BACKGROUND:Recent work suggests an altered duodenal mucosa-associated microbiota (d-MAM) in patients with functional dyspepsia (FD) when compared to controls. This may reflect alterations in host-microbiome homeostasis. Given the specific mucosal immune signatures identified in FD, we hypothesize that these signatures are associated with specific microbial changes. We aim to profile the d-MAM to identify microbes associated with known changes in FD mucosal and peripheral immunity. METHODS:Upper gastrointestinal biopsies were collected from 11 outpatient controls and 17 FD patients. Specific biopsies were collected for 16S rRNA sequencing, histology, and mucosal lamina propria mononuclear cell (LPMC) isolation. Where available, peripheral blood mononuclear cells (PBMC) were isolated. PBMC and LPMC populations were analyzed for T-cell populations by flow cytometry. KEY RESULTS:Comparing the histological and immune measures between FD and controls revealed significant differences with decreased villi goblet cells and increased LPMC CD4 Central Memory, LPMC CD8, and PBMC CD4+ Central Memory Th17 in FD patients. Specific microbiome associations found that in controls, villi goblet cells positively correlated with Massilia and negatively with Exiguobacterium. Additionally, controls had a negative correlation between LPMC CD4 Central Memory and Veillonella. Notably, FD patients demonstrated a significant negative correlation between LPMC CD8 and Sulfophobococcus, and a positive correlation between PBMC CD4+ Central Memory Th17 and both Gemella and Fusobacterium. CONCLUSIONS AND INFERENCES:Our findings contribute to a growing body of evidence, indicating FD patients exhibit distinct alterations in d-MAM and immune profiles compared to controls. Furthermore, the immune-microbiome associations within control populations were absent in FD patients, suggesting a loss of host-microbiome homeostasis that may contribute to FD pathophysiology.

The gastrointestinal (GI) microbiome is intrinsically linked to human health and disease, with dietary intake being a major modifiable variable contributing to microbial colonization and fermentation. Diet-microbiome studies are heterogeneous in the methods used to assess and record dietary intake, to sequence the microbiome data, and to analyze associations. To capture the extent of these inconsistencies, we performed a systematic scoping review to synthesize the information on methods used to assess and compare relationships between diet and the GI microbiome in human studies. Our search identified papers with metrics of both dietary intake and the GI microbiome (using either 16S rRNA or metagenomic shotgun sequencing) and specific diet-microbiome associative analysis. The databases searched were MEDLINE, EMBASE, CINAHL, Cochrane, and Google Scholar, and the search produced 22, 228 unique records after de-duplication. After full-text screening, 1,262 articles were selected for full extraction. A subset of 295 studies captured whole dietary intake and investigated associations with the GI microbiome. This subset assessed diet using 84 different food frequency questionnaires, 12 alternative surveys, and 4 types of diet recalls or diaries ranging from 1 to 14 days. Fifty-five percent (n = 163) of studies investigated habitual dietary intake, 35% (n = 101) investigated recent dietary intake, and 10% (n = 30) used methods to assess both. Eighty-one percent of studies employed 16S rRNA sequencing, with wide variation in extraction, sequencing, pre-processing, and annotation methods. Gaps in the reporting of the methods for each step of the sequencing and analysis process were evident, limiting future comparison of study outcomes. Microbiome-specific statistical methods were used in 11% of the subset-predominantly correlational methods that are not recommended for microbiome data. In conclusion, this review revealed extensive inconsistencies within the exploratory diet-microbiome studies, despite the existence of recommendations to assist researchers. Collaborative efforts to develop consensus in methods and reporting are needed to substantially progress the obtaining of high-quality evidence and meta-analysis in the diet-microbiome research field.

BACKGROUND:The irritable bowel syndrome (IBS) has long been considered a functional disorder, but recent work has demonstrated clear biological signatures in immune, microbiome and enteric nervous systems of patients with IBS. Despite this new knowledge, there is still no clear biological marker of IBS, with patient symptom reporting and exclusion of organic disease the main criteria for diagnosis. We aimed to perform a systematic review and meta-analysis to identify consistent biomarkers for IBS in serum and stool samples. METHODS:We searched Medline, EMBASE, Cochrane Library, Web of Science and Scopus to obtain all relevant publications published between 1992 and January 2026. Original, peer-reviewed research articles including adults with IBS and healthy or outpatient controls, and/or patients with organic gastrointestinal conditions (e.g. IBD) were included. All articles had quantification of blood and faecal markers between IBS and controls. Descriptive data presented as median and range or median (interquartile range) was converted to mean ± SD. To account for methodological assay differences between studies, standardised mean difference (SMD) with 95% confidence interval was used as the primary outcome measure for the meta-analyses, with a random effects model fitted to the data. FINDINGS:The search strategy identified 55,444 citations across all databases. 124 studies were included encompassing 14,930 patients with IBS, 7544 healthy/asymptomatic controls and 4317 patients with organic diseases. The top serum discriminators between IBS and healthy controls were TNF-⍺ (13 studies, 1025 controls and 1244 IBS, SMD = 2.74, 95% CI = 0.70, 4.70, p = 0.006), IL-6 (13 studies, 736 controls and 1022 IBS, SMD = 1.87, 95% CI = 0.13, 3.61, p = 0.035) and IFN-ɣ (4 studies, n = 195 controls, n = 372 IBS, SMD = 2.79, 95% CI = 1.07, 4.51, p = 0.002). For faecal markers calprotectin was significantly higher in patients with IBS over controls (11 studies, 1624 controls and 1383 IBS, SMD = 0.75, 95% CI = 0.30, 1.21, p = 0.001), while faecal valerate levels were lower in IBS versus controls (4 studies, 290 controls and 488 IBS, SMD = -0.79, 95% CI = -1.48, -0.11, p = 0.02). For discriminating IBS overall from organic diseases, serum albumin (4 studies, 282 IBS and 312 organic, SMD = 2.15, 95% CI = 0.20, 4.11, p = 0.031) and faecal calprotectin (16 studies, 1591 IBS and 1685 organic, SMD = -1.13, 95% CI = -1.51, -0.75, p < 0.0001) were significantly different. In discriminating IBS subtypes from controls, only diarrhoeal IBS (IBS-D) could be distinguished by albumin (3 studies, 248 controls and 219 IBS-D, SMD = -0.39, 95% CI = -0.68, -0.11, p = 0.007) and IL-6 (4 studies, 153 IBS-D and 169 controls, SMD = 2.53, 95% CI = 0.86, 4.21, p = 0.003). Heterogeneity across the studies ranged from moderate to high, but few overly influential studies were identified between comparisons. INTERPRETATION:Patients with IBS exhibit increased peripheral cytokine levels that are consistent with reports of increased epithelial permeability and may be important in distinguishing subgroups of IBS patients. Patients with IBS also demonstrated higher faecal calprotectin levels than healthy individuals, although these levels were still significantly lower than patients with organic diseases. Similarly, patients with IBS-D have lower serum albumin levels compared to healthy controls, while patients with organic disease had lower levels compared to patients with IBS, irrespective of subtype. There are clear biological signatures at play in IBS patients that may be useful clinically in establishing IBS diagnosis and may indicate the mechanisms of disease symptoms. FUNDING:National Health and Medical Research Council Centre for Research Excellence in Digestive Health (NJT, SK) G180219.

Introduction Understanding the microbial changes within the surgical site may enhance our understanding of the origin and subsequent role of microbes in the causation of incisional surgical site infections (SSIs). In this study we used 16S rRNA sequencing to establish the dynamic microbiota of the surgical site in patients undergoing bowel resection.Methods The surgical site of patients undergoing bowel resection was sampled at four different time points: on initial incision of the surgical site prior to peritoneal breach; on completion of the operation following fascial closure; from the lumen of the resected segment of bowel; and from the superficial skin of the surgical site in the follow-up period. DNA was extracted and used for 16S rRNA amplicon gene sequencing to establish the dynamic microbiota changes that occur within the surgical site.Results A total of 250 samples were collected from 50 patients. The native subcutaneous abdominal plane is a low biodiversity Gram positive aerobic community, which following resection of the bowel, reflects a high biodiversity obligate anaerobic community, suggestive of contamination from the GI lumen. The follow-up sampling shows resilience of skin commensals, depletion of the most abundant luminal microbes with emergence of Enterobacteriaceae and Staphylococaceae. These two families thrive to colonise the follow up wound in all patients, highlighting potential pathways of infection in colorectal surgery.Conclusions Whilst this study does not demonstrate causality, it does add to the body of literature in deciphering the poorly understood pathogenesis of SSIs in colorectal patients. This study should be used as a platform to perform further multiomics-based investigations to try and underpin the exact mechanisms behind SSIs in this form of surgery, thus allowing us to improve preventative strategies in the future.

Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines, as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases, such as the inflammatory, proliferative, and remodeling phase, may result in severe complications, characterized by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer to understanding the underlying AL etiology. It is clear that ALs are multifactorial in nature and contribute to by patient-, technical-, and biological-related factors; however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation, and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors to failed anastomotic healing and AL etiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing, and describe the advancements made to improve AL rates by targeting the healing response.

Inflammatory Bowel Diseases (IBD) are lifelong conditions. Current therapeutic approaches target inflammatory signalling rather than improving barrier permeability or repair. The gut microbiome provides an exciting opportunity for novel drug discovery to leverage its role in healthy gut homeostasis. There is a clear need to identify bioactive molecules within the microbiota that could protect the intestinal barrier. Our group has developed a systematic pipeline using metatranscriptomic data to identify, produce, purify, and test microbial proteins in IBD, pinpointing multiple novel microbiota-derived proteins linked to disease activity. We identified a new microbiota protein (BMG-1), that specifically inhibits human neutrophil elastase, a pathogenic protease in IBD. This protease inhibition allows protection of the intestinal epithelial barrier from permeability and promotes epithelial healing. BMG-1 also reduces colon damage in a mouse model of colitis. Finally, we show that the native BMG-1 protein is not only present in human stool, but also significantly decreased in patients with high IBD activity. These findings demonstrate the gut microbiota can specifically regulate the balance of protease/anti-protease activity in the colon, and this represents a novel therapeutic strategy for IBD.

Background Gastrointestinal dysfunction, including constipation, is a common non-motor feature of Parkinson’s disease (PD) and often precedes motor symptoms. The gut microbiome interacts with the host through neural, hormonal, and immune pathways, yet whether constipation represents a cause or consequence of PD remains unclear. Therefore, we aimed to interrogate the associations between microbiome and immune alterations in relation to constipation to provide novel insight into microbiome-gut-brain axis mechanisms in PD. Methods We analysed peripheral blood mononuclear cells (PBMCs) for circulating gut-homing T cell populations and used shotgun metagenomics to profile the stool microbiome composition and functional capacity in PD patients (n=18), healthy controls (n=21), and individuals with constipation-predominant irritable bowel syndrome (IBS-C; n=8). Associations between immune markers and microbial taxa were assessed, and functional pathway differences were evaluated. Results Circulating gut-homing T cell frequencies did not differ significantly between PD and controls, but constipated PD patients showed a trend toward increased circulating gut-homing T cells. Microbiome beta-diversity analyses revealed distinct taxonomic shifts in PD and IBS-C, while functional capacity was largely conserved. Of the differential functional pathways tryptophan biosynthesis, polyamine production, and vitamin B metabolism, processes critical for neurotransmitter synthesis, epithelial integrity, and neuroimmune regulation were reduced in PD compared to IBS-C. Conclusion Our findings highlight unique microbial and immune signatures in PD, partially overlapping with IBS-C, and underscore the importance of microbial metabolic pathways in gut-brain axis disorders. Collectively our findings suggest a contribution to dopaminergic dysfunction, neuroinflammation, and impaired gut motility. Future longitudinal studies are needed to clarify causal relationships and inform targeted interventions for PD-related gastrointestinal dysfunction.

INTRODUCTION AND AIMS: Disorders of gut-brain interaction (DGBI) are classified as chronic gastrointestinal symptoms with no apparent structural/organic origin. There is evidence that high-intensity interval training (HIIT) is beneficial for gut health, though no studies have explored this in people with DGBI. Therefore, this study assessed the efficacy, feasibility and safety of combined aerobic and resistance HIIT (C-HIIT) in people with DGBI. METHODS: Twenty-five low-active people with a DGBI (age 51.5±17.5years, 80% female, 84% irritable bowel syndrome) underwent 8weeks of usual care (waitlist control) before participating in 8weeks of C-HIIT (1x4min aerobic HIIT @ 85-95% HRpeak plus 8x1min whole-body resistance training @ RPE ≥8/10, 3times/week). Efficacy outcomes, assessed at baseline, 8weeks (post-control) and 16weeks (post-C-HIIT), included gastrointestinal symptoms (Irritable Bowel Syndrome-Symptom Severity scale), anxious and depressive symptoms (Hospital Anxiety and Depression scale), cardiorespiratory fitness (VO2peak), and neuromuscular fitness (30sec sit-to-stand; dominant hand grip strength). Statistical analyses were conducted using R; change data are presented as mean ± standard deviation. Attendance to sessions and adherence to the exercise prescription was assessed via training logs. Adverse events were also recorded throughout the intervention period. RESULTS: Participants attended 100% of sessions, though the average adherence to the C-HIIT prescription was 42±28.9%. Compared with usual care, 8weeks of C-HIIT resulted in significant improvement in gastrointestinal symptoms (CON -0.5±80.0 vs C-HIIT -48.1±75.5, p=0.024) and cardiorespiratory fitness (-0.6±2.4ml/kg/min vs 3.6±3.1ml/kg/min, p<0.001). There were no between-group differences in anxiety symptoms (-0.4±1.7 vs -1.2±2.1, p=0.1), depressive symptoms (0±2.2 vs -1.2±2.3, p=0.06), dominant handgrip strength (0.17±2.8kg vs 0.55±2.5kg, p=0.65) and 30sec sit-to-stand score (0.31±4.2 vs 0.33.±2.7, p=0.49). No serious adverse events were recorded. CONCLUSION: C-HIIT improved gastrointestinal and cardiorespiratory health in people with DGBI, despite low adherence to the prescription. C-HIIT therefore offers an effective exercise option for this population, that is safe and time efficient.

INTRODUCTION:Surgical Site Infection (SSI) of an abdominal incision is a dreaded infectious complication following colorectal surgery. Understanding the intraoperative microbiology holds the key to prevention. Genomic sequencing has revolutionised culture-independent techniques, allowing for a more sensitive tool in microbial detection. The purpose of this study is to determine whether an aberrant microbiota is present within the intraoperative surgical site in patients that develop an SSI. METHODS:The subcutaneous abdominal surgical site of patients undergoing elective bowel resection was opportunistically sampled, following fascial closure. DNA was recovered from the swabs and used for 16S rRNA gene amplicon sequencing. The intraoperative microbiota was compared in those with and without a subsequent SSI with focus on alpha diversity and beta diversity, as well as taxonomic composition. RESULTS:16/123 patients developed an SSI. The bacterial profile within the surgical site showed a strong presence of obligate anaerobes in all patients. Chao1, Shannon, and Simpson measures of alpha diversity from the intraoperative swabs were all significantly increased in SSI patients (p = 0.05, 0.05 and 0.05, respectively). Beta diversity demonstrated no significant separation between patients (Bray-Curtis dissimilarity index, PERMANOVA p = 0.394). CONCLUSIONS:To the best of our knowledge this is the first study to demonstrate an aberrant intraoperative microbiota of the surgical site associated with subsequent infection. Pending validation studies, this provides a target for the strategic manipulation of the surgical site to reduce the burden of infection.

Eosinophilic gastrointestinal disorders (EGIDs) comprise eosinophilic oesophagitis (EoE) and non-EoE EGIDs; these diseases may be increasing in prevalence and are likely underdiagnosed. Mortality is not increased in EoE but is in gastric and small intestinal EGIDs. A subtle increase in eosinophils has also been observed in other GI diseases including functional dyspepsia in the duodenum. Targeted drug therapy can markedly reduce eosinophil infiltration, although symptom response is more variable, suggesting that non-eosinophil pathways play a role in pathogenesis. Current standard therapies for EoE supported by randomized trials include proton pump inhibitors, corticosteroids (topical), diet restriction, and dupilumab, inhibiting IL-4/IL-13 signaling. In non-EoE EGIDs where little randomized trial data exist, management is based on a combination of dietary elimination and corticosteroids or immunomodulators; mast cell stabilizers and antihistamine therapy may have a role. The role of combination therapies is unclear. Pharmacologic approaches in testing include new steroid preparations and delivery systems; dupilumab in eosinophilic gastritis; and anti-IL-13, anti-IL-5, anti-IL-2, and anti-IL-15 receptor targeting monoclonal antibodies.

BACKGROUND:Alterations in the GI microbiome have been associated with increased anastomotic leak risk. Oral antibiotics and bowel preparations may both reduce anastomotic leak rates. OBJECTIVE:In patients undergoing colorectal surgery, we aimed to examine the impact of oral antibiotic use, bowel preparation, and other perioperative factors on the mucosa-associated microbiota and investigate the association with anastomotic leak rates. DESIGN:We opportunistically sampled Australian patients undergoing colorectal resection for any indication of anastomosis; mucosal swabs were taken from the proximal and distal extent of the resected specimen immediately after extraction. SETTINGS:A single-site, public tertiary referral hospital of 694 beds with an accredited specialist colorectal unit in Newcastle, Australia. PATIENTS:Of 192 patients, 31 patients received oral antibiotics presurgery (19 of whom also underwent mechanical preparation). In total, 31 patients received mechanical preparation and 58 received enema presurgery. Ninety-one patients did not receive antibiotics or undergo bowel preparation. MAIN OUTCOME MEASURES:The influence of patient factors on mucosa-associated microbiota composition and associations to rate of anastomotic leaks. RESULTS:The leak rate was 15% (N = 28/192). Preoperative oral antibiotic manipulation and bowel preparation minimally affected the mucosa-associated microbiota, but neither were associated with anastomotic leaks. Erythromycin (N = 14/192) had the greatest impact on the mucosa-associated microbiota. Of the different bowel preparation regimens, excluding patients given antibiotics, only Fleet enemas (N = 58/161) had a significant impact on the mucosa-associated microbiota. Bowel preparation was not associated with the occurrence of anastomotic leaks. There were only subtle differences observed in the mucosa-associated microbiota between patients who did and those who did not have anastomotic leaks. LIMITATIONS:A modest number of patients who received antibiotics were included. CONCLUSIONS:This is the largest series of routine colorectal anastomoses for which the mucosa-associated microbiota adjacent to the anastomoses was examined. We show that antibiotics and bowel preparation in the preoperative period exert only limited effects on the mucosa-associated microbiota and conclude that there are no obvious mucosa-associated microbiota characteristics that are predictive of an anastomotic leak. See Video Abstract . LOS ANTIBITICOS PREOPERATORIOS Y LA PREPARACIN INTESTINAL MECNICA AFECTAN A LA MICROBIOTA ASOCIADA A LA MUCOSA COLNICA, PERO NO A LA TASA DE FUGAS ANASTOMTICAS TRAS LA RESECCIN COLORRECTAL:ANTECEDENTES:Las alteraciones en el microbioma gastrointestinal se han asociado con un mayor riesgo de fugas anastomóticas. Los antibióticos orales y los preparados intestinales pueden reducir las tasas de fugas anastomóticas.OBJETIVO:En pacientes sometidos a cirugía colorrectal, nuestro objetivo fue examinar el impacto del uso de antibióticos orales, la preparación intestinal y otros factores perioperatorios en la microbiota asociada a la mucosa e investigar la asociación con las tasas de fugas anastomóticas.DISEÑO:Se tomaron muestras oportunistas de pacientes australianos sometidos a resección colorrectal por cualquier indicación con anastomosis, se tomaron muestras de mucosa de la extensión proximal y distal de la muestra resecada inmediatamente después de la extracción.AJUSTES:Un único centro, hospital público de referencia terciaria de 694 camas con una unidad especializada acreditada en colorrectal en Newcastle, Australia.PACIENTES:De 192 pacientes, se identificó que 31 pacientes recibieron antibióticos orales antes de la cirugía. Treinta y un pacientes recibieron preparación mecánica y 58 recibieron enema antes de la cirugía.PRINCIPALES MEDIDAS DE VALORACIÓN:La influencia de los factores del paciente en la composición de la microbiota asociada a la mucosa y las asociaciones con la tasa de fugas anastomóticas.RESULTADOS:La tasa de fugas fue del 15 % (N = 28/192). La manipulación preoperatoria con antibióticos orales y la preparación intestinal afectaron mínimamente a la microbiota asociada a la mucosa, pero ninguna de ellas se asoció a fugas anastomóticas. La eritromicina (N = 14/192) tuvo el mayor impacto en la microbiota asociada a la mucosa. De los diferentes regímenes de preparación intestinal, excluyendo a los pacientes a los que se les administraron antibióticos, solo los enemas de flúor (N = 58/161) tuvieron un impacto significativo en la microbiota asociada a la mucosa. La preparación intestinal no se asoció con la aparición de fugas anastomóticas. Solo se observaron diferencias sutiles en la microbiota asociada a la mucosa entre los pacientes con fugas anastomóticas y los pacientes sin fugas anastomóticas.LIMITACIONES:El número de receptores de antibióticos incluidos fue modesto.CONCLUSIONES:Esta es la mayor serie de anastomosis colorrectales rutinarias en las que se ha examinado la microbiota asociada a la mucosa adyacente a las anastomosis. Demostramos que los antibióticos y la preparación intestinal en el período preoperatorio ejercen solo efectos limitados sobre la microbiota asociada a la mucosa y concluimos que no hay características obvias de la microbiota asociada a la mucosa que sean predictivas de una fuga anastomótica. (Traducción--Ingrid Melo ).

A growing proportion of the non-celiac population experience adverse symptoms to gluten. The pathogenesis of non-coeliac gluten sensitivity (NCGS) is unclear, but elevated duodenal eosinophils and altered mucosa-associated microbiota (MAM) populations have been reported. Given the microbiome’s role in gluten digestion and its susceptibility to antibiotics, we hypothesised that altering the microbiome with antibiotics would modify immune responses to gluten in mice. BALB/C mice consuming gluten-free chow received amoxicillin/clavulanate (5mg/kg) or PBS-vehicle daily for 5 days. Mice were then treated with a 3mg wheat-gluten suspension, or vehicle, on days 4 and 5 before sacrifice on day 7. Duodenal immune cells were analysed by histology and flow cytometry, while the duodenal MAM and faecal microbiome were characterised via 16S rRNA and shotgun metagenomic sequencing, respectively. Antibiotic treatment followed by gluten reintroduction significantly reduced Staphylococcus in the duodenal MAM, enriched Bacteroides in faeces, and resulted in altered microbial carbohydrate and lipid metabolism, compared to vehicle controls. Treatment with antibiotics and gluten also increased duodenal eosinophils which positively correlated with the genus Blautia. Flow cytometry revealed that antibiotics and gluten treatment resulted in a greater proportion of active eosinophils and epithelial γδ T-cells, compared to vehicle control mice. This study demonstrated that modulating the microbiome with antibiotics was sufficient to alter the immune response to gluten in mice. These findings suggest that the microbiome may determine the capacity for gluten to induce an immune response and offers a valuable insight into potential mechanisms underlying NCGS. New & Noteworthy A mouse model examined how microbial modulation affects immune responses to gluten. Antibiotic treatment followed by gluten reintroduction reduced duodenal Staphylococcus and altered microbial carbohydrate and lipid metabolism pathways in the faecal microbiome. Antibiotics and gluten treatment resulted in increased abundance and activation of duodenal eosinophils, and elevated γδ T-cells in the duodenal epithelium. These findings highlight the role the microbiome plays in gluten-induced immune responses, providing insights into mechanisms behind non-coeliac gluten sensitivity. ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, , 2004860

The irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) are gastrointestinal (GI) diseases characterized by abdominal pain and altered bowel patterns. Fatigue and sleep disturbances are prevalent in these GI diseases, with a bidirectional relationship suggested between GI symptoms and sleep quality. If poor sleep results in increased GI symptoms, improving sleep quality may alleviate symptoms. However, if GI symptom burden independently drives poor sleep, alleviating symptoms by disease modification rather than targeting sleep should be the goal of management. Therefore, we aimed to determine if there is a relationship between gastrointestinal symptoms that influences sleep disturbances and/or fatigue. A systematic literature search in five databases was conducted using PRISMA guidelines to identify studies addressing fatigue, sleep disturbances, and GI diseases until June 2025. Inclusion criteria were original articles with confirmed GI disease diagnosis and healthy control groups. Data extraction included participant demographics, assessment tools, inflammatory findings, medication use, and disease severity. Quality assessment utilized the Newcastle Ottawa Scale. Of 14,664 articles, 18 studies were included: 7 focused on IBS, 9 on IBD, and 2 on both IBS and IBD. Findings revealed increased fatigue and sleep disturbances in GI patients compared to controls, with IBS patients reporting more fatigue and sleep disturbances than IBD. GI disease severity was strongly associated with sleep quality and fatigue levels. This systematic review highlights the strong association between fatigue and sleep disturbances and GI diseases, which are further exacerbated by disease severity.