Antibiotics are widely used during pregnancy. Recent epidemiological studies suggest that maternal exposure to antibiotics during pregnancy is associated with increased risks of various diseases in offspring; host-microbiome interactions are considered to be involved in pathogenesis, as antibiotic-induced perturbations (dysbiosis) of the maternal microbiome can be transmitted to offspring. We reviewed the current status of antibiotic usage during pregnancy, transmission of maternal antibiotic-induced dysbiosis to offspring, and several diseases in offspring reported to be associated with maternal antibiotic exposure. Antibiotics must be properly used when necessary. While the adverse effect of maternal antibiotic exposure during pregnancy on the health of offspring has been demonstrated by several studies, more robust clinical evidence is necessary to define the best practice for antibiotic use during pregnancy. Epidemiologic studies have limitations in establishing causal links beyond associations; animal studies provide benefits in examining these links, however, microbiomes, gestation courses, and aging vary between host species. Understanding the underlying mechanisms of epidemiologic findings as well as the healthy microbiome during pregnancy and early life in humans would contribute to developing future microbial interventions for restoring antibiotic-induced dysbiosis during pregnancy.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), exhibits a multifactorial pathogenesis influenced by genetic and environmental factors. Antibiotic usage has been implicated in modifying the gut microbiome, potentially leading to dysbiosis and contributing to IBD risk. Despite existing literature, the relationship remains inconclusive. This meta-analysis aimed to evaluate the association between prior antibiotic use and the onset of IBD.

A systematic literature search in PubMed was conducted to identify studies exploring the link between antibiotic use and subsequent IBD diagnosis. Studies reporting CD, UC, or both as primary outcomes were included. The meta-analysis, performed according to PRISMA guidelines, summarized risk estimates, represented as odds ratios (ORs), and corresponding confidence intervals (CIs). Subgroup analyses involved the categorization of antibiotics and the determination of the minimum number of antibiotic therapy courses administered.

Out of 722 publications, 31 studies comprising 102,103 individuals met eligibility criteria. The pooled OR for IBD in those with prior antibiotic exposure was 1.40 (95% CI: 1.25-1.56). Antibiotic use was associated with an increased risk of IBD (OR: 1.52, 95% CI: 1.19-1.94). Notably, this association was confined to CD (OR: 1.50, 95% CI: 1.27-1.77), while no significant association was observed with UC (OR: 1.21, 95% CI: 1.00-1.47). Risk augmentation for IBD correlated positively with the number of antibiotic courses (OR: 1.08, 95% CI: 1.05-1.12).

Previous antibiotic use is associated with the later development of CD. A positive dose-response effect was also observed. Against this background, antibiotics should be used rationally.

Antibiotic exposure for fever/cough has been rising alarmingly, especially among children under five in low- and middle-income countries (LMICs). This excessive use could result in higher healthcare costs, and antibiotic resistance is an alarming trend in developing countries. As a result, it's crucial to look at the variables that affect antibiotic exposure and highlight the subgroups among whom antibiotic abuse is the most prevalent.

We used the most recent standard Demographic and Health Survey (DHS) data for 64 LMICs. Sample weights were employed in studies to ensure exact standard errors and estimate p-values. To analyze antibiotic exposures across countries, continents, economic levels, and the top and bottom ten countries with fever/cough, we conducted descriptive statistics. Additionally, we provided accompanying bar diagrams for each descriptive finding to enhance visual understanding. For geospatial analysis, we utilized ArcGIS, a powerful tool for mapping and spatial analysis.

We used data from 141,018 children under five who were reported to have had fever/cough recently in 64 LMICs. Among them, 30.4 % were exposed to antibiotics for fever/cough. Congo (68.7 %), Egypt (65.5 %), and Tajikistan (61.8 %) had the highest prevalence of antibiotic consumption across LMICs. On the other hand, Cameroon (0.3 %), Armenia (4.0 %), and Mauritania (6.1 %) had the lowest. In the final binary logistic regression, mothers that had any formal education (Primary: OR = 1.28, 95 % CI:1.07-1.53, Secondary: OR = 1.38, 95 % CI:1.14-1.67, Higher Education: OR = 1.69, 95 % CI:1.23-2.33) were more likely to expose their children to antibiotics for fever/cough than illiterate ones. Additionally, children in richer households (Richer: OR = 1.38, 95 % CI:1.15-1.66, Richest: OR = 1.46, 95 % CI:1.19-1.80) were more likely to receive antibiotics than those in poorer households.

Antibiotic exposure for fever/cough in children under five was relatively moderate across 64 LMICs. However, the rate was incredibly high in some LMICs and incredibly low in others. The researchers recommend that the countries with high and low percentages of antibiotic exposure investigate either any possibility of antibiotic abuse or proper healthcare service at the national level.

Childhood antibiotic use has been associated with inflammatory bowel disease (IBD), although the potential contribution of infection frequency remains uncertain.

To explore the association between early-life infections, antibiotics and IBD development.

We used population-based data from ABIS (Sweden) and MoBa (Norway) cohorts following children from birth (1997-2009) until 2021. Prospectively collected questionnaires identified infection frequency (any, gastrointestinal and respiratory) and antibiotics (any, penicillin and non-penicillin) until age 3. IBD diagnosis required ≥ 2 records in national health registries. Cohort-specific hazard ratios (aHR), adjusted for parental education, smoking and IBD were estimated and pooled using a random-effects model. Antibiotic analyses were adjusted for infection frequency.

There were 103,046 children (11,872 ABIS and 91,174 MoBa), contributing to 1,663,898 person-years of follow-up, during which 395 were diagnosed with IBD. The frequency of any infection at 0 to < 1 and 1 to < 3 years showed a pooled aHR of 1.01 (95% confidence interval [CI] = 0.96-1.07) and 1.00 (95% CI = 0.99-1.01) per additional infection for IBD. Adjusting for infections, any versus no antibiotics in the first year was associated with IBD (pooled aHR = 1.33 [95% CI = 1.01-1.76]). The aHR for additional antibiotic course was 1.17 (95% CI = 0.96-1.44), driven by penicillin (per additional course, aHR = 1.28 [95% CI = 1.02-1.60]). Although antibiotics at 1 to < 3 years did not show an association with IBD or Crohn's disease, non-penicillin antibiotics were associated with ulcerative colitis (per additional course, aHR = 1.95 [95% CI = 1.38-2.75]).

Early-life antibiotic use was, a significant risk factor for childhood and early adult-onset IBD, independent of infection frequency.

The association between antibiotic exposure and inflammatory bowel disease (IBD) remains controversial, especially whether there is a dose-response relationship. We aimed to conduct a systematic review and meta-analysis to thoroughly evaluate the risk of new-onset IBD associated with antibiotic exposure.

Four databases were searched from their inception to September 30, 2023 for all relevant studies. The risk estimates were pooled together using random-effects models, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, stratified by IBD subtype, age, exposure period, study type, and antibiotic classes. Dose-response relationship between the number of antibiotic prescriptions and IBD risk was assessed using generalized least squares regression analysis.

Twenty-eight studies involving 153,027 patients with IBD were included. Antibiotic exposure was significantly associated with an increased risk of new-onset IBD for prescription-based studies (pooled OR, 1.41; 95% CI, 1.29-1.53) and for questionnaire-based studies (pooled OR, 1.35; 95% CI, 1.08-1.68). This association existed for both Crohn's disease and ulcerative colitis, as well as in children and adults for prescription-based studies. The majority of antibiotic classes were associated with an increased IBD risk, with metronidazole (OR, 1.70; 95% CI, 1.38-2.10) and quinolones (OR, 1.56; 95% CI, 1.37-1.77) having relatively higher risk estimates. A positive nonlinear dose-response association was observed between the number of antibiotic prescriptions and IBD risk.

Antibiotic exposure was significantly associated with an increased risk of new-onset IBD, and a positive nonlinear dose-response relationship was observed. Antibiotic stewardship may be important for reducing IBD risk.

Iron overload disrupts gut microbiota and induces ferroptosis, contributing to colitis. However, whether gut microbiota directly drives iron overload-induced colitis and its underlying mechanism remain unclear.

The study aimed to explore whether gut microbiota can directly regulate iron overload-induced colitis and its underling mechanism.

Male C57BL/6N mice were fed with ferrous sulfate to establish an iron overload model. Antibiotics and dextran sulfate sodium salt (DSS) were used to create germ-free and colitis models, respectively.

Results showed that iron overload caused disruption of systemic iron homeostasis via activating pro-inflammation response, which caused induction of ferroptosis and eventually resulted in colitis in mice. Notably, iron overload inhibited System Xc- and activated the nuclear factor E2-related factor 2/heme oxygenase-1 pathway, driving ferroptosis and colitis progression. Similar results were observed in mouse colon epithelial cells, which were treated with high doses ferric ammonium citrate. Additionally, iron overload exacerbated DSS-induced colitis by activating the ferroptosis and increasing harmful bacteria (e.g., Mucispirillum) abundance. Interestingly, eliminating gut microbiota attenuated iron overload-induced colitis, without affecting systemic inflammation through inhibiting ferroptosis of mice. Depletion of the gut microbiota partially mitigated the exacerbating effect of iron overload on DSS-induced colitis through inhibiting ferroptosis of mice.

Iron overload activates ferroptosis in colonic cells, increases the relative abundance of harmful bacteria, and exacerbates DSS-induced colitis in mice. Iron overload exacerbates DSS-induced ferroptosis and colitis in a microbiota-dependent manner. Targeting gut microbiota may offer new strategies for managing iron overload-induced colitis.

The human gut is a complex ecosystem that supports billions of living species, including bacteria, viruses, archaea, phages, fungi, and unicellular eukaryotes. Bacteria give genes and enzymes for microbial and host-produced compounds, establishing a symbiotic link between the external environment and the host at both the gut and systemic levels. The gut microbiome, which is primarily made up of commensal bacteria, is critical for maintaining the healthy host's immune system, aiding digestion, synthesizing essential nutrients, and protecting against pathogenic bacteria, as well as influencing endocrine, neural, humoral, and immunological functions and metabolic pathways. Qualitative, quantitative, and/or topographic shifts can alter the gut microbiome, resulting in dysbiosis and microbial dysfunction, which can contribute to a variety of noncommunicable illnesses, including hypertension, cardiovascular disease, obesity, diabetes, inflammatory bowel disease, cancer, and irritable bowel syndrome. While most evidence to date is observational and does not establish direct causation, ongoing clinical trials and advanced genomic techniques are steadily enhancing our understanding of these intricate interactions. This review will explore key aspects of the relationship between gut microbiota, eubiosis, and dysbiosis in human health and disease, highlighting emerging strategies for microbiome engineering as potential therapeutic approaches for various conditions.

The incidence of inflammatory bowel diseases [IBD] has risen over the past decade to become a global issue. The objectives of this review were to describe the incidence and/or prevalence of IBD in the era of advanced therapies, and to describe the association between environmental risk factors and both pathogenesis and disease course across the ages.

We performed a search of English language publications listed in PubMed regarding the epidemiology of IBD and key environmental factors implicated in IBD from January 2000 to December 2023.

Annual incidence rates varied by geographical region with IBD estimates ranging from 10.5 to 46.14 per 100 000 in Europe, 1.37 to 1.5 per 100 000 in Asia and the Middle East, 23.67 to 39.8 per 100 000 in Oceania, 0.21 to 3.67 per 100 000 in South America, and 7.3 to 30.2 per 100 000 in North America. The burden of IBD among children and adolescents, and older people is rising globally. Key environmental factors implicated in IBD pathogenesis include exposure to tobacco smoking, antibiotics, non-steroidal anti-inflammatory drugs, oral contraceptives, infections, and ultra-high processed foods. Breastfeeding and a high-quality diet rich in fruit, vegetables, fish, and other fibre sources are important protective factors. Smoking has consistently been shown to negatively impact disease outcomes for Crohn's disease.

The epidemiology of IBD has undergone considerable change in recent decades, with an increase in the burden of disease worldwide. Optimally studying and targeting environmental triggers in IBD may offer future opportunities for disease modification.

The prevalence of allergies has been globally escalating. While allergies could appear at any age, they often develop in early life. However, the significant knowledge gap in the field is the mechanisms by which allergies affect certain people but not others. Investigating early factors and events in neonatal life that have a lasting impact on determining the susceptibilities of children to develop allergies is a significant area of the investigation as it promotes the understanding of neonatal immune system that mediates tolerance versus allergies. This review focuses on the research over the recent 10 years regarding the potential maternal factors that influence offspring allergies with a view to food allergy, a potentially life-threatening cause of anaphylaxis. The role of breast milk, maternal diet, maternal antibodies, and microbiota that have been suggested as key maternal factors regulating offspring allergies are discussed here. We also suggest future research area to expand our knowledge of maternal-offspring interactions on the pathogenesis of food allergy.

Genetic and environmental factors influence pathogenesis and rising incidence of paediatric inflammatory bowel disease (PIBD). The aim was to meta-analyse evidence of diet and environmental factors in PIBD.

A systematic search was conducted to identify diet and environmental factors with comparable risk outcome measures and had been reported in two or more PIBD studies for inclusion in meta-analyses. Those with ≥2 PIBD risk estimates were combined to provide pooled risk estimates.

Of 4763 studies identified, 36 studies were included. PIBD was associated with higher risk with exposure to ≥/=4 antibiotic courses (includes prescriptions/purchases/courses), passive smoking, not being breastfed, sugary drink intake, being a non-Caucasian child living in a high-income country and infection history (odds ratio [OR] range: 2-3.8). Paediatric Crohn's disease (CD) was associated with higher risk with exposure to antibiotics during early childhood, ≥/=4 antibiotic courses, high socioeconomic status (SES), maternal smoking, history of atopic conditions and infection history (OR range: 1.6-4.4). A history of infection was also associated with higher risk of paediatric ulcerative colitis (UC) (OR: 3.73). Having a higher number of siblings (≥2) was associated with lower risk of paediatric CD (OR: 0.6) and paediatric UC (OR: 0.7). Pet exposure was associated with lower risk of paediatric UC (OR: 0.5).

Several factors associated with PIBD risk were identified that could potentially be used to develop a disease screening tool. Future research is needed to address risk reduction in PIBD.

Managing neonatal sepsis is challenging due to nonspecific clinical signs, hematological markers with poor accuracy, and a lengthy turnaround time for the identification of microorganisms. Delaying the initiation of antibiotics in truly infected infants can lead to severe morbidity and mortality. Therefore, decisions regarding empiric antibiotic treatment are risk stratified, which exposes many uninfected infants to antibiotics. This causes gut microbiota perturbation, unnecessary hospital admissions, and the generation of multi-resistant organisms. High-speed diagnostic assays could expedite discontinuation or avert the initiation of antibiotics in uninfected infants. This study will evaluate the diagnostic performance of molecular culture (MC), a rapid broad-range PCR-based bacterial profiling technique, for diagnosing neonatal sepsis in infants below 90 days old. A multi-center prospective observational cohort study will include infants evaluated for early and late-onset sepsis. Routine evaluation for suspected sepsis includes microbiological cultures of blood. Additionally, blood for MC will be collected. For early-onset sepsis, umbilical cord blood may be used alternatively. Primary outcome is the agreement between MC and conventional blood culture results. Secondary outcome is the agreement of both assays with clinical sepsis using four different, commonly used definitions. Faster diagnostic pathways for sepsis may reduce antibiotic exposure time. Broad-range molecular assays may identify pathogens undetectable by conventional methods. Employment of umbilical cord blood samples for early-onset sepsis diagnosis can resolve challenges in collecting adequate blood volume and could further expedite treatment decisions.

The management of patients with inflammatory bowel disease (IBD) aims to control inflammation through the use of immunosuppressive treatments that target various points in the inflammatory cascade. However, the efficacy of these therapies in the long term is limited, and they often are associated with severe side effects. Although the pathophysiology of the disease is not completely understood, IBD is regarded as a multifactorial disease that occurs due to an inappropriate immune response in genetically susceptible individuals. The gut microbiome is considered one of the main actors in the development of IBD. Gut dysbiosis, characterised by significant changes in the composition and functionality of the gut microbiota, often leads to a reduction in bacterial diversity and anti-inflammatory anaerobic bacteria. At the same time, bacteria with pro-inflammatory potential increase. Although changes in microbiome composition upon biological agent usage have been observed, their role as biomarkers is still unclear. While most studies on IBD focus on the intestinal bacterial population, recent studies have highlighted the importance of other microbial populations, such as viruses and fungi, in gut dysbiosis. In order to modulate the aberrant immune response in patients with IBD, researchers have developed therapies that target different players in the gut microbiome. These innovative approaches hold promise for the future of IBD treatment, although safety concerns are the main limitations, as their effects on humans remain unknown.

Colistin is renowned as a last-resort antibiotic due to the emergence of multidrug-resistant pathogens. However, its potential toxicity significantly hampers its clinical utilization. Melatonin, chemically known as N-acetyl-5-hydroxytryptamine, is an endogenous hormone produced by the pineal gland and possesses diverse biological functions. However, the protective role of melatonin in alleviating antibiotic-induced intestinal inflammation remains unknown. Herein, we reveal that colistin stimulation markedly elevates intestinal inflammatory levels and compromises the gut barrier. In contrast, pretreatment with melatonin safeguards mice against intestinal inflammation and mucosal damage. Microbial diversity analysis indicates that melatonin supplementation prevents a reduction in the abundance of Erysipelotrichales and Bifidobacteriales, as well as an increase in Desulfovibrionales abundance, following colistin exposure. Remarkably, short-chain fatty acids (SCFAs) analysis shows that propanoic acid contributes to the protective effect of melatonin on colistin-induced intestinal inflammation. Furthermore, the protection effects of melatonin and propanoic acid on LPS-induced cellular inflammation in RAW 264.7 cells are confirmed. Mechanistic investigations suggest that intervention with melatonin and propanoic acid can repress the activation of the TLR4 signal and its downstream NF-κB and MAPK signaling pathways, thereby mitigating the toxic effects of colistin. Our work highlights the unappreciated role of melatonin in preventing the potential detrimental effects of colistin on intestinal health and suggests a combined therapeutic strategy to effectively manage intestinal infectious diseases.

The human gastrointestinal ecosystem, or microbiome (comprising the total bacterial genome in an environment), plays a crucial role in influencing host physiology, immune function, metabolism, and the gut-brain axis. While bacteria, fungi, viruses, and archaea are all present in the gastrointestinal ecosystem, research on the human microbiome has predominantly focused on the bacterial component. The colonization of the human intestine by microbes during the first two years of life significantly impacts subsequent composition and diversity, influencing immune system development and long-term health. Early-life exposure to pathogens is crucial for establishing immunological memory and acquired immunity. Factors such as maternal health habits, delivery mode, and breastfeeding duration contribute to gut dysbiosis. Despite fungi's critical role in health, particularly for vulnerable newborns, research on the gut mycobiome in infants and children remains limited. Understanding early-life factors shaping the gut mycobiome and its interactions with other microbial communities is a significant research challenge. This review explores potential factors influencing the gut mycobiome, microbial kingdom interactions, and their connections to health outcomes from childhood to adulthood. We identify gaps in current knowledge and propose future research directions in this complex field.

Antibiotic, analgesic sedative, and antiseizure medications are among the most commonly used medications in preterm/sick neonates, who are at high risk of nosocomial infections, central nervous system complications, and are exposed to numerous painful/stressful procedures. These severe and potentially life-threatening complications may have serious short- and long-term consequences and should be prevented and/or promptly treated. The reported variability in the medications used in neonates indicates the lack of adequate neonatal studies regarding their effectiveness and safety. Important obstacles contributing to inadequate studies in preterm/sick infants include difficulties in obtaining parental consent, physicians' unwillingness to recruit preterm infants, the off-label use of many medications in neonates, and other scientific and ethical concerns. This review is an update on the use of antimicrobials (antifungals), analgesics (sedatives), and antiseizure medications in neonates, focusing on current evidence or knowledge gaps regarding their pharmacokinetics, indications, safety, dosage, and evidence-based guidelines for their optimal use in neonates. We also address the effects of early antibiotic use on the intestinal microbiome and its association with long-term immune-related diseases, obesity, and neurodevelopment (ND). Recommendations for empirical treatment and the emergence of pathogen resistance to antimicrobials and antifungals are also presented. Finally, future perspectives on the prevention, modification, or reversal of antibiotic resistance are discussed.

Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn's disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.

Microbial imbalance in the gut from antibiotic use may be an etiologic factor of Kawasaki disease (KD). We aimed to identify the association between the use of antibiotics and the development of KD, considering various antibiotic profiles.

A population-based, case-control study was performed using data from the Health Insurance Review and Assessment Service database. Children <5 years of age, who were diagnosed with KD between 2016 and 2019, were identified. Propensity score-matched controls were selected from the general population in a 1:5 ratio. Four separate study cohorts were created according to different periods of antibiotic use: (1) within 28 days and (2) 12 months after birth and (3) within 6 months and (4) 12 months from the index date. Profiles regarding antibiotic use were compared between patients with KD and matched controls.

We included 17,818 patients with KD and 89,090 matched controls. Use of antibiotics within 6 months [odds ratio (OR): 1.18; 95% confidence interval (CI): 1.12-1.26] and 12 months (OR: 1.23; 95% CI: 1.14-1.32) from the index date were associated with the development of KD. The association between antibiotic use and KD was most prominent in patients who had received 3 or more types of antibiotics within 12 months from the index date (OR: 1.26; 95% CI: 1.17-1.37).

Antibiotic use within the preceding 6 or 12 months was associated with KD. Alteration in gut microbiota due to antibiotic usage might play a role in the development of KD.

Early-onset neonatal sepsis (EONS) remains an important disease entity due to very serious adverse outcomes if left untreated. Lack of diagnostic tools in identifying healthy from diseased neonates, and clinicians' fear of the missing positive-culture sepsis babies, or babies with clinical sepsis have led to overtreating and unnecessary antibiotic exposure. Kaiser Permanente EONS risk calculator is an internally validated tool that can predict EONS. This sepsis risk calculator (SRC) classifies neonates into three subgroups: (1) ill-appearing, (2) equivocal and (3) well-appearing. We propose a modification to this tool that aims to use it solely for well-appearing babies. This modification represents a more conservative approach to decrease antibiotic exposure and offers an alternative for those hesitant to fully implement this tool.

This is a dual-centre retrospective study where data were extracted from the electronic medical records. Our primary outcome was to validate the modified use of the SRC with a two-by-two table. Specificity, negative predictive value and expected antibiotic reduction were used to evaluate the tool's feasibility.

Among 770 babies suspected of EONS, the feasibility of the modified use was tested. The expected antibiotic exposure reduction rate on the modification was 40.4% overall. The proposed modification resulted in a specificity and negative predictive value of 99.28% (95% CI: 97.92% to 99.85%) and 99.5% (95% CI: 99% to 99.8%), respectively.

The modified use of the sepsis risk calculator has shown that it can safely reduce antibiotic exposure in well-appearing babies. The modified use is used as a 'rule out' test that can identify very low risk of EONS babies, and safely minimise antibiotic exposure. Further prospective studies are needed to examine the efficacy of this use, and quality improvement projects are required to evaluate its applicability in different clinical settings.

To assess whether antibiotic exposure prenatally and before 2 years of age is associated with subsequent pediatric inflammatory bowel disease (PIBD), as earlier studies diverge substantially in risk estimations or do not include prenatal exposure.

We performed a register-based cohort study including all children in Norway born 2004-2012 until study's end on December 31, 2020. Exposures were defined as dispensed antibiotics to mothers during pregnancy and to children before 2 years of age. Main outcome was International Classification of Diseases, Tenth Revision, code registrations consistent with PIBD.

Among 536 819 children, 797 PIBD cases were identified. The aOR for developing PIBD if exposed to antibiotics before 2 years of age compared with no exposure was 1.33 (95% CI 1.15-1.53), adjusted for sex and prenatal antibiotic exposure. An adjustment for maternal smoking during pregnancy increased the aOR to 1.42 (1.22-1.66), but with minimal changes after further adjustments for potential confounders related to pregnancy, birth, or socioeconomic status. A dose-response association was observed in those receiving more than 2 antibiotic courses (aOR 1.47, 1.25-1.73), and with greater effect estimates for broad-spectrum antibiotics (aOR 2.57, 1.82-3.63). Antibiotic exposure during pregnancy was numerically but not significantly associated with offspring PIBD (aOR 1.15, 0.99-1.34).

Children exposed to antibiotics before 2 years of age were more likely to develop pediatric IBD than controls. Exposure prenatally to maternal antibiotics was numerically but not statistically significant associated to subsequent PIBD.

Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.

Aim: To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by Bifidobacterium breve (B. breve) and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of B. breve and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of B. breve. Efficacious molecules produced by B. breve were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. Results: B. breve alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of B. breve. Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following B. breve supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with B. breve in CAC mice and highly enriched in the culture supernatant of B. breve. Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs in vitro. The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of B. breve and ILA in relieving colitis and tumorigenesis. Conclusion: B. breve-mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.

The gut microbiota during early life plays a crucial role in infant development. This microbial-host interaction is also essential for metabolism, immunity, and overall human health in later life. Early-life pharmaceutical exposure, mainly referring to exposure during pregnancy, childbirth, and infancy, may change the structure and function of gut microbiota and affect later human health. In this Review, we describe how healthy gut microbiota is established in early life. We summarise the commonly prescribed medications during early life, including antibiotics, acid suppressant medications and other medications such as antidepressants, analgesics and steroid hormones, and discuss how these medication-induced changes in gut microbiota are involved in the pathological process of diseases, including infections, inflammatory bowel disease, metabolic diseases, allergic diseases and neurodevelopmental disorders. Finally, we review some critical methods such as dietary therapy, probiotics, prebiotics, faecal microbiota transplantation, genetically engineered phages, and vagus nerve stimulation in early life, aiming to provide a new strategy for the prevention of adverse health outcomes caused by prescribed medications exposure in early life.

Comparing antibiotic prescribing between countries can provide important insights into potential needs of improving antibiotic stewardship programs. We aimed to compare outpatient antibiotic prescribing in early life between children born in Denmark and Germany.

Using the Danish nationwide healthcare registries and a German claims database (GePaRD, ~ 20% population coverage), we included children born between 2004 and 2016, and followed them regarding outpatient antibiotic prescriptions until end of enrollment or the end of 2018. We then determined the median time to first antibiotic prescription. Based on all prescriptions in the first 2 years of life, we calculated the rate of antibiotic treatment episodes and for the children's first prescriptions in this period, we determined established quality indicators. All analyses were stratified by birth year and country.

In the 2016 birth cohorts, the median time to first antibiotic prescription was ~ 21 months in Denmark and ~ 28 in Germany; the rate of antibiotic treatment episodes per 1000 person-years was 537 in Denmark and 433 in Germany; the percentage of prescribed antibiotics with higher concerns regarding side effects and/or resistance potential was 6.2% in Denmark and 44.2% in Germany. In the 2016 birth cohorts, the age at first antibiotic prescription was 50-59% higher compared to the 2004 birth cohorts; the rate of antibiotic treatment episodes was 43-44% lower.

Infants in Denmark received antibiotics markedly earlier and more frequently than in Germany, while quality indicators of antibiotic prescribing were more favorable in Denmark. Although both countries experienced positive changes towards more rational antibiotic prescribing in early life, our findings suggest potential for further improvement. This particularly applies to prescribing antibiotics with a lower potential for side effects and/or resistance in Germany.

Watchful waiting management for acute otitis media (AOM), where an antibiotic is used only if the child's symptoms worsen or do not improve over the subsequent 2-3 days, is an effective approach to reduce antibiotic exposure for children with AOM. However, studies to compare the effectiveness of interventions to promote watchful waiting are lacking. The objective of this study is to compare the effectiveness and implementation outcomes of two pragmatic, patient-centered interventions designed to facilitate use of watchful waiting in clinical practice.

This will be a cluster-randomized trial utilizing a hybrid implementation-effectiveness design. Thirty-three primary care or urgent care clinics will be randomized to one of two interventions: a health systems-level intervention alone or a health systems-level intervention combined with use of a shared decision-making aid. The health systems-level intervention will include engagement of a clinician champion at each clinic, changes to electronic health record antibiotic orders to facilitate delayed antibiotic prescriptions as part of a watchful waiting strategy, quarterly feedback reports detailing clinicians' use of watchful waiting individually and compared with peers, and virtual learning sessions for clinicians. The hybrid intervention will include the health systems-level intervention plus a shared decision-making aid designed to inform decision-making between parents and clinicians with best available evidence. The primary outcomes will be whether an antibiotic was ultimately taken by the child and parent satisfaction with their child's care. We will explore the differences in implementation effectiveness by patient population served, clinic type, clinical setting, and organization. The fidelity, acceptability, and perceived appropriateness of the interventions among different clinician types, patient populations, and clinical settings will be compared. We will also conduct formative qualitative interviews and surveys with clinicians and administrators, focus groups and surveys of parents of patients with AOM, and engagement of two stakeholder advisory councils to further inform the interventions.

This study will compare the effectiveness of two pragmatic interventions to promote use of watchful waiting for children with AOM to reduce antibiotic exposure and increase parent satisfaction, thus informing national antibiotic stewardship policy development.

NCT06034080.

The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.

Most antibiotics prescribed to children are provided in the outpatient and emergency department (ED) settings, yet these prescribers are seldom engaged by antibiotic stewardship programs. We reviewed ED antibiotic prescriptions for three common infections to describe current prescribing practices.

Prescription data between 2018 and 2021 were extracted from the electronic records of children discharged from the Children's Hospital of Eastern Ontario ED with urinary tract infection (UTI), community acquired pneumonia (CAP), and acute otitis media ≥2 years of age (AOM). Antibiotic choice, duration, as well as the provider's time in practice and training background were collected. Antibiotic durations were compared with Canadian guideline recommendations to assess concordance. Provider-level prescribing practices were analyzed using k-means cluster analysis.

10,609 prescriptions were included: 2868 for UTI, 2958 for CAP, and 4783 for AOM. Guideline-concordant durations prescribed was generally high (UTI 84.9%, CAP 94.0%, AOM 52.8%), a large proportion of antibiotic-days prescribed were in excess of the minimally recommended duration for each infection (UTI 16.8%, 19.3%, AOM 25.5%). Cluster analysis yielded two clusters of prescribers, with those in one cluster more commonly prescribing durations at the lower end of recommended interval, and the others more commonly prescribing longer durations for all three infections reviewed. No statistically significant differences were found between clusters by career stage or training background.

While guideline-concordant antibiotic prescribing was generally high, auditing antibiotic prescriptions identified shifting prescribing towards the minimally recommended duration as a potential opportunity to reduce antibiotic use among children for these infections.

Symbiosis between the host and intestinal microbial communities is essential for human health. Disruption in this symbiosis is linked to gastrointestinal diseases, including inflammatory bowel diseases, as well as extra-gastrointestinal diseases. Unbalanced gut microbiome or gut dysbiosis contributes in multiple ways to disease frequency, severity and progression. Microbiome taxonomic profiling and metabolomics approaches greatly improved our understanding of gut dysbiosis features; however, the precise mechanisms involved in gut dysbiosis establishment still need to be clarified. The aim of this review is to present new actors and mechanisms underlying gut dysbiosis formation following parasitic infection or in a context of altered Paneth cells, revealing the existence of a critical crosstalk between Paneth and tuft cells to control microbiome composition.

The prevalence of inflammatory bowel disease (IBD) is increasing globally. In this context, identifying risk factors for severe disease is important. We examined how race/ethnicity and immigration status influence IBD manifestations, treatments, and outcomes in a diverse, tertiary-care safety-net hospital.

We conducted a single-center retrospective review of all IBD inpatients and outpatients treated from 1997-2017. Using logistic regression modeling, we compared disease onset, treatment, and outcomes by race (White, Black, Hispanic, or Asian) and immigration status (US-born vs foreign-born).

A total of 577 patients were identified, of which 29.8% were White, 27.4% were Hispanic, 21.7% were Black, and 13.0% were Asian. Compared to Whites, Asians were more likely to be male (odds ratio [OR] 2.63, 95% confidence interval [CI]: 1.45, 5.00), whereas Blacks were more likely to be diagnosed with Crohn's disease (OR 1.75, 95% CI: 1.10, 2.77) and more likely to undergo IBD-related intestinal resection (OR 2.49, 95% CI: 1.40, 4.50). Compared to US-born patients, foreign-born patients were more likely to be diagnosed with ulcerative colitis (OR 1.77, 95% CI: 1.04, 3.02). They were also less likely to be diagnosed before 16 years of age (OR 0.19, 95% CI: 0.08, 0.41), to have undergone intestinal resections (OR 0.39, 95% CI: 0.19, 0.83), to have received biologics (OR 0.43, 95% CI: 0.25, 0.76), or to have had dermatologic manifestations (OR 0.12, 95% CI: 0.03, 0.41).

IBD phenotype varies by race, although foreign-born patients of all races show evidence of later-onset and milder disease. These findings may aid in disease prognostication and clinical management and, furthermore, may provide insight into intrinsic and environmental influences on IBD pathogenesis.

The first 1000 days of life is a critical period that contributes significantly to the programming of an individual's future health. Among the many changes that occur during this period early in life, there is growing evidence that the establishment of healthy gut microbiota plays an important role in the prevention of both short- and long-term health problems. Numerous publications suggest that the quality of the gut microbiota colonisation depends on several dietary factors, including breastfeeding. In this respect, a relationship between breastfeeding and the risk of inflammatory bowel disease (IBD) has been suggested. IBDs are chronic intestinal diseases, and perinatal factors may be partly responsible for their onset. We review the existence of links between breastfeeding and IBD based on experimental and clinical studies. Overall, despite encouraging experimental data in rodents, the association between breastfeeding and the development of IBD remains controversial in humans, partly due to the considerable heterogeneity between clinical studies. The duration of exclusive breastfeeding is probably decisive for its lasting effect on IBD. Thus, specific improvements in our knowledge could support dietary interventions targeting the gut microbiome, such as the early use of prebiotics, probiotics or postbiotics, in order to prevent the disease.

Most antibiotics are prescribed in ambulatory setting and at least 30% to 50% of these prescriptions are unnecessary. The use of antibiotics when not needed promotes the development of antibiotic resistant organisms and harms patients by placing them at risk for adverse drug events and Clostridioides difficile infections. National guidelines recommend that health systems implement antibiotic stewardship programs in ambulatory settings. However, uptake of stewardship in ambulatory setting has remained low. This review discusses the current state of ambulatory stewardship in the United States, best practices for the successful implementation of effective ambulatory stewardship programs, and future directions to improve antibiotic use in ambulatory settings.

The intestinal microbiome plays a strong, complementary role in the development and integrity of the intestinal epithelium. This biology is crucial for intestinal adaptation, particularly after the mucosal insults that lead to short bowel syndrome (SBS). The purpose of this review is to discuss relationships between the intestinal microbiota and the physiology of intestinal adaptation.

We will address interactions between the intestinal microbiome and nutritional metabolism, factors leading to dysbiosis in SBS, and common compositional differences of the gut microbiome in SBS patients as compared to healthy controls. We will also discuss novel opportunities to expand diagnostic and therapeutic interventions in this population, by using our knowledge of the microbiome to manipulate luminal bacteria and study their resultant metabolites. As microbial therapeutics advance across so many fields of medicine, this review is timely in its advocacy for ongoing research that focuses on the SBS population.Our review will discuss 4 key areas: 1) physiology of the intestinal microbiome in SBS, 2) clinical and therapeutic insults that lead to a state of dysbiosis, 3) currently available evidence on microbiome-based approaches to SBS management, and 4) opportunities and innovations to inspire future research.

The clinical implications of this review are both current, and potential. Understanding how the microbiome impacts intestinal adaptation and host physiology may enhance our understanding of why we experience such clinical variability in SBS patients' outcomes. This review may also expand clinicians' understanding of what 'personalized medicine' can mean for this patient population, and how we may someday consider our nutritional, therapeutic, and prognostic recommendations based on our patients' host, and microbial physiology.

Early-life environmental exposures play a significant role in shaping long-lasting immune phenotypes and disease susceptibility. Nevertheless, comprehensive understanding of the developmental programming of immunity is limited. We propose that the vertebrate immune system contains durable programmable components established through early environmental interactions and maintained in a stable and homeostatic manner. Some immune components, such as immunological memory, are intrinsically programmable. Others are influenced by conditions during critical developmental windows in early life, including microbiota, hormones, metabolites, and environmental stress, which impact programming. Developmental immune programming can promote adaptation to an anticipated future environment. However, mismatches between predicted and actual environments can result in disease. This is relevant because understanding programming mechanisms can offer insights into the origin of inflammatory diseases, ideally enabling effective prevention and treatment strategies.

Aim: Preventing unnecessarily long durations of antibiotic therapy is a key opportunity to reduce antibiotic overuse in children 2 years of age and older with acute otitis media (AOM). Pragmatic interventions to reduce durations of therapy that can be effectively scaled and sustained are urgently needed. This study aims to fill this gap by evaluating the effectiveness and implementation outcomes of two low-cost interventions of differing intensities to increase guideline-concordant antibiotic durations in children with AOM. Methods: The higher intensity intervention will consist of clinician education regarding guideline-recommended short durations of antibiotic therapy; electronic health record (EHR) prescription field changes to promote prescribing of recommended short durations; and individualized clinician audit and feedback on adherence to recommended short durations of therapy in comparison to peers, while the lower intensity intervention will consist only of clinician education and EHR changes. We will explore the differences in implementation effectiveness by patient population served, clinician type, clinical setting and organization as well as intervention type. The fidelity, feasibility, acceptability and perceived appropriateness of the interventions among different clinician types, patient populations, clinical settings and intervention type will be compared. We will also conduct formative qualitative interviews with clinicians and administrators and focus groups with parents of patients to further inform the interventions and study. The formative evaluation will take place over 1.5 years, the interventions will be implemented over 2 years and evaluation of the interventions will take place over 1.5 years. Discussion: The results of this study will provide a framework for other healthcare systems to address the widespread problem of excessive durations of therapy for AOM and inform national antibiotic stewardship policy development. Clinical Trial Registration: NCT05608993 (ClinicalTrials.gov).

Inflammatory bowel disease (IBD), including subtypes Crohn disease and ulcerative colitis is a chronic inflammatory disorder most often diagnosed in young adulthood. The incidence and prevalence of pediatric-onset IBD is increasing globally. IBD is likely caused by an interplay of multiple environmental factors resulting in a dysregulated mucosal response to the commensal intestinal microbiota in genetically predisposed individuals. This article provides an overview of pediatric IBD epidemiology and environmental risk factors associated with its development, such as the Hygiene Hypothesis, air pollution, greenspace and blue space, neonatal factors, antibiotics, and diet.

Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort.

This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs.

During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P = .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P = .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P = .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity.

Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal anti-inflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates.

Early-life environmental triggers are thought to play a larger role in pediatric-onset inflammatory bowel disease (pIBD) compared to adult-onset IBD. We aimed to assess the risk of developing pIBD after exposure to oral antibiotics during the first 5 years of life.

In a nation-wide cohort study, we identified all patients diagnosed with pIBD (<18 years at diagnosis) in Denmark between 1995 and 2018 from the National Patient Registry and matched them with up to 10 reference individuals. Antibiotic exposure was defined as being prescribed antibiotics during first 5 years of life. Data were retrieved from the National Prescription Register. Outcome was developing pIBD. Risk estimates are presented by hazard ratios (HR) with 95% confidence intervals (CI).

We identified 1927 pIBD patients and 18,318 reference individuals. Oral antibiotic exposure during the first 5 years of life was associated with a higher risk of developing pIBD (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). The risk was also increased if patients had ≥4 antibiotic prescriptions compared to no antibiotics (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). Broad-spectrum antibiotics increased the risk of pIBD compared to narrow-spectrum antibiotics (HR = 1.29 [95% CI: 1.2-1.4], P < 0.0001). When stratified by IBD subtypes, only Crohn disease was significantly associated with exposure to antibiotics (HR = 1.37 [95% CI: 1.1-1.7], P = 0.002).

In this nationwide registry-based study, we found that oral antibiotic exposure during first 5 years of life was associated with an increased risk of pIBD. Repeated antibiotic exposures increased risk estimates.

Objective Early onset neonatal sepsis (EONS) remains a significant cause of morbidity and mortality in newborns in the immediate postnatal period. High empiric antibiotic use in well-appearing infants with known risk factors for sepsis led the American Academy of Pediatrics (AAP) to revise its 2010 guidelines for the evaluation and management of EONS to avoid overuse of antibiotics. In this recent clinical report, the AAP provided a framework that outlined several evidence-based approaches for sepsis risk assessment in newborns that can be adopted by institutions based on local resources and structure. One of these approaches, the sepsis risk calculator (SRC) developed by Kaiser Permanente, has been widely validated for reducing unnecessary antibiotic exposure and blood work in infants suspected of having EONS. In order to determine the utility and safety of modifying our institution's protocol to the SRC, we implemented a two-phased approach to evaluate the use of SRC in our newborn nursery. Phase 1 utilized a retrospective review of cases with SRC superimposition. If results from Phase 1 were found to be favorable, Phase 2 initiated a trial of the SRC for a six-month period prior to complete implementation. Methods Phase 1 consisted of retrospectively applying the SRC to electronic medical records (EMR) of infants ≥ 35 weeks' gestational age admitted to the newborn nursery with risk factors for EONS between June 2016 and May 2017. We compared actual antibiotic use as determined by the unit's EONS protocol for evaluation and management based on 2010 Centers for Disease Control and Prevention (CDC) and AAP guidelines to SRC-recommended antibiotic use. We used EMR to determine maternal and infant data, blood work results, and antibiotic usage as well as used daily progress notes by the clinical team to determine the clinical status of the infants retrospectively. Based on the projected reduction in blood work and antibiotics use with the retrospective superimposition of SRC on this cohort of infants and identification of our high-risk patient subset, we developed a novel, hybrid EONS protocol that we implemented and assessed throughout Phase 2, a six-month period from August 2018 to January 2019, as a prospective observational study. Results Phase 1 (SRC superimposition) demonstrated that the use of the SRC would have reduced empiric antibiotic use from 56% to 13% in the study cohort when compared with 2010 CDC/AAP guidelines. However, these same findings revealed use of the SRC would have resulted in delayed evaluation and initiation of antibiotics in 2 of 4 chorioamnionitis-exposed infants with positive blood cultures. During Phase 2 (n=302), with the implementation of our tailored approach (SRC implementation with additional blood culture in chorioamnionitis-exposed infants), 12 (4%) neonates received empiric antibiotic treatment compared to nine (3%) neonates who would have been treated per strict adherence to SRC recommendations. No neonate had culture-positive EONS. Continued use of 2010 CDC/AAP guidelines would have led to empiric antibiotic use in 38 (12.6%) infants in this cohort. Conclusion We developed a novel hybrid approach to the evaluation and management of neonates at increased risk of EONS by tailoring SRC recommendations to our safety-net population. Our stewardship effort achieved a safe and significant reduction in antibiotic usage compared to prior usage determined using CDC/AAP guidelines.

The association between antibiotic use and risk of inflammatory bowel disease (IBD), particularly among adults, remains unclear. Furthermore, there is a scarcity of data among non-Western countries.

To investigate the association and dose-response relationships between antibiotic use and subsequent IBD risk across all ages METHODS: This population-based case-control analysis used data from the Korean National Health Insurance Service database (2004-2018). We compared 68,633 patients with new-onset IBD to matched controls (n = 343,165) using multivariable conditional logistic regression analysis. We also examined the dose-response relationship using non-linear regression analysis, and separately analysed childhood-onset IBD (aged ≤14 years) risk following early-life antibiotic exposure.

The mean age at diagnosis was 45.2 ± 16.8 years. Antibiotic prescriptions between 2 and 5 years before diagnosis significantly increased the odds of developing IBD (adjusted odds ratio [OR], 1.24; 95% confidence interval [CI]: 1.21-1.27). Additionally, sensitivity analysis revealed an elevated risk up to 9 years before diagnosis. Broad-spectrum antibiotics increased IBD risk, independent of gastroenteritis. A distinct dose-response relationship was observed irrespective of the IBD subtype and study population (all p < 0.001). Furthermore, antibiotic exposure within the first year of life was linked with the risk of childhood-onset IBD (OR, 1.51; 95% CI: 1.25-1.82).

Broad-spectrum antibiotics dose-dependently increased the risk for IBD in the Korean population. Our findings provide a fundamental epidemiological basis for identifying antibiotic use as a significant risk factor for IBD across different environmental backgrounds.

Recent advances in our understanding of the pathogenesis of inflammatory bowel disease (IBD) have highlighted the complex interplay between the genome, the epigenome, and the environment. Despite the exciting advances in genomics that have enabled the identification of over 200 susceptibility loci, these only account for a small proportion of the disease variance and the estimated heritability in IBD. It is likely that gene-environment (GxE) interactions contribute to "missing heritability" and these may act through epigenetic mechanisms. Several environmental factors, such as the microbiome, nutrition, and tobacco smoking, induce alterations in the epigenome of children and adults, which may impact disease susceptibility. Other mechanisms for GxE interactions are also directly pertinent in early life. We discuss a model in which environmental factors imprint disease risk in a window of susceptibility during infancy that may contribute to later disease onset, whereas other elements of the exposome act later in life and contribute directly to the pathogenesis and course of the disease. Understanding the mechanisms underlying GxE interactions may provide the basis for new therapeutic targets or preventative strategies for IBD.