Ulcerative colitis is an idiopathic and chronic inflammatory bowel disease, characterized by inflammation of the mucosa of the colon and rectum. Clinical manifestations commonly include abdominal pain, diarrhea (with or without hematochezia), and weight loss. The pathogenesis of ulcerative colitis is multifactorial, involving a combination of genetic predispositions and lifestyle factors. High consumption of processed food, sedentary habits, alcohol intake, and stress are among the lifestyle factors implicated in disease onset and progression. Current treatment strategies focus on managing symptoms and inducing remission, however, the chronic nature of the disease, along with the adverse effects of conventional therapies, often compromises patient's quality of life. Therefore, exploring alternative therapies that can prolong remission and reduce symptom burden is important. Experimental evidence suggests that probiotics may extend remission duration in ulcerative colitis. Moreover, probiotics exhibit efficacy in amelioration clinical symptoms by reducing inflammation markers, preserving, and restoring intestinal epithelial. This review explores the advantages of the administration of probiotics in the treatment of ulcerative colitis, elucidating their mechanism of action.

The management of inflammatory bowel disease (IBD) in children and adolescents is challenging. Clear evidence-based guidelines are required for this population. This article provides recommendations for managing IBD in Saudi children and adolescents aged 6-19 years, developed by the Saudi Ministry of Health in collaboration with the Saudi Society of Clinical Pharmacy and the Saudi Gastroenterology Association. All 57 guideline statements are based on the most up-to-date information for the diagnosis and management of pediatric IBD.

The gut microbiota is a diverse ecosystem that significantly impacts human health and disease. This article focuses on how the gut microbiota interacts with inflammatory bowel diseases and colorectal tumors, especially through immune regulation. The gut microbiota plays a role in immune system development and regulation, while the body's immune status can also affect the composition of the microbiota. These microorganisms exert pathogenic effects or correct disease states in gastrointestinal diseases through the actions of toxins and secretions, inhibition of immune responses, DNA damage, regulation of gene expression, and protein synthesis. The microbiota and its metabolites are essential in the development and progression of inflammatory bowel diseases and colorectal tumors. The complexity and bidirectionality of this connection with tumors and inflammation might render it a new therapeutic target. Hence, we explore therapeutic strategies for the gut microbiota, highlighting the potential of probiotics and fecal microbiota transplantation to restore or adjust the microbial community. Additionally, we address the challenges and future research directions in this area concerning inflammatory bowel diseases and colorectal tumors.

Invading new territory is a central aspect of the microbial lifestyle. However, invading microbes rarely find novel territories uninhabited; resident microbes can interact with the newcomers and, in many cases, impede their invasion - an effect known as 'biotic resistance'. Accordingly, invasions are shaped by the interplay between dispersal and resistance. However, these two factors are difficult to disentangle or manipulate in natural systems, making their interplay challenging to understand. To address this challenge, we track microbial invasions in the lab over space and time - first in a model system of two interacting microbes, then in a multi-strain system involving a pathogen invading resident communities. In the presence of biotic resistance, we observe three qualitatively different invasion regimes: 'consistent', 'pulsed', and 'pinned', where, in the third regime, strong biotic resistance stalls the invasion entirely despite ongoing invader dispersal. These rich invasion dynamics could be qualitatively predicted with a simple, parameter-free framework that ignores individual species interactions, even for rather complex communities. Moreover, we show that this simple framework could accurately predict simulated invasions from different mechanistic models, indicating its broad applicability. Our work offers an understanding of how biotic resistance impacts invasions and introduces a predictive tool to identify invasion-resistant communities.

Among the emerging issues in probiotic safety, the possible presence of pks, a gene cluster synthetizing a genotoxin known as colibactin, is one of the most alarming. Indeed, indigenous E. coli strain pks-positive are found in 60% of patients with colorectal cancer, and the most widely used E. coli-based probiotic, known as E. coli Nissle 1917 (DSM 6601), is pks-positive. Starting from 25 potential candidates selected by screening 25 infant stool samples, we have selected an E. coli strain (named 5C, deposited as LMG S-33222) belonging to the phylotype A and having the serovar O173:H1. Having been previously completely sequenced by our group, we have further characterized this strain, demonstrating that it is (i) devoid of the most known potential pathogenic-related genes, (ii) devoid of possible plasmids, (iii) antibiotic-sensitive according to the EFSA panel, (iv) resistant in gastric and enteric juice, (v) significantly producing acetate, (vi) poorly producing histamine, (vii) endowed with a significant in vitro antipathogenic profile, (viii) promoting a significant in vitro immunological response based on IL-10 and IL-12, and (ix) devoid of the pks genes. A comparative genomics versus E. coli Nissle 1917 is also provided. Considering that the other two most commonly used E. coli-based probiotics (E. coli DSM 17252 and E. coli A0 34/86) are respectively pks-positive and alpha-hemolysin-(hly) and cytotoxic necrotizing factor-1-(cnf1) positive, this novel strain (E. coli 5C) is likely the probiotic E. coli strain with the best safety profile available to date for human use.

Inflammatory bowel disease is a long-standing inflammatory disorder that influences the intestinal tract. The intent of this research is to explore whether the relative abundance of Akkermansia muciniphila is related to the IL6/STAT3 pathway and the fundamental molecular mechanisms of A. muciniphila on a trinitrobenzene sulfonic acid (TNBS)-induced enteritis mouse model, including the expression of inflammatory cytokines and proteins in the IL6/STAT3 signaling pathway.

The association between the A. muciniphila and IL6/STAT3 was investigated by using mucosal biopsies and fecal samples. TNBS-induced colitis mouse models were performed to elucidate the underlying mechanisms. The alteration of intestinal microbiota was organized by 16s rRNA sequencing.

In Crohn's disease patients, the level of STAT3 and IL-6 presented a negative relationship with A. muciniphila. The expression of IL-6, p-STAT3, and STAT3 was downregulated in A.m+TNBS group, indicating A. muciniphila may inhibit the IL6/STAT3 pathway in TNBS-induced enteritis in vivo. To investigate the potential defensive role of A. muciniphila supplementation in vivo with TNBS-induced enteritis, 16S rRNA sequencing was performed to analyze changes in the intestinal microbiota composition. The results revealed a marked increase in microbial diversity and abundance within the A. muciniphila-treated group, suggesting a beneficial modulation of the gut microbiome associated with the supplementation.

Our findings declared that A. muciniphila supplementation alleviates gastrointestinal inflammation through IL-6/STAT3 signaling pathway. This protective effect was mediated by the downregulation of the IL-6 and STAT3, highlighting a potential mechanism by which A. muciniphila modulates inflammatory responses. This work disclosed that A. muciniphila demonstrates a defensive influence against TNBS-induced enteritis in vivo, proposing it qualified as a unique therapeutic focusing on modulating IL-6, STAT3, or p-STAT3 in the treatment of colitis.

Amebiasis is a globally prevalent infection that can lead to fatal outcomes if not adequately treated. Conventional treatment with imidazoles often fails due to side effects and resistance, emphasizing the need for alternative therapies. The probiotic Escherichia coli Nissle 1917 (EcN) has shown potential in combating intestinal pathogens. This study aimed to evaluate the amebicidal activity of EcN in vitro and its effect on the production of reactive oxygen species (ROS). Trophozoites of Entamoeba histolytica (2.5 × 10⁴ cells/mL) were cultured in 96-well plates and exposed to varying concentrations of EcN (102-109 cells/mL). Plates were incubated at 36 °C for 6, 12, and 18 h, after which trophozoite viability was assessed. Intracellular ROS production, including superoxide and hydrogen peroxide, was measured using fluorescent probes. The highest efficacy was observed after 18 h at a CFU concentration of 109 cells/mL. Increased ROS production at all probiotic concentrations suggested a role in EcN's amebicidal mechanism. Morphological changes in trophozoites, such as rounding, vacuolization, and size reduction, were noted after EcN exposure, indicating growth inhibition. These findings suggest EcN induces structural and morphological changes in E. histolytica, inhibiting its growth in vitro. The findings suggest the potential efficacy of EcN; however, definitive confirmation requires data from human clinical trials.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including "cannabinoids", "endocannabinoid system", "endocannabinoidome", "inflammatory bowel disease", and "extraintestinal manifestations" were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.

Foodborne bacterial diarrhea involves complex pathogen-microbiota-host interactions. Pathogen-displacing probiotics are increasingly popular, but heterogeneous patient outcomes highlighted the need to understand individualized host-probiotic activity. Using the mouse gut commensal Escherichia coli 8178 and the human probiotic E. coli Nissle 1917, we found that the degree of protection against the enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm) varies across mice with distinct gut microbiotas. Pathogen clearance is linked to enteropathy severity and subsequent recruitment of intraluminal neutrophils, which differs in a microbiota-dependent manner. By combining mouse knockout and antibody-mediated depletion models with bacterial genetics, we show that neutrophils and host-derived reactive oxygen species directly influence E. coli-mediated S. Tm displacement by potentiating siderophore-bound toxin killing. Our work demonstrates how host immune factors shape pathogen-displacing probiotic efficiency while also revealing an unconventional antagonistic interaction where a gut commensal and the host synergize to displace an enteric pathogen.

Perturbations in the intestinal microbiome are strongly linked to the pathogenesis of inflammatory bowel disease (IBD). Bacteria, fungi and viruses all make up part of a complex multi-kingdom community colonizing the gastrointestinal tract, often referred to as the gut microbiome. They can exert various effects on the host that can contribute to an inflammatory state. Advances in screening, multiomics and experimental approaches have revealed insights into host-microbiota interactions in IBD and have identified numerous mechanisms through which the microbiota and its metabolites can exert a major influence on the gastrointestinal tract. Looking into the future, the microbiome and microbiota-associated processes will be likely to provide unparalleled opportunities for novel diagnostic, therapeutic and diet-inspired solutions for the management of IBD through harnessing rationally designed microbial communities, powerful bacterial and fungal metabolites, individually or in combination, to foster intestinal health. In this Review, we examine the current understanding of the cross-kingdom gut microbiome in IBD, focusing on bacterial and fungal components and metabolites. We examine therapeutic and diagnostic opportunities, the microbial metabolism, immunity, neuroimmunology and microbiome-inspired interventions to link mechanisms of disease and identify novel research and therapeutic opportunities for IBD.

Considering the role of leukotrienes in inflammatory pathways, and owing to the anti-leukotrienes effect of montelukast, in the present clinical trial, we aimed to assess the effect of montelukast on remission maintenance in patients with ulcerative colitis (UC).

In the present double-blind randomized controlled clinical trial, 222 volunteer UC patients on high-dose corticosteroid and montelukast were recruited. The patients received 10 mg of montelukast (98 patients) or placebo (124 patients) for 22 weeks. Simultaneously, the prednisolone dose was tapered. The patients were followed up eight more weeks post-interventions. The primary efficacy of the treatment was remaining in remission.

194 patients completed this study. During the study, relapse occurred in 108 patients, 32 patients in the montelukast group and 76 patients in the placebo group. There were significant differences between groups regarding the relapse-free period (intervention group mean: 27.25 95% CI: 26.17-28.32 weeks and placebo group mean: 20.88; 95% CI: 19.36, 20.40 weeks, P < 0.001). At the end of the intervention period and six weeks' post-intervention, the mean partial Mayo score, and inflammatory biomarkers were significantly lower in the montelukast group compared with the placebo group. The frequency of patients with high fecal calprotectin levels was significantly higher in the placebo group compared with the montelukast Group.

The findings indicated that compared with placebo, montelukast had a significant positive effect on remission maintenance in UC patients who were in the steroid-tapering phase of therapy.

IRCT20121212011738N3.

The dysbiosis of the gut microbiota has been identified as a central factor in the pathogenesis of inflammatory bowel disease (IBD), a chronic condition characterized by frequent recurrence and various adverse effects of traditional therapies. While treatments targeting the gut microbiota show promise, their efficacy in IBD management still requires extensive evaluation. Our systematic review analyzes recent studies to elucidate the advancements and challenges in treating IBD using microbial-based therapies.

Through a comprehensive systematic review spanning key scientific databases-PubMed, Embase, Cochrane, Web of Science, Scopus, and Google Scholar-we scrutinized the impact of probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) on individuals with IBD. Our detailed analysis covered study and participant demographics, along with seven key outcome measures: disease activity index, inflammatory markers, serum cytokines, microbiome composition, adverse effects, and the rates of remission and relapse.

From 6,080 initial search hits, we included 71 studies that assessed various interventions compared to placebo or standard medical therapy. Although there was notable variation in clinical results while assessing different outcomes, overall, probiotics, prebiotics, and synbiotics enhanced the success rates in inducing remission among IBD patients. Furthermore, we noted significant reductions in levels of pro-inflammatory markers and cytokines. Additionally, the requirement for steroids, hospitalization, and poor outcomes in endoscopic and histological scores were significantly reduced in individuals undergoing FMT.

Our investigation highlights the potential of targeting gut microbiota dysbiosis with microbial-based therapies in patients with IBD. We recommend conducting larger, placebo-controlled randomized trials with extended follow-up periods to thoroughly assess these treatments' clinical efficacy and safety before widespread recommendations for clinical application.

The gastrointestinal tract has remarkable capacity to withstand considerable insults from exposure to abrasive food particles, chemicals, allergens, and pathogenic microbes. Maintaining a robust epithelial barrier sequesters these potentially harmful substances in the lumen, preventing absorption into the systemic circulation. Normal functioning of this barrier is central in diverse physiological processes including digestion, immunity, inflammation, and gut-brain signaling. One crucial component of the barrier is the mucus layer covering the epithelium. There is increased appreciation of the importance of mucus in maintenance of the gut barrier, and how dysregulation of the mucus layer contributes to several common gastrointestinal pathologies. This manuscript reviews the physical and chemical properties of mucus, its maintenance and turnover, and its role in maintaining gut barrier integrity. The dynamic interactions of the mucus layer within the gut ecosystem are illustrated by highlighting how a weakened mucus layer or defective mucus production facilitate pathogenic microbial colonization and mucosal biofilm formation. These may potentially contribute to the pathogenesis of gastrointestinal diseases such as inflammatory bowel diseases or result in secretion and mucosal damage and inflammation in bile acid diarrhea. A final goal is to review how certain dietary factors, especially low-fiber diets and emulsifiers common in Western diets, can harm the mucus layer. This report summarizes evidence from preclinical and human studies that document damage to the mucus layer, and reviews approaches, including diets and probiotics, that promote a healthy mucus layer and break down pathogenic biofilms, thereby potentially preventing and/or treating gastrointestinal diseases that impact mucosal integrity.

Mast cells (MCs) are essential components of the immune system that enter the circulation as immature bone marrow progenitors and differentiate in peripheral organs under the influence of microenvironment factors. As tissue-resident secretory immune cells, MCs rapidly detect the presence of bacteria and parasites because they harbor many surface receptors, which enable their activation via a multitude of stimuli. MC activation has been traditionally linked to IgE-mediated allergic reactions, but MCs play a pivotal role in different physiological and pathological processes. In gut, MCs are essential for the maintenance of gastrointestinal (GI) barrier function, and their interactions with neurons, immune cells, and epithelial cells have been related to various GI disorders. This review recapitulates intestinal MC roles in diseases with a main focus on inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Emerging therapies targeting MCs and their mediators in clinical practices will also be discussed.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that represents a significant public health challenge worldwide. This multifactorial condition results from complex interactions among genetic, environmental, immune, and microbial factors. Some beneficial microbes, known as probiotics, have been identified as promising therapeutic agents for inflammatory conditions, such as IBD. In this review, we explore the potential of probiotics as a therapeutic strategy for managing IBD. Probiotics have shown promise due to their ability to modulate the gut microbiota, regulate histamine levels, and enhance vitamin D metabolism, thereby promoting a tolerant immune profile and reducing inflammation. While the exact mechanisms underlying these benefits remain incompletely understood, probiotics represent a novel and emerging approach for alleviating the exacerbated inflammation characteristic of this disorder.

Bifidobacterium species are known for their efficacy in alleviating constipation. This study aimed to compare the constipation-relieving effects of different Bifidobacterium species (Bifidobacterium longum subsp. longum, Bifidobacterium bifidum, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, and Bifidobacterium adolescentis) and to explore the underlying mechanisms from both the bacterial and host perspectives. We evaluated six Bifidobacterium species for their physiological properties, including growth rate, oligosaccharide utilization, osmotic pressure resistance, cell adhesion, and bile acid dissociation capability. Mice with severe constipation induced by loperamide hydrochloride were treated with these bacteria at a density of 109 CFU per mL for 17 days. Gastrointestinal indices such as fecal water content, time to first black stool defecation, and small intestine propulsion rate were measured to assess constipation relief. Microbiome and metabolome (bile acid and tryptophan) analyses were conducted to elucidate the differences in constipation relief among the species. Our results demonstrated that Bifidobacterium longum subsp. longum exhibited superior physiological traits, including rapid growth, extensive oligosaccharide utilization, and high bile salt dissociation capacity. Notably, only Bifidobacterium longum subsp. longum significantly ameliorated constipation symptoms in the mouse model. Furthermore, this strain markedly restored bile acid and short-chain fatty acid levels in the intestines of constipated mice and altered the composition of the intestinal microbiota. These findings suggest that the enhanced efficacy of Bifidobacterium longum subsp. longum in relieving constipation is associated with its ability to modulate intestinal physiology and microbiota structure and metabolism.

Bacteria genetically engineered to execute defined therapeutic and diagnostic functions in physiological settings can be applied to colonize the human microbiome, providing in situ surveillance and conditional disease modulation. However, many engineered microbes can only respond to single-input environmental factors, limiting their tunability, precision, and effectiveness as living diagnostic and therapeutic systems. For engineering microbes to improve complex chronic disorders such as inflammatory bowel disease, the bacteria must respond to combinations of stimuli in the proper context and time. This work implements a previously characterized split activator AND logic gate in the probiotic Escherichia coli strain Nissle 1917 (EcN). Our system can respond to two input signals: the inflammatory biomarker tetrathionate and a second input signal, anhydrotetracycline (aTc), for manual control. We report 4-6 fold induction with a minimal leak when the two chemical signals are present. We model the AND gate dynamics using chemical reaction networks and tune parameters in silico to identify critical perturbations that affect our circuit's selectivity. Finally, we engineer the optimized AND gate to secrete a therapeutic anti-inflammatory cytokine IL-22 using the hemolysin secretion pathway in the probiotic E. coli strain. We used a germ-free transwell model of the human gut epithelium to show that our engineering bacteria produce similar host cytokine responses compared to recombinant cytokine. Our study presents a scalable workflow to engineer cytokine-secreting microbes driven by logical signal processing. It demonstrates the feasibility of IL-22 derived from probiotic EcN with minimal off-target effects in a gut epithelial context.

In this chapter, we update our 2004 review of "The Life of Commensal Escherichia coli in the Mammalian Intestine" (https://doi.org/10.1128/ecosalplus.8.3.1.2), with a change of title that reflects the current focus on "Nutrition of E. coli within the Intestinal Microbiome." The earlier part of the previous two decades saw incremental improvements in understanding the carbon and energy sources that E. coli and Salmonella use to support intestinal colonization. Along with these investigations of electron donors came a better understanding of the electron acceptors that support the respiration of these facultative anaerobes in the gastrointestinal tract. Hundreds of recent papers add to what was known about the nutrition of commensal and pathogenic enteric bacteria. The fact that each biotype or pathotype grows on a different subset of the available nutrients suggested a mechanism for succession of commensal colonizers and invasion by enteric pathogens. Competition for nutrients in the intestine has also come to be recognized as one basis for colonization resistance, in which colonized strain(s) prevent colonization by a challenger. In the past decade, detailed investigations of fiber- and mucin-degrading anaerobes added greatly to our understanding of how complex polysaccharides support the hundreds of intestinal microbiome species. It is now clear that facultative anaerobes, which usually cannot degrade complex polysaccharides, live in symbiosis with the anaerobic degraders. This concept led to the "restaurant hypothesis," which emphasizes that facultative bacteria, such as E. coli, colonize the intestine as members of mixed biofilms and obtain the sugars they need for growth locally through cross-feeding from polysaccharide-degrading anaerobes. Each restaurant represents an intestinal niche. Competition for those niches determines whether or not invaders are able to overcome colonization resistance and become established. Topics centered on the nutritional basis of intestinal colonization and gastrointestinal health are explored here in detail.

With the rising morbidity of inflammatory bowel disease (IBD) year by year, conventional therapeutic drugs with systemic side effects are no longer able to meet the requirements of patients. Probiotics can improve gut microbiota, enhance intestinal barrier function, and regulate mucosal immunity, making them a potential complementary or alternative therapy for IBD. To compensate for the low potency of probiotics, genetic engineering technology has been widely used to improve their therapeutic function. In this review, we systematically summarize the genetically engineered probiotics used for IBD treatment, including probiotic chassis, genetic modification strategies, methods for controlling probiotics, and means of improving efficacy. Finally, we provide prospects on how genetically engineered probiotics can be extended to clinical applications.

The understanding of the potential role of the microbiota in the pathogenesis of inflammatory bowel disease (IBD) is ever-evolving. Traditionally, the management of IBD has involved medical therapy and/or surgical intervention. IBD can be characterized by gut microbiome alterations through various pathological processes. Various studies delve into nontraditional methods such as probiotics and fecal microbiota transplant and their potential therapeutic effects. Fecal microbiota transplant involves the delivery of a balanced composition of gut microorganisms into an affected patient via multiple possible routes and methods, while probiotics consist of live microorganisms given via the oral route. At present, neither method is considered first-line treatment, however, fecal microbiota transplant has shown potential success in inducing and maintaining remission in ulcerative colitis. In a study by Kruis and colleagues, Escherichia coli Nissle 1917 was considered to be equivalent to mesalamine in mild ulcerative colitis. Alteration of the microbiome in the management of Crohn's disease is less well defined. Furthermore, variation in the clinical usefulness of 5-aminosalicylic acid medication has been attributed, in part, to its acetylation and inactivation by gut microbes. In summary, our understanding of the microbiome's role is continually advancing, with the possibility of paving the way for personalized medicine based on the microbiome.

The gut microbiome emerges as an integral component of precision medicine because of its signature variability among individuals and its plasticity, which enables personalized therapeutic interventions, especially when integrated with other multiomics data. This promise is further fueled by advances in next-generation sequencing and metabolomics, which allow in-depth high-precision profiling of microbiome communities, their genetic contents, and secreted chemistry. This knowledge has advanced our understanding of our microbial partners, their interaction with cellular targets, and their implication in human conditions such as inflammatory bowel disease (IBD). This explosion of microbiome data inspired the development of next-generation therapeutics for treating IBD that depend on manipulating the gut microbiome by diet modulation or using live products as therapeutics. The current landscape of artificial microbiome therapeutics is not limited to probiotics and fecal transplants but has expanded to include community consortia, engineered probiotics, and defined metabolites, bypassing several limitations that hindered rapid progress in this field such as safety and regulatory issues. More integrated research will reveal new therapeutic targets such as enzymes or receptors mediating interactions between microbiota-secreted molecules that drive or modulate diseases. With the shift toward precision medicine and the enhanced integration of host genetics and polymorphism in treatment regimes, the following key questions emerge: How can we effectively implement microbiomics to further personalize the treatment of diseases like IBD, leveraging proven and validated microbiome links? Can we modulate the microbiome to manage IBD by altering the host immune response? In this review, we discuss recent advances in understanding the mechanism underpinning the role of gut microbes in driving or preventing IBD. We highlight developed targeted approaches to reverse dysbiosis through precision editing of the microbiome. We analyze limitations and opportunities while defining the specific clinical niche for this innovative therapeutic modality for the treatment, prevention, and diagnosis of IBD and its potential implication in precision medicine.

Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects. Gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and identified two major molecular subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD). Each subtype shows internal consistency in the transcriptome, genome, and phenome. The spectrum of morphometric, phenotypic, and functional changes within the "living biobank" reveals distinct differences between the molecular subtypes. Drug screens reverse subtype-specific phenotypes, suggesting phenotyped-genotyped CD PDOs can bridge basic biology and patient trials by enabling preclinical phase "0" human trials for personalized therapeutics.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.

Inflammatory bowel disease (IBD) is a recurring chronic inflammatory disease. Current treatment strategies are aimed at alleviating clinical symptoms and are associated with gastrointestinal or systemic adverse effects. New delivery strategies are needed for the treatment of IBD. Bacteria are promising biocarriers, which can produce drugs in situ and sense the gut in real time. Herein, we focus on recent studies of engineered bacteria used for IBD treatment and introduce the application of engineered bacteria in the diagnosis. On this basis, the current dilemmas and future developments of bacterial delivery systems are discussed.

The complex relationship between probiotics and human health goes beyond their traditional function in gut health, generating considerable interest for their broad potential in disease treatment. This review explores the various functions of probiotics, highlighting their impact on the immune system, their benefits for gut and oral health, their effects on metabolic and neurological disorders, and their emerging potential in cancer therapy. We give significant importance to studying the effects of probiotics on the gut-brain axis, revealing new and non-invasive therapeutic approaches for complex neurological disorders. In addition, we expand the discussion to encompass the impact of probiotics on the gut-liver and gut-lung axes, recognizing their systemic effects and potential in treating respiratory and hepatic conditions. The use of probiotic "cocktails" to improve cancer immunotherapy outcomes indicates a revolutionary approach to oncological treatments. The review explores the specific benefits associated with various strains and the genetic mechanisms that underlie them. This study sets the stage for precision medicine, where probiotic treatments can be tailored to meet the unique needs of each patient. Recent developments in delivery technologies, including microencapsulation and nanotechnology, hold great potential for enhancing the effectiveness and accuracy of probiotic applications in therapeutic settings. This study provides a strong basis for future scientific research and clinical use, promoting the incorporation of probiotics into treatment plans for a wide range of diseases. This expands our understanding of the potential benefits of probiotics in modern medicine.

Limosilactobacillus reuteri ZJ625 and Ligilactobacillus salivarius ZJ614 are potential probiotic bacteria with improved benefits when administered to the host as a multi-strain preparation. To elucidate the mechanisms of cell-to-cell crosstalk between these two strains, we studied their intracellular and extracellular proteomes in co-culture by liquid-chromatography mass-spectrometry (LC-MS) using Dionex Nano-RSLC and fusion mass spectrometer. The experiment consisted of five biological replicates, and samples were collected during the mid-exponential growth phase. The quantitative proteomic profiles revealed several differentially expressed proteins (DEPs), which are down- or up-regulated between and within groups for both the intracellular and extracellular proteomes. These DEPs include proteins synthesising autoinducer-2, a sensor compound for cell-to-cell bacterial crosstalk during quorum sensing in mixed culture. Other important DEPs identified include enolase, phosphoglycerate kinase, and l-lactate dehydrogenase, which play roles in carbohydrate metabolism. Proteins associated with transcription, ATP production and transport across the membrane, DNA repair, and those with the potential to bind to the host epithelium were also identified. The post-translational modifications associated with the proteins include oxidation, deamidation, and ammonia loss. Importantly, this study revealed a significant expression of S-ribosylhomocysteine lyase (luxS) involved in synthesising autoinducer-2 that plays important roles in quorum sensing, aiding bacterial cell-to-cell crosstalk in co-cultures. The proteome of L. salivarius ZJ614 was most affected when co-cultured with L. reuteri ZJ625. In contrast, omitting some medium components from the defined medium exerted more effects on L. reuteri ZJ625 than L. salivarius ZJ614.

Probiotics show promise in inflammatory bowel disease (IBD), yet knowledge gaps persist. We performed an overview of systematic reviews and an updated metanalysis of randomized controlled trials (RCT) assessing the effect of probiotics on Crohn's disease (CD) and ulcerative colitis (UC).

MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched up to September 2023. Primary outcomes were clinical remission and recurrence; secondary outcomes included endoscopic response and remission, and adverse events. We calculated odds ratios (OR) using a random-effects model in R. The quality of systematic reviews was assessed using the AMSTAR-2; the trials' risk of bias was evaluated using the Cochrane Collaboration tool. Evidence certainty was rated using the GRADE framework.

Out of 2613 results, 67 studies (22 systematic reviews and 45 RCTs) met the eligibility criteria. In the updated meta-analysis, the OR for clinical remission in UC and CD was 2.00 (95% CI 1.28-3.11) and 1.61 (95% CI 0.21-12.50), respectively. The subgroup analysis suggested that combining 5-ASA and probiotics may be beneficial for inducing remission in mild-to-moderate UC (OR 2.35, 95% CI 1.29-4.28). Probiotics decreased the odds of recurrence in relapsing pouchitis (OR 0.03, 95% CI 0.00-0.25) and trended toward reducing clinical recurrence in inactive UC (OR 0.65, 95% CI 0.42-1.01). No protective effect against recurrence was identified for CD. Multi-strain formulations appear superior in achieving remission and preventing recurrence in UC. The use of probiotics was not associated with better endoscopic outcomes. Adverse events were similar to control. However, the overall certainty of evidence was low.

Probiotics, particularly multi-strain formulations, appear efficacious for the induction of clinical remission and the prevention of relapse in UC patients as well as for relapsing pouchitis. Notwithstanding, no significant effect was identified for CD. The favorable safety profile of probiotics was also highlighted.

Convincing evidence suggests that aberrant gut microbiota changes play a critical role in the progression and pathogenesis of inflammatory bowel disease (IBD). Probiotic therapeutic interventions targeting the microbiota may provide alternative avenues to treat IBD, but currently available probiotics often suffer from low intestinal colonization and limited targeting capability. Here, we developed azido (N3)-modified Prussian blue nanozyme (PB@N3) spatio-temporal guidance enhances the targeted colonization of probiotics to alleviate intestinal inflammation. First, clickable PB@N3 targets intestinal inflammation, simultaneously, it scavenges reactive oxygen species (ROS). Subsequently, utilizing "click" chemistry to spatio-temporally guide targeted colonization of dibenzocyclooctyne (DBCO)-modified Lactobacillus reuteri DSM 17938 (LR@DBCO). The "click" reaction between PB@N3 and LR@DBCO has excellent specificity and efficacy both in vivo and in vitro. Despite the complex physiological environment of IBD, "click" reaction can prolong the retention time of probiotics in the intestine. Dextran sulfate sodium (DSS)-induced colitis mice model, demonstrates that the combination of PB@N3 and LR@DBCO effectively mitigates levels of ROS, enhances the colonization of probiotics, modulates intestinal flora composition and function, regulates immune profiles, restores intestinal barrier function, and alleviates intestinal inflammation. Hence, PB@N3 spatio-temporal guidance enhances targeted colonization of LR@DBCO provides a promising medical treatment strategy for IBD.

Chronic urinary infection may have implications for disease because of reactivation of toxins in the urine or damage to bladder defences. Exploration of these possibilities requires a scrupulous scientific approach.

Mild-to-moderate ulcerative colitis (UC) management is centred on 5-aminosalicylic acid (5-ASA) derivatives. Whether supplementing 5-ASA with nutraceuticals can provide real advantages in UC-relevant outcomes is unclear. This retrospective multicentre study compared clinical remission, response rates, and faecal calprotectin levels in a two-arm design, including patients treated with 5-ASA alone and those with additional H. erinaceus-based multi-compound supplementation. In the 5-ASA alone group, clinical response rates were 41% at three months (T1) and 60.2% at six months (T2), while corresponding clinical remission rates were 16.9% and 36.1%. In the nutraceutical supplementation group, clinical response rates were 49.6% (T1) and 70.4% (T2), with clinical remission rates of 30.4% (T1) and 50.9% (T2). No significant differences in clinical response rates between the groups at T1 (p = 0.231) and T2 (p = 0.143) emerged. Clinical remission rates differed significantly at both time points (p = 0.029 and p = 0.042, respectively). Faecal calprotectin levels decreased significantly in both groups during the retrospective follow-up (p < 0.05), and this was more pronounced in nutraceutical supplementation patients at both T1 (p = 0.005) and T2 (p = 0.01). No adverse events were reported. This multi-component nutraceutical supplementation offers real-world potential in controlling disease activity in patients with mild-to-moderate UC.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation with no cure and limited treatment options that often have systemic side effects. In this study, we developed a target-specific system to potentially treat IBD by engineering the probiotic bacterium Escherichia coli Nissle 1917 (EcN). Our modular system comprises three components: a transcription factor-based sensor (NorR) capable of detecting the inflammation biomarker nitric oxide (NO), a type 1 hemolysin secretion system, and a therapeutic cargo consisting of a library of humanized anti-TNFα nanobodies. Despite a reduction in sensitivity, our system demonstrated a concentration-dependent response to NO, successfully secreting functional nanobodies with binding affinities comparable to the commonly used drug Adalimumab, as confirmed by enzyme-linked immunosorbent assay and in vitro assays. This newly validated nanobody library expands EcN therapeutic capabilities. The adopted secretion system, also characterized for the first time in EcN, can be further adapted as a platform for screening and purifying proteins of interest. Additionally, we provided a mathematical framework to assess critical parameters in engineering probiotic systems, including the production and diffusion of relevant molecules, bacterial colonization rates, and particle interactions. This integrated approach expands the synthetic biology toolbox for EcN-based therapies, providing novel parts, circuits, and a model for tunable responses at inflammatory hotspots.

This study explores whether Escherichia coli Nissle 1917 (EcN) can preserve the integrity of the intestinal barrier by modulating the metabolism pathway of short-chain fatty acids (SCFAs) in a C57BL/6J mouse model of lipopolysaccharide (LPS)-induced acute enteritis and a model of a Caco-2 monolayer. The study involved establishing a septic shock model in mice through lipopolysaccharide (LPS) injection. Clinical scores and intestinal permeability were meticulously documented. Immunofluorescence was utilized to localize the tight junction proteins. A quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the expression of G protein-coupled receptors (GPRs) signaling. Additionally, the supplement of acetate and butyrate with Caco-2 monolayers to elucidate the potential of EcN in augmenting the intestinal barrier primarily via the modulation of SCFAs and qRT-PCR was performed to detect the expression of tight junction proteins and the activation of the GPRs protein signaling pathway. EcN mitigated the clinical symptoms and reduced intestinal permeability in the colon of LPS-induced mice. It also enhanced the production of SCFAs in the gut and upregulated the expression of SCFA receptor proteins GPR41 and GPR43 in the colon tissue. Our findings reveal that EcN activates the SCFA/GPRs pathway, thereby preserving intestinal barrier function and alleviating inflammation in a mouse sepsis model.

Probiotics are living microorganisms that may confer health benefits to their host if administered in sufficient quantities. However, data on the use of probiotics in transplant recipients are scarce.

This multi-center survey of pediatric nephrologists aimed to examine variations in practice regarding the use of probiotics in pediatric kidney transplant recipients. The survey was conducted via a 10-item questionnaire (developed in Survey Monkey) administered to pediatric nephrologists participating in the Pediatric Nephrology Research Consortium meeting in April 2023.

Sixty-four pediatric nephrologists completed the survey. Twenty-seven (42.2%) respondents reported having prescribed probiotics to pediatric kidney transplant recipients. The primary reason for probiotic use was the treatment of antibiotic-associated diarrhea (n = 20), with other reasons including recurrent Clostridium difficile infection (n = 15), general gut health promotion (n = 12), recurrent urinary tract infections (n = 8), and parental request (n = 1). Of those who prescribed probiotics, 48.1% held them during periods of neutropenia and 14.8% during central venous line use. Of the 64 respondents, 20 reported the lack of safety data as a concern for using probiotics in kidney transplant recipients.

Pediatric nephrologists are increasingly prescribing probiotics to pediatric kidney transplant recipients; nevertheless, substantial practice variations exist. The paucity of safety data is a significant deterrent to probiotic use in this population.

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1β expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

Guanylate binding protein 5 (GBP5) is an emerging immune component that has been increasingly recognized for its involvement in autoimmune diseases, particularly inflammatory bowel disease (IBD). IBD is a complex disease involving inflammation of the gastrointestinal tract. Here, we explored the functional significance of GBP5 using Gbp5 knockout mice and wildtype mice exposed to dextran sulfate sodium (DSS) to generate chronic colitis model. We found that Gbp5 deficiency protected mice from DSS-induced chronic colitis. Transcriptome analysis of colon tissues showed reduced immune responses in Gbp5 knockout mice compared to those in corresponding wildtype mice. We further observed that after repeated DSS exposure, the gut microbiota was altered, both in wildtype mice and Gbp5 knockout mice; however, the gut microbiome health index was higher in the Gbp5 knockout mice. Notably, a probiotic murine commensal bacterium, Dubosiella, was predominantly enriched in these knockout mice. Our findings suggest that GBP5 plays an important role in promoting inflammation and dysbiosis in the intestine, the prevention of which might therefore be worth exploring in regards to IBD treatment.

Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases of the digestive system with a multifactorial and not fully understood etiology. There is research suggesting that they may be initiated by genetic, immunological, and lifestyle factors. In turn, all of these factors play an important role in the modulation of intestinal microflora, and a significant proportion of IBD patients struggle with intestinal dysbiosis, which leads to the conclusion that intestinal microflora disorders may significantly increase the risk of developing IBD. Additionally, in IBD patients, Toll-like receptors (TLRs) produced by intestinal epithelial cells and dendritic cells treat intestinal bacterial antigens as pathogens, which causes a disruption of the immune response, resulting in the development of an inflammatory process. This may result in the occurrence of intestinal dysbiosis, which IBD patients are significantly vulnerable to. In this study, we reviewed scientific studies (in particular, systematic reviews with meta-analyses, being studies with the highest level of evidence) regarding the microflora of patients with IBD vs. the microflora in healthy people, and the use of various strains in IBD therapy.

Bacteria-mediated cancer therapeutic strategies have attracted increasing interest due to their intrinsic tumor tropism. However, bacteria-based drugs face several challenges including the large size of bacteria and dense extracellular matrix, limiting their intratumoral delivery efficiency. In this study, we find that hyperbaric oxygen (HBO), a noninvasive therapeutic method, can effectively deplete the dense extracellular matrix and thus enhance the bacterial accumulation within tumors. Inspired by this finding, we modify Escherichia coli Nissle 1917 (EcN) with cypate molecules to yield EcN-cypate for photothermal therapy, which can subsequently induce immunogenic cell death (ICD). Importantly, HBO treatment significantly increases the intratumoral accumulation of EcN-cypate and facilitates the intratumoral infiltration of immune cells to realize desirable tumor eradication through photothermal therapy and ICD-induced immunotherapy. Our work provides a facile and noninvasive strategy to enhance the intratumoral delivery efficiency of natural/engineered bacteria, and may promote the clinical translation of bacteria-mediated synergistic cancer therapy.

There are wide-ranging probiotic choices in Australasia. We reviewed the efficacy of probiotics for the management of gastrointestinal (GI) conditions in adults and assessed relevance to clinical practice. The benefits of probiotics were inconsistent, with a strong consensus reached for only a few of the indications. As different species/strains and combinations differ in efficacy, results cannot be extrapolated from one to another. This review endorses specific probiotics for limited indications. Efficacy of most marketed probiotic formulations remains unstudied and unproven, warranting further research.