SUMMARY: Given the importance of gut microbial homeostasis in maintaining health, there has been considerable interest in developing innovative therapeutic strategies for restoring gut microbiota. One such approach, fecal microbiota transplantation (FMT), is the main “whole gut microbiome replacement” strategy and has been integrated into clinical practice guidelines for treating recurrent Clostridioides difficile infection (rCDI). Furthermore, the potential application of FMT in other indications such as inflammatory bowel disease (IBD), metabolic syndrome, and solid tumor malignancies is an area of intense interest and active research. However, the complex and variable nature of FMT makes it challenging to address its precise functionality and to assess clinical efficacy and safety in different disease contexts. In this review, we outline clinical applications, efficacy, durability, and safety of FMT and provide a comprehensive assessment of its procedural and administration aspects. The clinical applications of FMT in children and cancer immunotherapy are also described. We focus on data from human studies in IBD in contrast with rCDI to delineate the putative mechanisms of this treatment in IBD as a model, including colonization resistance and functional restoration through bacterial engraftment, modulating effects of virome/phageome, gut metabolome and host interactions, and immunoregulatory actions of FMT. Furthermore, we comprehensively review omics technologies, metagenomic approaches, and bioinformatics pipelines to characterize complex microbial communities and discuss their limitations. FMT regulatory challenges, ethical considerations, and pharmacomicrobiomics are also highlighted to shed light on future development of tailored microbiome-based therapeutics.

As Helicobacter pylori management has become more challenging and less efficient over the last decade, the interest in innovative interventions is growing by the day. Probiotic co-supplementation to antibiotic therapies is reported in several studies, presenting a moderate reduction in drug-related side effects and a promotion in positive treatment outcomes. However, the significance of gut microbiota involvement in the competence of probiotic co-supplementation is emphasized by a few researchers, indicating the alteration in the host gastrointestinal microbiota following probiotic and drug uptake. Due to the lack of long-term follow-up studies to determine the efficiency of probiotic intervention in H. pylori eradication, and the delicate interaction of the gut microbiota with the host wellness, this review aims to discuss the gut microbiota alteration by probiotic co-supplementation in H. pylori management to predict the comprehensive effectiveness of probiotic oral administration. Abbreviations: acyl-CoA- acyl-coenzyme A; AMP- antimicrobial peptide; AMPK- AMP-activated protein kinase; AP-1- activator protein 1; BA- bile acid; BAR- bile acid receptor; BCAA- branched-chain amino acid; C2- acetate; C3- propionate; C4- butyrate; C5- valeric acid; CagA- Cytotoxin-associated gene A; cAMP- cyclic adenosine monophosphate; CD- Crohn’s disease; CDI- C. difficile infection; COX-2- cyclooxygenase-2; DC- dendritic cell; EMT- epithelial-mesenchymal transition; FMO- flavin monooxygenases; FXR- farnesoid X receptor; GPBAR1- G-protein-coupled bile acid receptor 1; GPR4- G protein-coupled receptor 4; H2O2- hydrogen peroxide; HCC- hepatocellular carcinoma; HSC- hepatic stellate cell; IBD- inflammatory bowel disease; IBS- irritable bowel syndrome; IFN-γ- interferon-gamma; IgA immunoglobulin A; IL- interleukin; iNOS- induced nitric oxide synthase; JAK1- janus kinase 1; JAM-A- junctional adhesion molecule A; LAB- lactic acid bacteria; LPS- lipopolysaccharide; MALT- mucosa-associated lymphoid tissue; MAMP- microbe-associated molecular pattern; MCP-1- monocyte chemoattractant protein-1; MDR- multiple drug resistance; mTOR- mammalian target of rapamycin; MUC- mucin; NAFLD- nonalcoholic fatty liver disease; NF-κB- nuclear factor kappa B; NK- natural killer; NLRP3- NLR family pyrin domain containing 3; NOC- N-nitroso compounds; NOD- nucleotide-binding oligomerization domain; PICRUSt- phylogenetic investigation of communities by reconstruction of unobserved states; PRR- pattern recognition receptor; RA- retinoic acid; RNS- reactive nitrogen species; ROS- reactive oxygen species; rRNA- ribosomal RNA; SCFA- short-chain fatty acids; SDR- single drug resistance; SIgA- secretory immunoglobulin A; STAT3- signal transducer and activator of transcription 3; T1D- type 1 diabetes; T2D- type 2 diabetes; Th17- T helper 17; TLR- toll-like receptor; TMAO- trimethylamine N-oxide; TML- trimethyllysine; TNF-α- tumor necrosis factor-alpha; Tr1- type 1 regulatory T cell; Treg- regulatory T cell; UC- ulcerative colitis; VacA- Vacuolating toxin A.

Background: Helicobacter pylori resistance to antibiotics commonly used in eradication regimens is increasing dramatically in many locations; new strategies are needed to manage this infectious disease. Objective: This study’s aim was to collect and update information on antibiotic resistance (AR) rates in H. pylori as well as current strategies for H. pylori management, including public health issues, from a global perspective. Design: An international survey was conducted in 31 countries on 6 continents to address key issues concerning the management of H. pylori -related AR. Individual aspects included the prevalence of AR for specific antibiotics, antibiotic susceptibility testing (AST) in different healthcare systems, availability of drugs, reimbursement issues and strategies for H. pylori AR surveillance. Results: Resistance to the most effective antibiotics used in H. pylori eradication regimens is increasing globally, with clarithromycin and levofloxacin resistance exceeding 15% in 24/31 and 18/31 countries, respectively. Amoxicillin remains an exception, with resistance rates under 2% in 14/31 countries; though African countries have reported amoxicillin resistance rates of over 90%. Bismuth-based treatment regimens are the most effective and are recommended as first-line treatment in several countries. However, more than 1 billion inhabitants worldwide have no access to bismuth-based regimens. PCR-based tests for AR are used in 16/26 countries but are reimbursed in only 4, while next generation sequencing-based tests are available, but not reimbursed, in 3 countries. In 22/26 countries only culture-based methods are available (reimbursed in 9/26 countries). AR surveillance programmes have only been established in 4/26 countries. Therefore, in most countries, empirical therapy with the most effective local regimen available locally is practiced. Conclusion: The dramatic global rise in H. pylori antibiotic resistance requires an urgent revision of current management strategies. Possible solutions include AST-based selection of effective treatment regimens, identification of novel combinations of existing drugs and exploration of novel drugs.

Helicobacter pylori infection causes gastritis, peptic ulcers, and gastric cancer. The infection is typically acquired in childhood and persists throughout life. The major impediment to successful therapy is antibiotic resistance. This systematic review and meta-analysis aimed to comprehensively assess the global prevalence of antibiotic resistance in pediatric H. pylori infection. We performed a systematic search of publication databases that assessed H. pylori resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, and tetracycline in children. The WHO region classification was used to group pooled primary and secondary resistance estimates along with 95% confidence interval (CI). H. pylori antibiotic resistance rates were retrieved and combined with odds ratios (95% CI) to investigate the global prevalence and temporal trends. Subgroup analysis of the prevalence of antibiotic resistance was conducted by country, age groups, and susceptibility testing methods. Among 1417 records obtained initially, 152 studies were selected for eligibility assessment after applying exclusion criteria in multiple steps. Ultimately, 63 studies involving 15,953 individuals were included comprising data from 28 countries in 5 WHO regions. The primary resistance rates were metronidazole 35.3% (5482/15,529, 95% CI: 28.7–42.6), clarithromycin 32.6% (5071/15,555, 95% CI: 27.7–37.9), tetracycline 2.1% (148/7033, 95% CI: 1.3–3.6), levofloxacin 13.2% (1091/8271, 95% CI: 9.3–18.4), and amoxicillin 4.8% (495/10305, 95% CI: 2.5–8.8). Raising antibiotic resistance was detected in most WHO regions. The escalating trend of H. pylori antibiotic resistance in children warrants urgent attention globally. National and regional surveillance networks are required for antibiotic stewardship in children infected with H. pylori.