtures of protective commensal bacterial strains demonstrate impressive preclinical results. Resident microbial-based and microbial-targeted therapies are currently being studied with increasing intensity for IBD primary therapy with favorable early results. This review presents current evidence and therapeutic mechanisms of microbiota modulation, emphasizing clinical studies, and outlines prospects for future IBD treatment using new approaches, such as LBPs, bacteriophages, bacterial function-editing substrates, and engineered bacteria. We believe that the optimal clinical use of microbial manipulation may be as adjuvants to immunosuppressive for accelerated and improved induction of deep remission and as potential safer solo approaches to sustained remission using personalized regimens based on an individual patient’s microbial profile.
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Akihiko Oka
R. Balfour Sartor
Introduction
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD), ulcerative colitis (UC), and pouchitis, are chronic intestinal inflammatory disorders characterized by dysregulated immune responses to enteric resident microbiota in genetically susceptible hosts [1,2,3]. Based on the requirement of microbiota colonization to develop colitis in germ-free (GF) susceptible rodents [4,5,6,7], gut microbiota play a crucial role in the pathogenesis of IBD [1, 3, 8]. Microbiota include potentially pathogenic microbes driving inflammation (pathobionts), as well as potentially beneficial microbes inducing protective immune responses (commensals) [1, 9, 10]. However, most IBD patients exhibit unbalanced gut microbiota profiles (dysbiosis), with expanded potentially pathogenic Proteobacteria (especially Enterobacteriaceae that include E. coli and Klebsiella), Fusobacteria, Ruminococcus gnavus, and Candida tropicalis [11] and reduced potentially protective Firmicutes (especially Faecalibacterium prausnitzii, Ruminococci, and Clostridium clusters IV and XIVa) [12, 13] (Table 1). The immunologic consequences of dysbiosis and its causal role in experimental colitis provide a strong rationale for therapeutically modifying the enteric microbiota in patients with IBD [1, 3, 8, 14]. Current primary therapies in IBD, such as corticosteroids, methotrexate, 5-aminosalicylic acid (5-ASA), JAK inhibitors, anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-12p40 antibody, and anti-integrin antibodies and surgical resection, mostly target effector immune responses [15,16,17]. These therapies can induce remission in many IBD patients, but can have severe adverse events with impaired quality of life (QOL). Microbiota-based therapies, including fecal microbiota transplant (FMT), probiotics, and prebiotics, are suggested to be safe and can potentially correct the dysbiosis driving the dysregulated immune response [1, 3, 18]. Recent success of FMT in recurrent or refractory Clostridium difficile infection (rCDI) [19] achieved a major breakthrough in microbial-based therapy, which is being studied with increasing intensity as IBD primary therapy with favorable reported results [20]. In response to this trend, the United States Food and Drug Administration (FDA) created a new category, live biotherapeutic products (LBPs), for ‘live organisms, such as bacteria, which are applicable to the prevention, treatment, or cure of a disease or condition of human beings’ and issued a guidance for clinical trials [21]. This review provides an overview of current microbial-based and microbiota-targeted therapies (Tables 2, 3, 4, 5) and prospects for future treatments in IBD (Table 6) (Fig. 1).
Graphic overview. The concept of manipulating microbiota to correct dysbiosis is a relatively new approach to treating inflammatory bowel disease (IBD). This review updates the status of current microbial-based and microbial-targeted therapies and prospects for future treatments in IBD. Tx, therapy; 5-ASA, 5-aminosalicylic acid; MTX, methotrexate; JAK, Janus kinase; IL, interleukin; TNF, tumor necrosis factor; SCFA, short-chain fatty acid; PXR, pregnane X receptor; PPAR, peroxisome proliferator-activated receptor; Treg, regulatory T cell; GOS, galacto-oligosaccharide; FOS, fructo-oligosaccharide; GBF, germinated barley foodstuff; OI, oligofructose-enriched inulin; BGS, bifidogenic growth stimulator; FODMAP, fermentable oligosaccharide disaccharide, monosaccharide, and polyol; FMT, fecal microbiota transplant; LBP, live biotherapeutic product; PolyP, polyphosphate; KFXL, Kangfuxin liquid; path, pathogenic; AIEC, adherent-invasive Escherichia coli, Images of antibiotics and prebiotics are adopted from KEGG. Image of prebiotic diet is adopted from Monash University (https://www.monashfodmap.com/blog/a-low-fodmap-mediterranean-style-diet/). Red: aggressive microbial species and cells, blue: protective microbial species and cells
Microbiota in IBD: The Rationale for Therapeutic Microbial Manipulation
In general, ‘microbiota (or microbes)’ includes bacteria, fungi, and viruses (mostly bacteriophages) while ‘microbiome’ refers to microbiota and their genes and metabolites [1, 22, 23]. A huge number of microbial cells in the distal intestine (1014 bacteria/g), species (approximately equal to human cells), genes (outnumber human genes by 100-fold), bacteriophages (outnumber bacteria by tenfold), and their weight (1–2 kg) [13, 22, 24, 25] are considered a ‘superorganism’ and ‘forgotten organ’ [26, 27]. The colonic lumen contains the densest bacteria concentration in the human body (1011–1014 bacteria/g), followed by oral (108/g), ileum (107–108/g), jejunum (104/g), duodenum (103/g), and stomach (101/g) [22, 23, 28]. An individual’s enteric bacterial composition varies greatly, and each individual harbors 100–150 diverse intestinal species [22, 29]. This diversity allows humans to obtain a variety of benefits, such as digesting various foods (especially fiber), producing vitamins and other protective metabolites, activating homeostatic gut and systemic immune responses, and preventing colonization by exogenous pathogens [1]. However, the diversity of bacteria in IBD patients is significantly decreased [12, 13, 30, 31], whereas fungi and bacteriophages are expanded [11, 31,32,33]. Furthermore, the composition and function of enteric microbiota in IBD patients are frequently disrupted, characterized by expanded potentially pathogenic microbes and reduced protective microbes producing short-chain fatty acids (SCFAs) [12, 13, 34,35,36,37,38,39]. This microbial imbalance, termed as ‘dysbiosis,’ was first noted in the intestine of IBD patients [12, 13, 30, 34,35,36,37,38], but recently oral dysbiosis is also reported [40,41,42], the latter indicating that dysbiosis can be independent of local inflammatory processes. Although more careful assessment is needed in various patient subsets using modern detection techniques, consistent changes occur in CD and UC (Table 1). The link between this dysbiosis and gut inflammation is supported by many experimental studies. CD-associated adherent-invasive Escherichia coli (AIEC) invades epithelial cells and replicates within macrophages and can cause chronic experimental colitis [43, 44]. Another Enterobacteriaceae, Klebsiella pneumoniae isolated from a CD patient, induces experimental colitis with high Th1 response compared to other control strains and species [42]. Fusobacterium varium strains from UC patients invade epithelial cells compared to strains from healthy controls and induce experimental colitis [45]. Alternatively, certain Clostridium species and F. prausnitzii are putative anti-inflammatory microbes. Clostridia are dominant intestinal microbes, accounting for over 60% of mucosa-associated bacteria [46]. A subset of resident Clostridium species produce SCFAs and can induce colonic regulatory T cells (Tregs) or IL-10-producing B cells and macrophages to protect against experimental colitis [47,48,49,50] with reduction in the abundance of Enterobacteriaceae [50]. F. prausnitzii another major SCFA producer induces IL-10 production by human and murine dendritic cells [51]. Indeed, IBD-derived fecal bacteria stool did not induce colonic Treg in GF mice [9]. Interestingly, most expanded bacteria in IBD are aerotolerant species (aerobes or facultative anaerobes), such as E. coli, F. varium, Haemophilus, Enterococcus faecalis, and Neisseriaceae. In contrast, the majority of reduced bacteria are obligate anaerobes, such as Clostridium clusters IV, XIVa, XVIII, and F. prausnitzii. This trend gives rise to the ‘oxygen hypothesis’ wherein disruption in anaerobiosis indicates to a role for oxygen in intestinal dysbiosis [52]. Recent studies support this hypothesis by showing that Clostridium strains inhibit dysbiotic Enterobacteriaceae expansion by reducing luminal oxygen via activation of epithelial PPAR-γ [53, 54]. Notably, decreased PPAR-γ gene expression is associated with IBD pathogenesis [55]. Dysbiosis of fungi and bacteriophages in IBD were also noted recently [31,32,33] with interactions between C. tropicalis, E. coli, and Serratia marcescens [11]. Further investigations may determine the significance of elevated anti-fungus antibody in many CD patients [56]. A causal association between dysbiosis and IBD is further supported by results from recent FMT trials, as a shift of the recipient’s dysbiotic microbiota toward the donor’s non-dysbiotic microbiota is associated with clinical response [57,58,59,60]. In addition to its causal role in driving inflammation, microbiota influence efficacy of certain immunomodulatory therapies, including anti-TNF-α [61, 62], steroids [63], and PD-1-based treatments [64]. Understanding microbial dynamics is necessary for optimal current and future IBD therapies, particularly personalized management. Technologic developments and ongoing human microbiome projects have improved the culture of previously ‘unculturable’ human microbiota [65], access to more extensive multi-omics databases [66], and gene catalogues established by metagenomic sequencing [12, 24].
Antibiotics
Antibiotics, antimicrobial substances active against bacteria, are widely used treat complications of IBD (bacteremia, abscess, opportunistic, and surgical site infections) [1]. Antibiotics are also used as primary therapy for inducing or maintaining remission based on the hypothesis that certain bacteria cause IBD, the pathologic similarities between CD and Mycobacterium avium subspecies paratuberculosis infection and isolation of this organism in some CD patients [67]. IBD is considered to be caused by intricately intertwined gut microbiota, host genes, immune system, and environmental factors rather than a specific infectious colitis [1, 3]. However, as potential pathobionts are expanded in dysbiotic IBD intestines, targeted antibiotic therapy is a rational strategy. Unfortunately, most antibiotics decrease overall bacterial diversity and inhibit not only pathobionts but also beneficial bacteria, which can lead to overgrowth of pathogenic bacteria (C. difficile), fungi (candida), and bacteriophages [32]. Despite their inhibitory effects, some antibiotics increase protective bacteria [68,69,70] and modulate host immune functions [71]. This section updates clinical efficacy of antibiotics in IBD (Table 2) and their therapeutic mechanisms.
Ulcerative Colitis
Two meta-analyses of antibiotic therapy for active UC demonstrated improved remission rates overall (64% vs 48% placebo) [72, 73]. With a broad variety of different agents and protocols (vancomycin, metronidazole, tobramycin, ciprofloxacin, amoxicillin, ethambutol, tetracycline, and rifamycin), it is difficult to choose optimal antibiotic agents. Of note, all randomized controlled trials (RCTs) using intravenous antibiotics failed to achieve therapeutic benefit over control treatment. In contrast, most oral antibiotics achieved clinical response except for 2 RCTs of ciprofloxacin. Two RCTs of a promising 2-week triple antibiotic primary therapy cocktail including oral amoxicillin, tetracycline, and metronidazole (ATM) showed significantly improved remission rates, clinical, and endoscopic scores [74, 75]. This regimen, designed based on susceptibility testing of F. varium [75], significantly reduced mucosal F. varium abundance in Japanese UC patients [76]. Further, a new RCT of the ATM triple cocktail versus AT cocktail, excluding metronidazole, has been initiated (ClinicalTrials.gov identifier: NCT03986996), given metronidazole’s potential negative effect on gut barrier function and poor patient acceptance. Only a few reports address the long-term outcomes of antibiotics: One trial reported that 7 days of oral tobramycin significantly improved remission rates at 1 week (74% vs 43% placebo) [77], but no statistical difference in relapse rates at 2-year follow-up (24% vs 12%) [78]. Another trial showed 6-month oral ciprofloxacin improved endoscopic and histological appearances at early 3 month, but the benefit disappeared by 6 and 12 months [79]. In contrast, the ATM cocktail therapy demonstrated significantly higher remission rates and lower clinical and endoscopic scores at both intermediate (3–5 months) and long-term (12–14 months) follow-ups [74, 75].
Pouchitis
All three RCTs (including metronidazole, ciprofloxacin, and rifaximin) showed therapeutic benefit, matching widespread clinical use. Three meta-analyses including RCTs and cohort studies support the favorable results [80,81,82]. A meta-analysis concludes that antibiotics and biologics (anti-TNF-α) are more beneficial for chronic refractory pouchitis than are corticosteroids, bismuth, elemental diet, and tacrolimus [81]. Furthermore, ciprofloxacin is suggested to be more effective than metronidazole [82]. Ciprofloxacin reduced Clostridium perfringens and E. coli and did not affect abundance of anaerobic bacteria, while metronidazole reduced C. perfringens, but not E. coli, and reduced anaerobic bacteria in a cohort study [83], indicating that ciprofloxacin is more active against pathogenic species and less harmful to beneficial species. Major concerns with sustained or intermittent use of antibiotics include antibiotic resistance and side effects, such as tendon rupture with ciprofloxacin and peripheral neuropathy with metronidazole. Regarding antibiotic dependency observed in many pouchitis cases, a recent clinical trial proposed a unique hypothesis that antibiotics enrich antibiotic resistance in nonpathogenic species, which might prevent colonization with pathogenic species as long as antibiotics are used [84]. Based on this, a new RCT is currently underway that alternates antibiotics short term with dietary interventions to support growth of beneficial species to avoid progression to antibiotic-dependent disease (NCT04082559).
Crohn’s Disease
A meta-analysis of studies designed to maintain remission after surgical resections demonstrates significant benefit of antibiotics alone and as adjuvants to immunomodulators (azathioprine or 6-mercaptopurine) or anti-TNF-α therapies [85]. However, three meta-analyses suggest that the benefit of antibiotics is weak for overall treatment of CD [80, 86, 87]. However, anti-Mycobacterium agents (especially rifamycin-containing regimens) demonstrate some benefit for inducing remission [73, 88] but do not induce a sustained remission to support clearance of a pathogen [89, 90]. Long-term responses have been studied in a few reports, indicating that the protective effects of antibiotics wane over time; Aberra et al. suggested efficacy over 60 days [90, 91]. Multiple additional RCTs of rifamycin for active CD (NCT02240108, NCT00603616, NCT02240121, NCT02620007) and prevention of postoperative CD recurrence (NCT03185624, NCT03185611) are ongoing (Table 6) or recently completed (NCT01951326). One of these trials specifically targets CD-associated E. coli-colonized patients (NCT02620007). Other agents, including ciprofloxacin and metronidazole alone or in combination, also show remission induction [72, 73]. Given the fungal dysbiosis in CD, an ongoing RCT investigates whether addition antifungal fluconazole to an antibiotic cocktail can improve remission rates (NCT02765256). For specific conditions such as anal or internal fistula, ciprofloxacin and metronidazole reduce drainage [73], improve symptoms, and improve fistula closure rates [92,93,94]. For abscesses, the first choice is surgical treatment, but frequently emergency surgery can be avoided by antibiotics and percutaneous drainage [95]. Although meta-analyses of antibiotics in IBD are quite positive, clinical use of these agents is largely restricted to patients with active pouchitis and septic complications of CD. This disparity is in part due to publication bias that favors publication of positive results.
Therapeutic Mechanisms
Several mechanisms mediate therapeutic actions of antibiotics. (1) Inhibiting pathobionts Each antibiotic has a unique spectrum against bacteria, and most antibiotics inhibit pathogenic species and decrease overall bacterial diversity. Long-term metronidazole eliminates Bacteroides, with bacterial concentrations correlated with disease activity [96]. Ciprofloxacin is effective against enteric pathogens and most Gram-negative Enterobacteriaceae. Although rifamycin does to alter the overall microbiota composition in IBD patients [71], it reduces bacterial attachment [71]. (2) Increasing beneficial bacteria Despite many antibiotics reducing beneficial species, such as F. prausnitzii [84], some antibiotics can increase protective species. For example, rifamycin increases Lactobacillus [70], Bifidobacterium, and F. prausnitzii [69]. (3) Modifying bacterial metabolites Shifts in microbiota composition alter microbial metabolites, with increased SCFAs and other beneficial products [12, 69] that correlate with clinical response in IBD patients [69, 97]. (4) Immunomodulatory effect Rifamycins, ciprofloxacin, metronidazole, and macrolides have mucosal immunomodulatory effects [71, 98,99,100]. Specifically, rifaximin is a gut-specific agonist of the human pregnane X receptor (PXR) that helps maintain mucosal homeostasis [71, 99].
Clinical Concerns
Safety
In clinical trials, IBD patients exhibited no increased risk of severe adverse events with antibiotics compared to placebo [86], but safety issues must be considered. Anti-Mycobacterium therapy has more frequent adverse events, such as rashes and skin pigmentation, but not increased withdrawal rate [88]. Long-term use of metronidazole can cause peripheral neuropathy [80, 101].
Risk of Resistance
Probably due to higher antibiotic exposure, the prevalence rates of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and extended-spectrum beta-lactamases (ESBL)-producing E. coli are significantly higher among IBD patients [102].
Risk of CDI
Antibiotics increase CDI in IBD patients [103] through decreased lactate-producing bacteria numbers and increased succinic acid [104] although others reported rare CDI in CD patients [105]. Antibiotic-resistant probiotics may prevent CDI after antibiotic therapy [106].
Effective Protocols
While oral antibiotics appear to be effective as adjunctive therapy for IBD flares based on their direct effects on luminal bacteria and mucosal immune function, the benefits of intravenous antibiotics are not proven [107]. For fulminant colitis, such as toxic megacolon at risk of severe bacteremia, especially when receiving corticosteroids, intravenous broad-spectrum antibiotics appear to be reasonable [108]. The most effective therapy duration remains unclear, but Ledder provides recommendations [109]. The short-term benefit (induction of remission) of antibiotics is promising, while the long-term benefits (maintenance) appear low with increased toxicity or antibiotic-resistant bacteria [78, 90, 91]. Sequential maintenance approaches, such as protective nutrients, probiotics, or FMT, need to be considered after induction of remission with antibiotics.
Risk of Dysbiosis
Compelling epidemiologic evidence indicates that multiple early childhood exposures to antibiotics carry higher risk of developing CD [1]. It is unclear whether this risk is due to antibiotics themselves, an infection that required antibiotic use, or early IBD symptoms.
Conclusions
Despite the many different antibiotics, protocols, and endpoint assessments in clinical trials with publication bias, oral antibiotics provide a promising primary or adjuvant therapy for inducing remission of IBD. Specific pathobiont-targeted strategy has recently emerged as an area of interest (F. varium, AIEC, C. perfringens), supporting future personalized antibiotic use. For active UC, the oral ATM cocktail is promising. For active pouchitis, ciprofloxacin > metronidazole is effective. For active CD, rifamycins are promising. Given the negative potential effects of long-term use such as host toxicity and antibiotic resistance, short-term use followed by alternative maintenance therapies, such as probiotics, prebiotics, diet, and standard immunotherapies, should be considered.
Standard Probiotics and LBPs Using Resident Protective Microbiota
Probiotics are living microorganisms such as bacteria or yeasts with beneficial health effects [110], which included LBP [21]. Since Metchnikoff first published the concept of probiotics (yogurt containing Lactobacillus bulgaricus) in 1907, many probiotic strains have been studied in clinical trials including IBD [108, 110] (Table 3). Probiotic strains used in IBD trials have mostly belonged to two genera, Bifidobacterium and Lactobacillus, and isolated from limited sources (yogurt, milk, etc.) [108, 110]. Recently, a variety of LBP candidates (Clostridium, Firmicutes spores, Bacteroides, Roseburia) isolated from healthy human microbiota have been investigated [1, 3].
Ulcerative Colitis
A meta-analysis of 18 RCTs in UC patients, including pediatric, demonstrates therapeutic benefit over placebo [111]. Also another meta-analysis including Chinese-based RCTs supports the use of adjuvant probiotics with 5-ASA in active UC [112]. Multiple strains have been investigated with favorable results (Table 3). A systematic sub-analysis suggests Bifidobacterium-containing probiotics significantly benefit active UC [113]. Because different strains have different metabolomic and immunomodulatory activities and provide complementary help, a cocktail of different strains may be more efficient than a single strain. Indeed, VSL#3, a cocktail of 8 strains, Lactobacillus casei, L. plantarum, L. acidophilus, L. delbrueckii subspecies bulgaricus, Bifidobacterium longum, B. breve, B. infantis, and Streptococcus salivarius subspecies thermophilus, improved remission and relapse rates [111, 112]. Additional RCTs of VSL#3 (NCT03415711) and L. rhamnosus (NCT04102852) in active UC are underway. More recently, a SERES Therapeutics (Boston, MA) cocktail of purified Firmicutes spore (SER-287) from feces of healthy screened donors was tested in a Phase 1B RCT in active UC [114,115,116]. Treatment arms included 6 days of vancomycin pre-treatment followed by 8 weeks of SER-287 either daily or weekly or placebo pre-treatment followed by weekly SER-287 versus placebo/placebo. Vancomycin improves engraftment of microbes from SER-287 [114] and improved remission rates (placebo/placebo daily: 0%, vanco/SER-287 daily: 40%, placebo/SER-287 weekly: 13.3%, vanco/SER-287 weekly: 17.7%) and endoscopic scores [115]. SER-287-treated remitters exhibited widespread transcriptional shifts from baseline, with by decreased expression of inflammatory genes and increased expression of homeostatic mediators [116]. These promising results led to a Phase 2B, 3-arm RCT in active UC (NCT03759041). Based on improved engraftment of SER-287 by vancomycin pre-treatment, two patient groups receive different doses of SER-287, both following short courses of oral vancomycin. In pediatric UC, 2 RCTs demonstrated that oral VSL#3 [117] or rectal L. reuteri ATCC55730 [118] significantly improved clinical and endoscopic scores. Long-term follow-up data are limited, but a 2-year follow-up showed promising results [119].
Pouchitis
Meta-analyses indicate that probiotics significantly induce remission and prevent relapse in pouchitis [80, 120, 121]. A RCT of oral C. butyricum MIYAIRI showed improved relapse rates (11% vs 50%) [122]. Gionchetti and colleagues reported strikingly decreased relapses (15% vs 100% placebo) in recurrent pouchitis after 9 months of oral VSL#3 therapy [123], but these positive results were not replicated in the USA [124]. In naïve ileal pouches within a year after surgery, VSL#3 prevented onset of pouchitis over placebo (10% vs 40%, P < 0.05) [125]. Microbial analysis revealed that the probiotic enriched lactobacilli and bifidobacteria and increased bacteria diversity while reducing fungal diversity [126]. In contrast, probiotics containing Lactobacillus and Bifidobacterium did not improve pouch dysfunction nor pouchitis activity [127].
Crohn’s Disease
In contrast to UC and pouchitis, several meta-analyses in CD suggest very weak or no benefit of standard probiotics [111, 128] with benefits limited to maintaining remission after surgery [111, 129, 130]. However, there is a strong strain-specific effect [131]; VSL#3 improved endoscopic features [129, 130] and decreased mucosal inflammatory cytokine levels [129]. E. coli Nissle 1917 and other Lactobacillus strains tested in RCTs lacked benefit [111, 128,129,130, 132], but significantly induced Treg numbers in peripheral blood [132]. Bifidobacterium strains, some of which are included in VSL#3, have not been tested alone, but the combination with prebiotics (synbiotics) significantly improved remission rates, clinical activity, and histological scores in CD patients with active disease compared to placebo [133].
Therapeutic Mechanisms
Most orally administered current probiotics pass through, although E. coli Nissle 1917 [134] can colonize the intestine and perform several documented protective functions [135, 136]. Subsets of resident microbiota have extensive evidence of preventing and treating experimental colitis mediated by well-documented mechanisms [1, 48, 50, 137]. Several comprehensive reviews more extensively document protective effects of probiotics and commensal bacteria [135, 136]. The protective mechanisms of traditional probiotics and LBPs include the bacteria themselves (DNA, cytoplasmic, and cell wall contents) and their metabolites, such as organic acids, SCFAs, and lactic acid that stimulate homeostatic immune and mucosal protection [1, 138]. (1) Inhibiting pathobionts Certain protective bacteria inhibit resident potentially pathogenic microbiota, such as Enterobacteriaceae [50, 139], Fusobacterium [50], and Bacteroideceae [140]. Many pathobionts adhere intestinal epithelial cells to induce inflammation, i.e., AIEC and F. varium [45, 141, 142]. Probiotic E. coli Nissle 1917 and L. johnsonii La1 can compete for ecologic niches, epithelial binding, and nutrients with pathobionts and inhibit their adhesion and proliferation [143]. Furthermore, decreased luminal pH by organic acids (SCFAs, etc.) produced by probiotics and protective resident bacteria [144], anti-bacterial peptides (bacteriocins) [145], and bile acids modulated by probiotics [146] can inhibit pathobionts. In addition to these bacterial cross talks, probiotics and resident bacterial species can indirectly (via host cells) affect pathobionts: mucosal PPAR-γ signaling activated by probiotic Clostridium and VSL#3 reduce luminal oxygen and inhibit aerobic Enterobacteriaceae [53, 147]; E. coli Nissle 1917 induces defensin production by epithelial cells through flagellin–Toll-like receptor binding (TLR) [148]. (2) Increasing beneficial resident bacteria Probiotics and LBPs can increase growth of other resident beneficial bacterial species and improve the intestinal ecosystem [50, 123, 149]; increase lactobacilli [126, 139], bifidobacteria [123, 126, 149], S. thermophilus [123], and bacterial diversity [126], while reducing fungal diversity [126]. (3) Improving mucosal barrier function Bifidobacterium strains strengthen epithelial barrier function in UC [150]. SCFAs provide the main energy source of colonic epithelial cells, improve mucosal barrier function, and activate colonic Tregs [151, 152]. However, in clinical studies, some probiotics work without elevating SCFA [153]. Other protective bacterial metabolites include indoles that bind aryl hydrolase receptors, PXR, and sphingolipids [135]. TLR and NOD2-recognition pathways mediate some bacterial protective functions [154]. (4) Mucosal and systemic immunomodulation Probiotics and resident bacteria can induce anti-inflammatory cytokines (IL-10, TGF-β, etc.) and mucosal and systemic regulatory cells (Treg, IgA+, and regulatory B cells) and attenuate inflammatory cytokines (IFN-γ, IL-12p40, TNF-α, etc.) [47, 48, 118, 132, 154,155,156].
Clinical Concerns
Safety
Probiotics are well tolerated with low rates of adverse effects [157, 158] although rare cases of sepsis, endocarditis, and liver abscess with use of Lactobacillus and fungemia by S. boulardii have occurred, primarily in hospitalized and severely ill or immunocompromised patients with intravenous catheters [158].
Optimal Protocols
Resident microbiota compete with exogenous microbes. Therefore, antibiotic pre-treatment seems reasonable to improve engraftment of exogenous probiotics and LBPs. SERES’s RCT demonstrates that pre-treatment with vancomycin enhances engraftment of Firmicutes spores [114, 115]. Some papers suggest that beneficial effects require 106–108 probiotics/g stool [159]. Given that only 20% of probiotic cells survive [160, 161] and stool weight is 1 kg, 5 × 108–1011 probiotic cells administration may be required. However, lower doses may be sufficient for resident LBP strains that proliferate in the intestine. The rectal route (enema) can be considered for pouchitis and pouchitis. D’Inca et al. compared oral versus enema with L. casei GG in active UC and showed a significant advantage of the rectal route for reducing mucosal inflammatory cytokines and modifying the microbiota (Lactobacillus increased, Enterobacteriaceae decreased) [139]. Matthes et al. showed that E. coli Nissle 1917 enemas are effective in a dose-dependent manner in active UC patients [162].
Conclusions
Some standard probiotics benefit UC and pouchitis activities. In contrast, the benefits of probiotics for CD seem to be strain specific and limited in maintaining remission after surgery for CD patients. However, VSL#3 containing Bifidobacterium, Lactobacillus, and S. salivarius has more beneficial effects. These positive reported results are subject to publication bias. Although clinical trials of LBPs are just beginning, providing protective resident microbiota to reverse dysbiosis and restore homeostatic microbial community structure and function is an attractive approach that will be actively investigated in the near future.
Prebiotics
Prebiotics are food ingredients that are selectively fermented by host microbes to confer a health benefit. Examples include dietary fiber and oligosaccharides naturally contained in fruits, vegetables, and grains [163]. IBD patients are traditionally advised to lower their fiber intake and sometimes fast during flares to reduce mechanical stimulation of the damaged mucosa [164]. However, many studies of various dietary fiber and oligosaccharides suggest favorable results as an emerging treatment approaches (Table 4). Their ability to increase potentially beneficial bacteria and beneficial metabolic effects (SCFAs, etc.) has been verified in humans and murine models [163, 165].
Ulcerative Colitis
Many studies focus on QOL, symptoms, and bacterial metabolites in UC treated with various prebiotics. Psyllium, germinated barley foodstuff (GBF), lactulose, and oligofructose-enriched inulin significantly improve QOL and symptoms in UC patients [166,167,168,169]. Intake of psyllium and wheat bran significantly increased fecal butyrate [170, 171]. A large RCT with psyllium demonstrated equivalent effectiveness to 5-ASA to maintain remission in UC [171] and a crossover trial in active UC is underway (NCT03998488). GBF contains low-lignified hemicellulose that is efficiently fermented by colonic microbiota [161, 165]. GBF reduced CRP [172] and improved clinical and endoscopic scores in active UC in an uncontrolled long-term study [173]. Supplemental oligofructose-enriched inulin with 5-ASA significantly reduced fecal calprotectin (fourfold change) at day 7 compared with 5-ASA alone [168]; a RCT is underway (NCT03653481). A RCT of Synergy1, composed of equal proportions of fructo-oligosaccharide and inulin in active UC, has been completed without published results (NCT02093767), and an additional RCT in inactive UC is currently recruiting (NCT02865707). Curcumin, the biologically active component of turmeric with anti-inflammatory and antioxidant effects, can support the growth of protective bacteria [174], so it is a promising prebiotic. A large RCT in UC improved remission rates with clinical and endoscopic scores compared to controls [175]. Additional RCTs of curcumin have recently been registered in pediatric (NCT02277223) and adult (NCT02683759) UC patients. Fucosyllactose modifies microbiota [176]; 2 RCTs are underway (NCT03847467, NCT03847467). Glycomacropeptide can modify microbiota and metabolites, reducing Proteobacteria and increasing SCFAs [177]; the first RCT is recruiting UC patients (NCT02825914).
Pouchitis
Two crossover studies focused on disease activity. Three weeks of inulin supplementation significantly improved clinical and histological scores from baselines associated with increased butyrate levels and reduced pH, B. fragilis and increased secondary bile acids levels [178]. However, the same treatment protocol failed to show significant benefit although a slightly increased butyrate level correlated with reduced disease activity [179]. One possible explanation is variable microbiota in individuals, since efficacy of prebiotics can depend on abundance of resident Bifidobacteria [180].
Crohn’s Disease
Restricted dietary fiber did not improve symptoms need for surgery or hospitalization in CD patients [181]. On the contrary, fiber-rich diets significantly reduced surgery in active CD [182] and prevented relapse during remission [183]. Two recent RCTs using oligofructose-enriched inulin inhibited disease activity of active CD associated with increased SCFAs [184] and B. longum and reduced R. gnavus, a potential pathogen in CD [185]. An additional RCT is underway (NCT03653481). 2 RCTs are underway (NCT03847467, NCT03847467) testing fucosyllactose a prebiotic that modifies microbiota [176].
Therapeutic Mechanisms
Prebiotics are substrates fermented by resident microbiota to organic acids (SCFAs), CO2, H2, and methane gas [163, 165]. (1) Increasing beneficial bacteria Prebiotics enriched Bifidobacteria [185, 186], lactobacilli [186], F. prausnitzii [187], and Clostridium clusters IV and XIVa [188]. (2) Inhibiting pathobionts Prebiotics can decrease Proteobacteria [177], Bacteroides [178, 186], R. gnavus [185], and Candida [186]. (3) Improving mucosal barrier SCFAs improve mucosal barrier function by providing a key nutrient for colonic epithelial cells [47, 48, 135], while inulin prevents mucus defects [189]. (4) Mucosal and systemic immunomodulation Some prebiotics induce Tregs [47, 48, 135], likely through SCFA production, and intestinal IgA [190]. (5) Absorption of toxic substances Dietary fiber can adsorb toxic substances, cholesterol, bile acids and provide bacterial scaffolds to benefit inflammation [191].
Clinical Concerns
Safety
Because prebiotics derive from natural foods, prebiotics are considered to be safe [166, 167, 169, 192]. There were no severe adverse events reported in RCT, although a few food-allergy events occurred [192, 193]. Of note, psyllium may cause gastrointestinal obstruction, especially at stenotic sites [192, 193], and has not used in CD trials.
Tolerability
Clinical use is limited by high participant dropout due to bloating and discomfort among IBD patients [184].
Conclusions
Improved beneficial bacteria community structure and metabolism by prebiotics are documented in human volunteers and IBD patients, but relatively few clinical RCTs have been conducted. Although more high-quality and disease activity-focused clinical studies are needed, prebiotic therapy is a promising safe and physiologic treatment and maintenance approach to IBD, perhaps in combination with LBPs.
Prebiotic Diets
Diet greatly affects microbiota composition and metabolism, and IBD dysbiosis is associated with diet [194,195,196]. Many rigorously designed RCTs have been newly registered. Exclusive enteral nutrition (EEN) is used as first-line therapy for inducing remission in CD with mucosal healing and histological improvement [194, 197]. This approach is most widely used in pediatric patients. Responses may be partially attributed to EEN-mediated microbial changes, despite decreased diversity [32]. The Mediterranean-style diet (MSD), Asian diet, and semi-vegetarian diet increase beneficial bacteria [198], potentially reduce pathobionts [199], and may benefit IBD patients [200], leading to a RCT investigating the effectiveness of MSD in UC (NCT03053713). The specific carbohydrate diet (SCD), consisting of mostly meat, fruits, vegetables, nuts, oils, and honey with the elimination of grains, has shown efficacy in a retrospective IBD study [201] leading to multiple RCTs, investigating its effects microbial profile and clinical outcome (NCT02858557) (NCT02412553) and efficacy in pediatric (NCT02610101, NCT03301311) and adult (NCT03058679, NCT02412553, NCT02858557) IBD and comparison versus MSD (NCT04082559, NCT03058679). Other promising diets are under investigation, such as the fasting-mimicking diet in UC (NCT03165690), Mashiha in IBD (NCT02796339), and the low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet in UC (NCT02469220). Several of these diets, including SCD and low FODMAP, are low in fiber and prebiotics, so they may affect symptoms more than disease efficacy. A better understanding of prebiotics may provide improved advice for patients’ food choices.
Synbiotics
Synbiotics are mixtures of probiotics and prebiotics that beneficially affect the host by improving the survival and implantation of live microbial dietary supplements in the gastrointestinal tract by selectively stimulating the growth and/or by activating the metabolism of one or a limited number of health-promoting bacteria, thus improving host welfare [163]. Given that IBD patients harbor less beneficial intestinal bacteria (Table 1), administration of synbiotics may improve treatment with probiotics or LBPs. Indeed, some papers demonstrated that the benefit of prebiotics depends on baseline abundance of resident protective species [180]. However, clinical studies of synbiotics are limited (Table 4). Ishikawa et al. demonstrated that bifidobacterial strains plus galacto-oligosaccharide synbiotics improved endoscopic scores and decreased inflammatory markers in treated UC patients [202]. Furrie et al. detected higher numbers of total bifidobacteria on the mucosal surface in active UC patients fed a synbiotic containing B. longum and Synergy1 than in those taking placebo [203]. In CD, B. longum plus Synergy1 was effective [133]. Overall, prebiotic therapy appears safe and promising, but RCTs are needed to assess the efficacy of dietary/prebiotic interventions. The concept of combined therapies is supported by observations that partial EN plus an exclusion diet high in fiber and fresh fruits and vegetables was better tolerated and induced a more sustained remission in pediatric CD patients compared with standard EEN therapy [197].
FMT
After the breakthrough success of FMT therapy in rCDI in 2013 [19], several accessible fecal banks have been established (OpenBiome, etc.) and multiple clinical studies have been performed in IBD patients. This section updates FMT clinical trials in IBD (Table 5), which have been extensively reviewed [57, 204, 205].
Ulcerative Colitis
After initial success of FMT for induction of remission in UC in 1989 [206], four RCTs and several case series have provided promising results. Three out of four RCTs demonstrated a significantly improved clinical, endoscopic, and histological scores [58, 59, 207] although clinical response rates (24–32%) are not as dramatic as in FMT for rCDI (93%). In the unsuccessful RCT [60], the FMT group showed a higher clinical remission rate over controls (41% vs 25%) without statistical significance, likely due to limited subject numbers. However, clinical efficacy was strikingly different with different donors [58]. Indeed, pooled analyses show effectiveness of FMT for active UC [57, 204, 205]. Bacterial taxa analyses revealed that FMT significantly improved bacterial diversity, which correlates with clinical responses [59, 204]. Interestingly, several bacteria taxa were associated with remission after FMT, such as Clostridium clusters IV and XVIII, while the presence of Proteobacteria (Sutterella species) and Fusobacterium species was associated with lack of remission [59]. Ishikawa et al. modified the Fusobacterium-targeted antibiotic ATM cocktail (tetracycline replaced by fosfomycin, AFM cocktail) and showed that the pre-AFM + FMT combination improved outcomes [208]. Moreover, they showed that the reduced abundance of Bacteroidetes by AFM antibiotics pre-treatment was clearly restored in FMT responders, but not non-responders. Bacteroidetes is one of the symbiotic taxa [209], which can inhibit C. perfringens [145] and induce Treg [47, 48, 137]. Two RCTs investigating antibiotics prior to FMT are currently underway (NCT02606032, NCT02033408). Based on limited long-term follow-up reports, the effects of FMT seem to gradually decrease over 3 months [210, 211]. However, some responders exhibit long-term remission (> 1–2 years) [207, 212]. Multiple RCTs are underway in several countries.
Pouchitis
Herfarth et al. [213] demonstrated the difficulty of engraftment of FMT: One out of six patients showed successful engraftment and remission. This could be due to several factors, including donor selection, the dose, frequency and route of administration of FMT, and the pouch microenvironment. Pouches are constructed from the small intestine where potentially beneficial Firmicutes bacteria such as Clostridia are rarely detectable in normal conditions. Of note, Stallmach et al. [214] showed impressive clinical benefits and engraftment by multiple FMT in antibiotic-refractory pouchitis patients: All 5 patients who received FMT achieved clinical response (4/5 remission) and 3/5 patients maintained remission with sequential FMTs. A RCT is currently recruiting (NCT02049502).
Crohn’s Disease
Although some case series showed less benefit of FMT in CD patients compared with UC [212, 215], many promising case reports and series describe induction of CD remission [204]. Meta-analysis of 6 prospective and uncontrolled trials [204] shows 52% clinical remission rate with publication bias. For adult CD, 58–87% clinical responses were reported [216, 217]. Responders showed greater improvement in microbial diversity with a significant shift in fecal microbial composition toward their donor’s profile than non-responders and increased lamina propria Tregs following FMT [216]. FMT via nasogastric tube induced remission in 77.8% of pediatric CD patients 2 weeks after FMT with evidence of engraftment [218]. As seen in UC, responders of FMT in CD showed rapidly improved symptoms and clinical activity several weeks after FMT, but this effect diminished over several months after FMT [216,217,218,219] with return to bacterial composition patterns close to pre-FMT levels [219]. To maintain the clinical benefits from FMT, Li et al. [220] suggested performing the next course of FMT less than 4 months after the previous FMT, based on the large-scale clinical trial. Multiple RCTs are currently underway.
Therapeutic Mechanisms
The therapeutically relevant components of FMT remain elusive [221]. Increased bacterial diversity is clearly associated with successful response of FMT in IBD [59, 204, 216]. Further, the recipient microbiota after successful FMT resemble donor microbiota, likely due to implantation of donor bacteria and/or donor feces promoting growth of resident bacteria that resemble the donor’s species [221]. Although several potentially relevant species are reported [59], more data are required to support the protective species. FMT is a complex material containing bacteriophages, fungi, and metabolites as well as bacteria [59]. Given the therapeutic benefits of filtrated FMT in rCDI studies [222], cell-free components (bacteriophages and metabolites) in FMT need to be included as research targets. A RCT of filtrated FMT in UC has been registered (NCT03843385).
Clinical Concerns
Safety
FMT is safe and well tolerated in IBD clinical trials [57, 204, 223,224,225]. Importantly, two bacteremias (one death) by ESBL E. coli were reported in immunocompromised patients who received donor stool harboring these strains [226]. Exclusion criteria now include ESBL-producing species. Fecal banks are one source for donor stool.
Effective Donor
FMT success depends on microbial diversity and composition of the donor’s stool, leading to the proposed existence of FMT ‘super donors’ [58, 212, 227]. The optimal microbial characteristics of donor feces have not defined in IBD. A family member is often chosen as a donor. Because siblings and relatives share similar gut microbiota because of similar lifestyles, diets, and genetics [228, 229], they may not be optimal donors if the goal is to modulate the recipient’s microbial composition. Switching donors rescued non-responders in a rCDI trial [19]. Whether donors can be optimized by various methods is under investigation.
Optimal Protocol
Engraftment is important factor of efficacy in FMT [230]. A 2018 meta-analysis of FMT protocols indicated that fresh or frozen donor stools, delivery route, and antibiotic pre-treatment have no impact on FMT efficacy in IBD [205]. Multiple administrations appear more effective rather than single FMT [205]. Costello et al. [207] demonstrated marked benefit of anaerobically prepared FMT, while Cui et al. [217] established a laboratory preparation of fecal materials. Vermeire et al. [212] demonstrated that increased CRP levels at week 2 were an early marker of failure, which could allow early rescue therapy in those IBD patients that will not benefit from FMT or guide repeat FMT with a different donor. Because mucosal inflammation reduces microbial diversity and increases pathobionts [231], pre-treatment with immunosuppression to reduce local inflammation and antibiotics to eliminate competing native microbiota may improve engraftment of beneficial species.
Conclusions
Successful FMT has been reported primarily in UC patients. A few positive results exist for CD and pouchitis from case reports and open-label studies. Ongoing multiple RCTs and efforts to optimize protocols, engraftment, donor and recipient selection, and matching the optimal donor with individual recipients based on microbial sequencing could improve FMT as a primary therapy. However, we continuously need to consider possible transmission of ‘undefined’ infectious agents in human stools, in contrast to the safety of defined therapeutic LBP cocktails.
Emerging Options (Bugs as Drugs)
This section discusses recent and ongoing preclinical studies, technologies, and emerging therapeutic concepts [1,2,3].
Rationally Defined Human-Derived Bacterial Consortia—LBPs
A potentially better, more consistent therapeutic approach uses well-characterized, rationally defined and orally delivered LBPs from resident bacterial species from the intestine of healthy subjects. The most advanced LBP for IBD investigation is a Clostridium cocktail. Atarashi et al. [48] isolated 17 Clostridium strains from healthy human stool screened for induction of FOXP3+ murine CD4+ Tregs. These strains protected several experimental colitis models with high production of SCFAs and induction of colonic IL-10-producing Tregs [48]. All 17 strains belong to Clostridium clusters IV, XIVa, or XVIII, which are reduced in IBD patients [13, 30]. Administering these strains is designed to restore a normal ecology in IBD patients [232]. Based on these results [40] and mechanistic preclinical studies that identified additional mechanisms beyond the Treg and SCFA pathways, such as correcting dysbiosis and altering non-SCFAs metabolites [50], Janssen Research & Development and Vedanta initiated a Phase 1 clinical study in healthy volunteers (NCT03723746). Many other LBPs based on different in vitro and in vivo screening methods are in development and should reach clinical trials soon.
Screening LBPs
Choosing protective resident bacterial strains has been performed in vivo by reductionist [48] and combinatorial [233] approaches in gnotobiotic mice by screening for Treg activation and in vitro with cell lines and human blood lymphocytes [234]. However, results of in vitro studies do not always predict in vivo effects [235]. Peran et al. [236] showed that a specific strain of Lactobacillus salivarius prevented colitis in a TNBS rat model. This strain was selected from 30 laboratory strains for eliciting the highest IL-10/IL-12 and IL-10/TNFα ratios in macrophages. Unfortunately, no strains exhibiting a moderate or low IL-10/IL-12 profile were included in the in vivo study. Similarly strains ranked on their induction of in vitro IL-10/IL-12 cytokine induction closely match their in vivo attenuation of experimental colitis [234, 237]. Our group established a novel in vivo/in vitro combined method using gnotobiotic IL-10-reporter mice to measure individual resident bacterial strain induction of IL-10/IFNγ ratios, with high ratio strains preventing and reversing experimental colitis induced by low IL-10/IFNγ-inducing strains [10].
Substrates from Microbiota
Although SCFAs are an important anti-inflammatory substrate in microbe–microbe and microbe–host interactions [144], many other candidate bacterial metabolites affect microbiota and host responses to attenuate mucosal inflammation. Because microbial-based therapies have strong strain- and donor-specific effects [131], purified substrates from defined microbes may provide more consistent results. Examples of established protective bioactive substances produced by probiotic and resident bacteria include p75/p40 from L. rhamnosus that acts through an EGFR-dependent mechanism [238], polyphosphate from lactobacilli [239], lactocepin from VSL#3 [240], polysaccharide-A from B. fragilis [137], an anti-inflammatory protein from F. prausnitzii [241], and kangfuxin liquid extracted from Periplaneta americana dried worms [242]. Most investigators focus on ‘beneficial’ strains to discover a new therapeutic microbial-based tool. In contrast, a unique product from a ‘pathogenic’ E. coli strain, QBECO, is used to immunize hosts (Qu Biologics). Interestingly, purified major macromolecules of an inactivated pathogenic strain of E. coli isolated from a patient with an E. coli infection restored the immune system’s ability to respond productively to invading bacteria in the gastrointestinal tract and rebuild normal barrier function. QBECO treatment improved endoscopic and histological scores in active UC [243] and CD patients cohort [244]. A RCT in CD patients is ongoing [245].
Editing Microbiota
Improved understanding of microbiology and metabolic functions suggests ways to modify or block bacterial functions (enzymes and surface molecules) that provide virulence traits. In mice, tungstate treatment, which inhibits molybdenum-cofactor-dependent microbial respiratory pathways, inhibits Enterobacteriaceae expansion and experimental inflammation [246]. Of note, this effect on microbiota was observed only during inflammation. Additional approaches to selectively inhibit pathobiont numbers and functions in IBD include blocking AIEC epithelial attachment through FimH (NCT03709628) and pathobiont-specific bacteriophages (NCT03808103).
Bacteriophages, Yeasts, and Engineered Bacteria
Virus (mostly bacteriophages targeting specific bacteria) improves intestinal homeostasis and protects against intestinal injury and pathogen infection [247]. This is potentially clinically relevant, since specific bacteria-targeted bacteriophages may act without affecting beneficial resident bacteria. A RCT examining therapeutic effects of a bacteriophage against AIEC is recruiting CD patients (NCT03808103). Interestingly, bacteriophage DNA can induce colitis and activate IFN-γ responses [248], so clinical toxicity must be examined. Probiotic yeast, including Candida glabrata, produces chitin that reduces bacteria/fungus overgrowth and attenuates DSS colitis with activation of PPAR-γ and induction of IL-10 [249, 250]. Although genetically engineered organisms must be carefully handled, several unique bacterial strain expresses anti-inflammatory substrates such as IL-10, IL-35, trefoil factors, and elafin [251,252,253,254].
Screening Patients: Personalized Treatment
Based on the heterogeneity of individual IBD patient’s microbiota and patient therapeutic responses, a pilot RCT investigating effects of personalized microbiota-based therapy (antibiotics and prebiotics) is underway in pouchitis (NCT04082559). As described above, efficacy of probiotics, prebiotics, and FMT (and anti-TNF-α therapy) depends on a patient’s microbiota [255]. Therefore, the best strategy for personalized management of IBD is to identify intestinal microbial profiles prior to beginning therapy or in non-responders [2] to guide optimal microbiome-based therapies.
Conclusions
Microbial-based and microbial-targeted therapies for IBD are emerging with favorable results. The rational for correcting the established dysbiosis in CD, UC, and pouchitis patients is well established. Certain antibiotics are promising short-term primary therapies with relatively safety. However, the risk of resistant bacteria and CDI and uncertain long-term benefit/toxicity profiles limit maintenance use of antibiotics. FMT is also a promising primary therapy with well-designed RCTs underway. However, the risk of transmission of ‘unknown’ pathogens and long-term benefits remain unclear. A major limitation is variable efficacy of different donors. In contrast, LBPs, prebiotics, and diet are well defined, safe for long-term use and could be designed for personalized use based on the microbial community structure of individual recipients. Hopefully, these new generation microbial-related therapies will be validated by high-quality preclinical and clinical trials. The best clinical applications for microbial therapy in IBD remain uncertain. Current studies concentrate on single agents inducing remission of active UC. However, we believe that preventing relapse after achieving clinical remission with corticosteroids or biologic therapies in UC or CD patients or with antibiotics in chronic relapsing or antibiotic-dependent pouchitis might be more important areas to investigate. Other clinical needs possibly fulfilled by microbial-based therapies are use of these agents as adjuncts to standard biologic or immunologic therapies to hasten or increase the frequency of deep remission or to maintain quiescent disease after removing the more toxic immune-suppressing agent. Long-term use of physiologic approaches to restore microbial homeostatic function should be less toxic and more acceptable to patients (and physicians) who are concerned about the risk of infection and neoplasia with sustained immunosuppression. We advocate use of concomitant companion diagnostic tests that profile an individual’s microbiota to guide optimal personalized microbial therapies, determine best timing of intervention, and ultimately prevent disease onset in high-risk individuals.
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Acknowledgments
This research supported by National Institute of Health Grants, P01DK094779, P30DK34987, P40OD010995 to RBS and by the Crohn’s and Colitis Foundation, 407007 to AO.
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Dr. Oka declares no competing financial interests. Dr. Sartor has grant support from Janssen, Gusto Global, SERES, BiomX, and Vedanta and serves on advisory boards for BiomX, Second Genome, Qu Biologics, and Biomica.
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Oka, A., Sartor, R.B. Microbial-Based and Microbial-Targeted Therapies for Inflammatory Bowel Diseases. Dig Dis Sci 65, 757–788 (2020). https://doi.org/10.1007/s10620-020-06090-z
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DOI: https://doi.org/10.1007/s10620-020-06090-z