Intergenerational protective anti-gut commensal immunoglobulin G originates in early life.

Maternal immunoglobulins of the class G (IgGs) protect offspring from enteric infection, but when, where, and how these antibodies are physiologically generated and confer protection remains enigmatic. We found that circulating IgGs in adult mice preferentially bind early-life gut commensal bacteria over their own adult gut commensal bacteria. IgG-secreting plasma cells specific for early-life gut bacteria appear in the intestine soon after weaning, where they remain into adulthood. Manipulating exposure to gut bacteria or plasma cell development before, but not after, weaning reduced IgG-secreting plasma cells targeting early-life gut bacteria throughout life. Further, the development of this anti-gut commensal IgG response coincides with the early-life interval in which goblet cell-associated antigen passages (GAPs) are present in the colon. Offspring of dams "perturbed" by B cell ablation or reduced bacterial exposure in early life were more susceptible to enteric pathogen challenge. In contrast to current concepts, protective maternal IgGs targeted translocating gut commensals in the offspring, not the enteric pathogen. These early-life events affecting anti-commensal IgG production have intergenerational effects for protection of the offspring.

Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability.

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes. STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation. RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intraindividual stability. fCal, fLcn2, and neopterin were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score, and forced expiratory volume in 1 second. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with Δbody mass index/weight-for-length z-score or ΔFEV1. CONCLUSIONS: fLcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.

Maternal Obesogenic Diet Attenuates Microbiome-Dependent Offspring Weaning Reaction with Worsening of Steatotic Liver Disease.

The mechanisms by which maternal obesity increases the susceptibility to steatotic liver disease in offspring are incompletely understood. Models using different maternal obesogenic diets (MODEs) display phenotypic variability, likely reflecting the influence of timing and diet composition. This study compared three maternal obesogenic diets using standardized exposure times to identify differences in offspring disease progression. This study found that the severity of hepatic inflammation and fibrosis in the offspring depends on the composition of the maternal obesogenic diet. Offspring cecal microbiome composition was shifted in all MODE groups relative to control. Decreased α-diversity in some MODE offspring with shifts in abundance of multiple genera were suggestive of delayed maturation of the microbiome. The weaning reaction typically characterized by a spike in intestinal expression of Tnfa and Ifng was attenuated in MODE offspring in an early microbiome-dependent manner using cross-fostering. Cross-fostering also switched the severity of disease progression in offspring dependent on the diet of the fostering dam. These results identify maternal diet composition and timing of exposure as modifiers in mediating transmissible changes in the microbiome. These changes in the early microbiome alter a critical window during weaning that drives susceptibility to progressive liver disease in the offspring.

Social and psychological adversity are associated with distinct mother and infant gut microbiome variations.

Health disparities are driven by underlying social disadvantage and psychosocial stressors. However, how social disadvantage and psychosocial stressors lead to adverse health outcomes is unclear, particularly when exposure begins prenatally. Variations in the gut microbiome and circulating proinflammatory cytokines offer potential mechanistic pathways. Here, we interrogate the gut microbiome of mother-child dyads to compare high-versus-low prenatal social disadvantage, psychosocial stressors and maternal circulating cytokine cohorts (prospective case-control study design using gut microbiomes from 121 dyads profiled with 16 S rRNA sequencing and 89 dyads with shotgun metagenomic sequencing). Gut microbiome characteristics significantly predictive of social disadvantage and psychosocial stressors in the mothers and children indicate that different discriminatory taxa and related pathways are involved, including many species of Bifidobacterium and related pathways across several comparisons. The lowest inter-individual gut microbiome similarity was observed among high-social disadvantage/high-psychosocial stressors mothers, suggesting distinct environmental exposures driving a diverging gut microbiome assembly compared to low-social disadvantage/low-psychosocial stressors controls (P = 3.5 × 10-5 for social disadvantage, P = 2.7 × 10-15 for psychosocial stressors). Children's gut metagenome profiles at 4 months also significantly predicted high/low maternal prenatal IL-6 (P = 0.029), with many bacterial species overlapping those identified by social disadvantage and psychosocial stressors. These differences, based on maternal social and psychological status during a critical developmental window early in life, offer potentially modifiable targets to mitigate health inequities.

Infants exposed in utero to Hurricane Maria have gut microbiomes with reduced diversity and altered metabolic capacity.

The gut microbiome is a potentially important mechanism that links prenatal disaster exposures with increased disease risks. However, whether prenatal disaster exposures are associated with alterations in the infant's gut microbiome remains unknown. We established a birth cohort study named Hurricane as the Origin of Later Alterations in Microbiome (HOLA) after Hurricane Maria struck Puerto Rico in 2017. We enrolled vaginally born Latino term infants aged 2 to 6 months, including n = 29 infants who were exposed in utero to Hurricane Maria in Puerto Rico and n = 34 infants who were conceived at least 5 months after the hurricane as controls. Shotgun metagenomic sequencing was performed on infant stool swabs. Infants exposed in utero to Hurricane Maria had a reduced diversity in their gut microbiome compared to the control infants, which was mainly seen in the exclusively formula-fed group (P = 0.02). Four bacterial species, including Bacteroides vulgatus, Clostridium innocuum, Bifidobacterium pseudocatenulatum, and Clostridium neonatale, were depleted in the exposure group compared to the control group. Compositional differences in the microbial community and metabolic genes between the exposure and control groups were significant, which were driven by the formula feeding group (P = 0.02 for the microbial community and P = 0.008 for the metabolic genes). Metabolic modules involved in carbohydrate metabolism were reduced in the exposure group. Prenatal maternal exposure to Hurricane Maria was associated with a reduced gut commensal and an altered microbial composition and metabolic potential in the offspring's gut. Breastfeeding can adjust the composition of the gut microbiomes of exposed infants. IMPORTANCE Climate change is a serious issue that is affecting human health. With more frequent and intense weather disasters due to climate change, there is an urgent need to evaluate and understand the impacts of prenatal disaster exposures on the offspring. The prenatal stage is a particularly vulnerable stage for disease origination. However, the impact of prenatal weather disaster exposures on the offspring's gut microbiome has not been evaluated. Our HOLA study starts to fill this knowledge gap and provides novel insights into the microbiome as a mechanism that links prenatal disaster exposures with elevated disease risks. Our major finding that reduced microbial diversity and altered metabolic capacity are associated with prenatal hurricane exposures warrants further studies to evaluate the impact of weather disasters on the unborn.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Gut microbiome composition may be an indicator of preclinical Alzheimer's disease.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with ß-amyloid (Aß) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Microbiome-targeting therapies in the neonatal intensive care unit: safety and efficacy.

Microbiome-targeting therapies have received great attention as approaches to prevent disease in infants born preterm, but their safety and efficacy remain uncertain. Here we summarize the existing literature, focusing on recent meta-analyses and systematic reviews that evaluate the performance of probiotics, prebiotics, and/or synbiotics in clinical trials and studies, emphasizing interventions for which the primary or secondary outcomes were prevention of necrotizing enterocolitis, late-onset sepsis, feeding intolerance, and/or reduction in hospitalization length or all-cause mortality. Current evidence suggests that probiotics and prebiotics are largely safe but conclusions regarding their effectiveness in the neonatal intensive care unit have been mixed. To address this ambiguity, we evaluated publications that collectively support benefits of probiotics with moderate to high certainty evidence in a recent comprehensive network meta-analysis, highlighting limitations in these trials that make it difficult to support with confidence the routine, universal administration of probiotics to preterm infants.

Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit.

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.

Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: a multinational embedded cluster crossover randomized trial (the HIKO STEC trial).

BACKGROUND: Shiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15-20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis. METHODS: We will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction. DISCUSSION: HUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT05219110 . Registered on February 1, 2022.

Study design and methods of the Wells and Enteric disease Transmission (WET) Trial: a randomised controlled trial.

INTRODUCTION: The burden of disease attributed to drinking water from private wells is not well characterised. The Wells and Enteric disease Transmission trial is the first randomised controlled trial to estimate the burden of disease that can be attributed to the consumption of untreated private well water. To estimate the attributable incidence of gastrointestinal illness (GI) associated with private well water, we will test if the household treatment of well water by ultraviolet light (active UV device) versus sham (inactive UV device) decreases the incidence of GI in children under 5 years of age. METHODS AND ANALYSIS: The trial will enrol (on a rolling basis) 908 families in Pennsylvania, USA, that rely on private wells and have a child 3 years old or younger. Participating families are randomised to either an active whole-house UV device or a sham device. During follow-up, families will respond to weekly text messages to report the presence of signs and symptoms of gastrointestinal or respiratory illness and will be directed to an illness questionnaire when signs/symptoms are present. These data will be used to compare the incidence of waterborne illness between the two study groups. A randomly selected subcohort submits untreated well water samples and biological specimens (stool and saliva) from the participating child in both the presence and absence of signs/symptoms. Samples are analysed for the presence of common waterborne pathogens (stool and water) or immunoconversion to these pathogens (saliva). ETHICS: Approval has been obtained from Temple University's Institutional Review Board (Protocol 25665). The results of the trial will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04826991.

Characterizing the Pain Experience of Children With Acute Gastroenteritis Based on Identified Pathogens.

OBJECTIVES: Pain is common with acute gastroenteritis (AGE) yet little is known about the severity associated with specific enteropathogens. We sought to explore the correlation of pain severity with specific enteropathogens in children with AGE. METHODS: Participants were prospectively recruited by the Alberta Provincial Pediatric EnTeric Infection TEam at 2 pediatric emergency departments (EDs) (December 2014-August 2018). Pain was measured (by child and/or caregiver) using the 11-point Verbal Numerical Rating Scale. RESULTS: We recruited 2686 participants; 46.8% (n = 1256) females, with median age 20.1 months (interquartile range 10.3, 45.3). The mean highest pain scores were 5.5 [standard deviation (SD) 3.0] and 4.2 (SD 2.9) in the 24 hours preceding the ED visit, and in the ED, respectively. Prior to ED visit, the mean highest pain scores with bacterial detection were 6.6 (SD 2.5), compared to 5.5 (SD 2.9) for single virus and 5.5 (SD 3.1) for negative stool tests. In the ED, the mean highest pain scores with bacterial detection were 5.5 (SD 2.7), compared to 4.1 (SD 2.9) for single virus and 4.2 (SD 3.0) for negative stool tests. Using multivariable modeling, factors associated with greater pain severity prior to ED visit included older age, fever, illness duration, number of diarrheal or vomiting episodes in the preceding 24 hours, and respiratory symptoms, but not enteropathogen type. CONCLUSION: Children with AGE experience significant pain, particularly when the episode is associated with the presence of a bacterial enteric pathogen. However, older age and fever appear to influence children's pain experiences more than etiologic pathogens.

Enteric Pathogen Testing Importance for Children with Acute Gastroenteritis: a Modified Delphi Study.

The application of clinical diagnostics for gastroenteritis in children has implications for a broad collection of stakeholders, impacting clinical care, communicable disease control, and laboratory utilization. To support diagnostic stewardship as gastroenteritis testing options continue to advance, it is critical to understand which enteropathogens constitute priorities for testing across stakeholder groups. Using a modified Delphi technique, we elicited opinions of subject matter experts to determine clinical and public health testing priorities. There was a high level of overall agreement (≥80%) among stakeholders (final round n = 15) that testing was important for Campylobacter, Escherichia coli O157 and other Shiga toxin-producing E. coli, Salmonella, Shigella, Vibrio, Yersinia, norovirus, and rotavirus. Immunocompromised children were identified as a special population that warranted the additional testing of three to four bacterial and parasitic targets. To support these clinical and public health testing priorities, diagnostic stewardship strategies can be employed, such as educating clinicians, developing new decision support tools, and using multiplex testing in concert with selective result reporting and annotation. IMPORTANCE Children with diarrhea and vomiting who seek care can be infected with a wide variety of infectious agents. This study reports findings from a survey of clinical, public health, and laboratory subject matter experts on the infectious agents that are most important to test for. The majority agreed on the importance of testing children likely infected with several bacterial agents, as well as two common viruses. Although confirming a child is positive for a viral agent is unlikely to change clinical care, participants noted the importance of monitoring these viruses for public health purposes. To avoid over-testing children, however, these results should be used to support diagnostic stewardship strategies and design new decision support tools.

Longitudinal gut virome analysis identifies specific viral signatures that precede necrotizing enterocolitis onset in preterm infants.

Necrotizing enterocolitis (NEC) is a serious consequence of preterm birth and is often associated with gut bacterial microbiome alterations. However, little is known about the development of the gut virome in preterm infants, or its role in NEC. Here, using metagenomic sequencing, we characterized the DNA gut virome of 9 preterm infants who developed NEC and 14 gestational age-matched preterm infants who did not. Infants were sampled longitudinally before NEC onset over the first 11 weeks of life. We observed substantial interindividual variation in the gut virome between unrelated preterm infants, while intraindividual variation over time was significantly less. We identified viral and bacterial signatures in the gut that preceded NEC onset. Specifically, we observed a convergence towards reduced viral beta diversity over the 10 d before NEC onset, which was driven by specific viral signatures and accompanied by specific viral-bacterial interactions. Our results indicate that bacterial and viral perturbations precede the sudden onset of NEC. These findings suggest that early life virome signatures in preterm infants may be implicated in NEC.

Maternal obesogenic diet enhances cholestatic liver disease in offspring.

Human and animal model data show that maternal obesity promotes nonalcoholic fatty liver disease in offspring and alters bile acid (BA) homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS) diet and then bred them with lean males. Offspring were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 2 weeks to induce cholestasis, and a subgroup was then fed CON for an additional 10 days. Additionally, to evaluate the role of the gut microbiome, we fed antibiotic-treated mice cecal contents from CON or HF/HS offspring, followed by DDC for 2 weeks. We found that HF/HS offspring fed DDC exhibited increased fine branching of the bile duct (ductular reaction) and fibrosis but did not differ in BA pool size or intrahepatic BA profile compared to offspring of mice fed CON. We also found that after 10 days recovery, HF/HS offspring exhibited sustained ductular reaction and periportal fibrosis, while lesions in CON offspring were resolved. In addition, cecal microbiome transplant from HF/HS offspring donors worsened ductular reaction, inflammation, and fibrosis in mice fed DDC. Finally, transfer of the microbiome from HF/HS offspring replicated the cholestatic liver injury phenotype. Taken together, we conclude that maternal HF/HS diet predisposes offspring to increased cholestatic injury after DDC feeding and delays recovery after returning to CON diets. These findings highlight the impact of maternal obesogenic diet on hepatobiliary injury and repair pathways during experimental cholestasis.

Derivation of the Pediatric Acute Gastroenteritis Risk Score to Predict Moderate-to-Severe Acute Gastroenteritis.

OBJECTIVES: Although most acute gastroenteritis (AGE) episodes in children rapidly self-resolve, some children go on to experience more significant and prolonged illness. We sought to develop a prognostic score to identify children at risk of experiencing moderate-to-severe disease after an index emergency department (ED) visit. METHODS: Data were collected from a cohort of children 3 to 48 months of age diagnosed with AGE in 16 North American pediatric EDs. Moderate-to-severe AGE was defined as a Modified Vesikari Scale (MVS) score ≥9 during the 14-day post-ED visit. A clinical prognostic model was derived using multivariable logistic regression and converted into a simple risk score. The model's accuracy was assessed for moderate-to-severe AGE and several secondary outcomes. RESULTS: After their index ED visit, 19% (336/1770) of participants developed moderate-to-severe AGE. Patient age, number of vomiting episodes, dehydration status, prior ED visits, and intravenous rehydration were associated with MVS ≥9 in multivariable regression. Calibration of the prognostic model was strong with a P value of 0.77 by the Hosmer-Lemenshow goodness-of-fit test, and discrimination was moderate with an area under the receiver operator characteristic curve of 0.68 (95% confidence interval [CI] 0.65-0.72). Similarly, the model was shown to have good calibration when fit to the secondary outcomes of subsequent ED revisit, intravenous rehydration, or hospitalization within 72 hours after the index visit. CONCLUSIONS: After external validation, this new risk score may provide clinicians with accurate prognostic insight into the likely disease course of children with AGE, informing disposition decisions, anticipatory guidance, and follow-up care.

Alterations of host-gut microbiome interactions in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. METHODS: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. FINDINGS: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. INTERPRETATION: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. FUNDING: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.