Current and future microbiome-based therapies in inflammatory bowel disease.

PURPOSE OF REVIEW: The role of the microbiome and dysbiosis is increasingly recognized in the pathogenesis of inflammatory bowel disease (IBD). Intestinal microbiota transplant (IMT), previously termed fecal microbiota transplant has demonstrated efficacy in restoring a healthy microbiome and promoting gut health in recurrent Clostridioides difficile infection. Several randomized trials (RCTs) highlighted IMT's potential in treating ulcerative colitis, while smaller studies reported on its application in managing Crohn's disease and pouchitis. RECENT FINDINGS: This review delves into the current understanding of dysbiosis in IBD, highlighting the distinctions in the microbiota of patients with IBD compared to healthy controls. It explores the mechanisms by which IMT can restore a healthy microbiome and provides a focused analysis of recent RCTs using IMT for inducing and maintaining remission in IBD. Lastly, we discuss the current knowledge gaps that limit its widespread use. SUMMARY: The body of evidence supporting the use of IMT in IBD is growing. The lack of a standardized protocol impedes its application beyond clinical trials. Further research is needed to identify patient profile and disease phenotypes that benefit from IMT, to delineate key donor characteristics, optimize the delivery route, dosage, and frequency.

Pollutants, microbiota and immune system: frenemies within the gut.

Pollution is a critical concern of modern society for its heterogeneous effects on human health, despite a widespread lack of awareness. Environmental pollutants promote several pathologies through different molecular mechanisms. Pollutants can affect the immune system and related pathways, perturbing its regulation and triggering pro-inflammatory responses. The exposure to several pollutants also leads to alterations in gut microbiota with a decreasing abundance of beneficial microbes, such as short-chain fatty acid-producing bacteria, and an overgrowth of pro-inflammatory species. The subsequent intestinal barrier dysfunction, together with oxidative stress and increased inflammatory responses, plays a role in the pathogenesis of gastrointestinal inflammatory diseases. Moreover, pollutants encourage the inflammation-dysplasia-carcinoma sequence through various mechanisms, such as oxidative stress, dysregulation of cellular signalling pathways, cell cycle impairment and genomic instability. In this narrative review, we will describe the interplay between pollutants, gut microbiota, and the immune system, focusing on their relationship with inflammatory bowel diseases and colorectal cancer. Understanding the biological mechanisms underlying the health-to-disease transition may allow the design of public health policies aimed at reducing the burden of disease related to pollutants.

Helicobacter pylori infection found during upper endoscopy performed for the diagnosis of celiac, inflammatory bowel diseases, and eosinophilic esophagitis: A multicenter pediatric European study.

BACKGROUND: Helicobacter pylori may be found during upper gastrointestinal endoscopy (UGE) performed to diagnose celiac disease (CeD), inflammatory bowel disease (IBD), and eosinophilic esophagitis (EoE). We aimed to describe the frequency of H. pylori in children undergoing UGE for CeD, IBD, and EoE and the number of children receiving eradication treatment. MATERIALS AND METHODS: A retrospective multicenter study from 14 countries included pediatric patients diagnosed with CeD, IBD, and EoE between January 2019 and December 2021. DATA COLLECTED: age, gender, hematologic parameters, endoscopic, histologic, and H. pylori culture results, and information on eradication treatment. RESULTS: H. pylori was identified in 349/3890 (9%) children [167 (48%) male, median 12 years (interquartile range 8.1-14.6)]. H. pylori was present in 10% (173/1733) CeD, 8.5% (110/1292) IBD and 7.6% (66/865) EoE patients (p = NS). The prevalence differed significantly between Europe (Eastern 5.2% (28/536), Southern 3.8% (78/2032), Western 5.6% (28/513)) and the Middle East 26.6% (215/809) [odds ratio (OR) 7.96 95% confidence interval (CI) (6.31-10.1) p < 0.0001]. Eradication treatment was prescribed in 131/349 (37.5%) patients, 34.6% CeD, 35.8% IBD, and 56.1% EoE. Predictors for recommending treatment included erosions/ulcers [OR 6.45 95% CI 3.62-11.47, p < 0.0001] and nodular gastritis [OR 2.25 95% CI 1.33-3.81, p 0.003]. Treatment rates were higher in centers with a low H. pylori prevalence (<20%) [OR 3.36 95% CI 1.47-7.66 p 0.004]. CONCLUSIONS: Identifying H. pylori incidentally during UGE performed for the most common gastrointestinal diseases varies significantly among regions but not among diseases. The indications for recommending treatment are not well defined, and less than 40% of children received treatment.

Restoration of Lactobacillus johnsonii and Enterococcus faecalis Caused the Elimination of Tritrichomonas sp. in a Model of Antibiotic-Induced Dysbiosis.

Inflammatory bowel disease (IBD) is a multifactorial disease involving the interaction of the gut microbiota, genes, host immunity, and environmental factors. Dysbiosis in IBD is associated with pathobiont proliferation, so targeted antibiotic therapy is a rational strategy. When restoring the microbiota with probiotics, it is necessary to take into account the mutual influence of co-cultivated microorganisms, as the microbiota is a dynamic community of species that mediates homeostasis and physiological processes in the intestine. The aim of our study was to investigate the recovery efficacy of two potential probiotic bacteria, L. johnsonii and E. faecalis, in Muc2-/- mice with impaired mucosal layer. Two approaches were used to determine the efficacy of probiotic supplementation in mice with dysbiosis caused by mucin-2 deficiency: bacterial seeding on selective media and real-time PCR analysis. The recovery time and the type of probiotic bacteria relocated affected only the number of E. faecalis. A significant positive correlation was found between colony-forming unit (CFU) and the amount of E. faecalis DNA in the group that was replanted with probiotic E. faecalis. As for L. johnsonii, it could be restored to its original level even without any additional bacteria supplementation after two weeks. Interestingly, the treatment of mice with L. johnsonii caused a decrease in the amount of E. faecalis. Furthermore, either L. johnsonii or E. faecalis treatment eliminated protozoan overgrowth caused by antibiotic administration.

Gut Microbiota Profile Changes in Patients with Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease: A Metagenomic Study.

Gut microbiota imbalances have a significant role in the pathogenesis of Inflammatory Bowel Disease (IBD) and Non-Alcoholic Fatty Liver Disease (NAFLD). Herein, we compared gut microbial composition in patients diagnosed with either IBD or NAFLD or a combination of both. Seventy-four participants were stratified into four groups: IBD-NAFLD, IBD-only, NAFLD-only patients, and healthy controls (CTRLs). The 16S rRNA was sequenced by Next-Generation Sequencing. Bioinformatics and statistical analysis were performed. Bacterial α-diversity showed a significant lower value when the IBD-only group was compared to the other groups and particularly against the IBD-NAFLD group. ß-diversity also showed a significant difference among groups. The higher Bacteroidetes/Firmicutes ratio was found only when comparing IBD groups and CTRLs. Comparing the IBD-only group with the IBD-NAFLD group, a decrease in differential abundance of Subdoligranulum, Parabacteroides, and Fusicatenibacter was found. Comparing the NAFLD-only with the IBD-NAFLD groups, there was a higher abundance of Alistipes, Odoribacter, Sutterella, and Lachnospira. An inverse relationship in the comparison between the IBD-only group and the other groups was shown. For the first time, the singularity of the gut microbial composition in IBD and NAFLD patients has been shown, implying a potential microbial signature mainly influenced by gut inflammation.

Dual engineered bacteria improve inflammatory bowel disease in mice.

Currently, there are many different therapies available for inflammatory bowel disease (IBD), including engineered live bacterial therapeutics. However, most of these studies focus on producing a single therapeutic drug using individual bacteria, which may cause inefficacy. The use of dual drugs can enhance therapeutic effects. However, expressing multiple therapeutic drugs in one bacterial chassis increases the burden on the bacterium and hinders good secretion and expression. Therefore, a dual-bacterial, dual-drug expression system allows for the introduction of two probiotic chassis and enhances both therapeutic and probiotic effects. In this study, we constructed a dual bacterial system to simultaneously neutralize pro-inflammatory factors and enhance the anti-inflammatory pathway. These bacteria for therapy consist of Escherichia coli Nissle 1917 that expressed and secreted anti-TNF-α nanobody and IL-10, respectively. The oral administration of genetically engineered bacteria led to a decrease in inflammatory cell infiltration in colon and a reduction in the levels of pro-inflammatory cytokines. Additionally, the administration of engineered bacteria did not markedly aggravate gut fibrosis and had a moderating effect on intestinal microbes. This system proposes a dual-engineered bacterial drug combination treatment therapy for inflammatory bowel disease, which provides a new approach to intervene and treat IBD. KEY POINTS: • The paper discusses the effects of using dual engineered bacteria on IBD • Prospects of engineered bacteria in the clinical treatment of IBD.

The Role of Prebiotics in Modulating Gut Microbiota: Implications for Human Health.

The human gut microbiota, an intricate ecosystem within the gastrointestinal tract, plays a pivotal role in health and disease. Prebiotics, non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of beneficial microorganisms, have emerged as a key modulator of this complex microbial community. This review article explores the evolution of the prebiotic concept, delineates various types of prebiotics, including fructans, galactooligosaccharides, xylooligosaccharides, chitooligosaccharides, lactulose, resistant starch, and polyphenols, and elucidates their impact on the gut microbiota composition. We delve into the mechanisms through which prebiotics exert their effects, particularly focusing on producing short-chain fatty acids and modulating the gut microbiota towards a health-promoting composition. The implications of prebiotics on human health are extensively reviewed, focusing on conditions such as obesity, inflammatory bowel disease, immune function, and mental health. The review further discusses the emerging concept of synbiotics-combinations of prebiotics and probiotics that synergistically enhance gut health-and highlights the market potential of prebiotics in response to a growing demand for functional foods. By consolidating current knowledge and identifying areas for future research, this review aims to enhance understanding of prebiotics' role in health and disease, underscoring their importance in maintaining a healthy gut microbiome and overall well-being.

Novel approaches in IBD therapy: targeting the gut microbiota-bile acid axis.

Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.

Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

To address the unmet medical needs of patients with inflammatory bowel diseases (IBD) and move toward cures, preclinical human-relevant research must center on mechanistic questions pertinent to patients with IBD in the 3 areas of disease interception, remission, and restoration.

Oral bacteria relative abundance in faeces increases due to gut microbiota depletion and is linked with patient outcomes.

The detection of oral bacteria in faecal samples has been associated with inflammation and intestinal diseases. The increased relative abundance of oral bacteria in faeces has two competing explanations: either oral bacteria invade the gut ecosystem and expand (the 'expansion' hypothesis), or oral bacteria transit through the gut and their relative increase marks the depletion of other gut bacteria (the 'marker' hypothesis). Here we collected oral and faecal samples from mouse models of gut dysbiosis (antibiotic treatment and DSS-induced colitis) and used 16S ribosomal RNA sequencing to determine the abundance dynamics of oral bacteria. We found that the relative, but not absolute, abundance of oral bacteria increases, reflecting the 'marker' hypothesis. Faecal microbiome datasets from diverse patient cohorts, including healthy individuals and patients with allogeneic haematopoietic cell transplantation or inflammatory bowel disease, consistently support the 'marker' hypothesis and explain associations between oral bacterial abundance and patient outcomes consistent with depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and could potentially identify cases where therapies are needed to rebuild the resident microbiome rather than protect against invading oral bacteria.

A step closer to understanding how a diet high in simple carbohydrates may cause dysbiosis.

The gut microbiota is an integral part of the human metaorganism that is required to shape physiologic host immune responses including host defense against pathogens. Disease-associated gut dysbiosis has been characterized by blooms of pathobionts, which are bacterial species that can drive disease under certain conditions. Pathobionts like Enterobacteriaceae often bloom during flares of inflammatory bowel disease (IBD) and are causally linked with IBD in murine models. In this issue of the JCI, Hecht and colleagues investigated how simple carbohydrates are causally linked to the bloom of the gut pathobiont Klebsiella pneumoniae, which belong to the Enterobacteriaceae family. Notably, the presence of fiber reduced the dissemination of K. pneumoniae into the blood and liver in a colitis model. Their findings provide a diet-related mechanism for gut dysbiosis, which has implications in the management of IBD and other conditions in which gut dysbiosis is an underlying factor.

Bowel function and inflammation: Is motility the other side of the coin?

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel. On the flip side, functions also arise from its role as an interface with the environment. Indeed, the gut houses microorganisms, collectively known as the gut microbiota, which interact with the host, and is the site of complex immune activities. Its role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut, especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and systems. This editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease.

INTRODUCTION: A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. METHODS: A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. RESULTS: Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann-Whitney's test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p < .05) and included important health-associated bacteria, such as Agathobacter and Faecalibacterium. CONCLUSIONS: The fecal microbiota in IBD patients with EIMs is distinct from that in IBD patients without EIM and could be important for EIM pathogenesis.

Dissecting the respective roles of microbiota and host genetics in the susceptibility of Card9-/- mice to colitis.

BACKGROUND: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. RESULTS: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3ß and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. CONCLUSIONS: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract.

Ginsenoside CK Alleviates DSS-Induced IBD in Mice by Regulating Tryptophan Metabolism and Activating Aryl Hydrocarbon Receptor via Gut Microbiota Modulation.

Dysbiosis of gut microbiota is believed to be associated with inflammatory bowel disease (IBD). Ginsenoside compound K (CK), the main metabolite of Panax ginseng ginsenoside, has proven effective as an anti-inflammatory agent in IBD. However, the mechanisms by which CK modulates gut microbiota to ameliorate IBD remain poorly understood. Herein, CK demonstrated the potential to suppress the release of proinflammatory cytokines by gut microbiota modulation. Notably, supplementation with CK promoted the restoration of a harmonious balance in gut microbiota, primarily by enhancing the populations of Lactobacillus and Akkermansia. Furthermore, CK considerably elevated the concentrations of tryptophan metabolites derived from Lactobacillus that could activate the aryl hydrocarbon receptor. Overall, the promising alleviative efficacy of CK primarily stemmed from the promotion of Lactobacillus growth and production of tryptophan metabolites, suggesting that CK should be regarded as a prospective prebiotic agent for IBD in the future.

Bacterial membrane vesicles in the pathogenesis and treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and debilitating condition of relapsing and remitting inflammation in the gastrointestinal tract. Conventional therapeutic approaches for IBD have shown limited efficacy and detrimental side effects, leading to the quest for novel and effective treatment options for the disease. Bacterial membrane vesicles (MVs) are nanosized lipid particles secreted by lysis or blebbing processes from both Gram-negative and Gram-positive bacteria. These vesicles, known to carry bioactive components, are facsimiles of the parent bacterium and have been implicated in the onset and progression, as well as in the amelioration of IBD. This review discusses the overview of MVs and their impact in the pathogenesis, diagnosis, and treatment of IBD. We further discuss the technical challenges facing this research area and possible research questions addressing these challenges. We summarize recent advances in the diverse relationship between IBD and MVs, and the application of this knowledge as a viable and potent therapeutic strategy for IBD.

The colon targeting efficacies of mesalazine medications and their impacts on the gut microbiome.

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.

Probiotics: Shaping the gut immunological responses.

Probiotics are live microorganisms exerting beneficial effects on the host's health when administered in adequate amounts. Among the most popular and adequately studied probiotics are bacteria from the families Lactobacillaceae, Bifidobacteriaceae and yeasts. Most of them have been shown, both in vitro and in vivo studies of intestinal inflammation models, to provide favorable results by means of improving the gut microbiota composition, promoting the wound healing process and shaping the immunological responses. Chronic intestinal conditions, such as inflammatory bowel diseases (IBD), are characterized by an imbalance in microbiota composition, with decreased diversity, and by relapsing and persisting inflammation, which may lead to mucosal damage. Although the results of the clinical studies investigating the effect of probiotics on patients with IBD are still controversial, it is without doubt that these microorganisms and their metabolites, now named postbiotics, have a positive influence on both the host's microbiota and the immune system, and ultimately alter the topical tissue microenvironment. This influence is achieved through three axes: (1) By displacement of potential pathogens via competitive exclusion; (2) by offering protection to the host through the secretion of various defensive mediators; and (3) by supplying the host with essential nutrients. We will analyze and discuss almost all the in vitro and in vivo studies of the past 2 years dealing with the possible favorable effects of certain probiotic genus on gut immunological responses, highlighting which species are the most beneficial against intestinal inflammation.

Colorectal Disease and the Gut Microbiome: What a Surgeon Needs to Know.

The gut microbiome is defined as the microorganisms that reside within the gastrointestinal tract and produce a variety of metabolites that impact human health. These microbes play an intricate role in human health, and an imbalance in the gut microbiome, termed gut dysbiosis, has been implicated in the development of varying diseases. The purpose of this review is to highlight what is known about the microbiome and its impact on colorectal cancer, inflammatory bowel disease, constipation, Clostridioides difficile infection, the impact of bowel prep, and anastomotic leaks.