The consumption of high-fat diets (HFD) and an imbalance in gut microbiome are linked to obesity. However, the intricate connection between them and the underlying mechanisms involved in lipid digestion and absorption remain largely unclear. This study shows that after 12 weeks of HFD feeding, mice exhibit two distinct metabolic phenotypes with significant differences in gut microbiota composition. The LOW and LOW FMT group mice with increased Bacteroides are protected from obesity, insulin resistance, and lipid accumulation. Supplementation with or cholic acid (CA) alleviates HFD-induced obesity and metabolic dysfunction. This is due to the accumulation of lipid droplets and the retention of chyle particles in jejunal epithelial cells, which reduces chyle intake in the jejunal mesentery after HFD. Decreased 5-HT synthesis in the jejunal enterochromaffin cells of these mice, along with reduced chyle intake in the jejunal mesentery after HFD in , suggests that intestinal 5-HT is required for host lipid absorption. TRPV1, a calcium-permeable ion channel, mediates the basolateral 5-HT-induced increase of and ion channel open probability. This study uncovers a novel signaling axis of microbiota-metabolite-5-HT and intracellular calcium-dependent lipid absorption, which may serve as the potential therapeutic targets for treating HFD-induced obesity.

Rotavirus (RV) accounts for 19.11% of global diarrheal deaths. Though GAVI assisted vaccine introduction has curtailed RV induced mortality, factors like RV strain diversity, differential infantile gut microbiome, malnutrition, interference from maternal antibodies and other administered vaccines, etc. often compromise vaccine efficacy. Herein emerges the need of antivirals which can be administered adjunct to vaccination to curb the socio-economic burden stemming from frequent RV infection. Cognisance of pathogen-perturbed host cellular physiology has revolutionized translational research and aided precision-based therapy, particularly for viruses, with no metabolic machinery of their own. To date there has been limited exploration of the host cellular metabolome in context of RV infection. In this study, we explored the endometabolomic landscape of human intestinal epithelial cells (HT-29) on RV-SA11 infection. Significant alteration of host cellular metabolic pathways like the nucleotide biosynthesis pathway, alanine, aspartate and glutamate metabolism pathway, the host citric acid cycle was observed in RV-SA11 infection scenario. Detailed study further revealed that RV replication is exclusively dependent on glutamine metabolism for their propagation in host cells. Glutamine metabolism generates glutamate, aspartate, and asparagine which facilitates virus infection. Abrogation of aspartate biogenesis from glutamine by use of Aminooxyacetic acid (AOAA), significantly curbed RV-SA11 infection in-vitro and in-vivo. Overall, the study improves our understanding of host-rotavirus interactome and recognizes host glutamine metabolism pathway as a suitable target for effective therapeutic intervention against RV infection.

Human milk oligosaccharides (HMOs) are the third most important nutrient in human milk and are the gold standard for infant nutrition. Due to the lack of an enzyme system capable of utilizing HMOs in the infant intestine, HMOs cannot be directly utilized. Instead, they function as natural prebiotics, participating in the establishment of the intestinal microbiota as a "bifidus factor." A crucial colonizer of the early intestine is (), particularly its subspecies subsp. , which is the most active consumer of HMOs. However, due to the structural diversity of HMOs and the specificity of strains, studies on their synergy are limited. An in-depth investigation into the mechanisms of HMO utilization by is essential for applying both as synbiotics to promote early intestinal development in infants. This review describes the colonization advantages of in the infant intestinal tract and its metabolic strategies for HMOs. It also summarizes recent studies on the effect and mechanism of and HMOs in infant intestinal development directly or indirectly through the action of metabolites. In conclusion, further structural analysis of HMOs and a deeper understanding of the interactions between and HMOs, as well as clinical trials, are necessary to lay the foundation for future practical applications as synbiotics.

The foodborne mycotoxin deoxynivalenol (DON) produced by species threats animal and human health through disruption of the intestinal barrier. Targeting the gut microbiota and its products appears as a promising strategy to mitigate DON intestinal toxicity. In this study, we investigated whether the bacterial metabolite butyrate could alleviate epithelial barrier disruption induced by DON. We used a model of cell monolayers derived from porcine jejunum organoids allowing to reproduce the cellular complexity of the intestinal epithelium. Our results show that DON dose-dependently disrupted the epithelial barrier integrity, reduced epithelial differentiation, and altered innate immune defenses. Butyrate attenuated the DON-induced increase in paracellular permeability. Butyrate also prevented epithelial barrier dysfunction triggered by anisomycin, a ribosome inhibitor like DON. Moreover, butyrate partially counteracted the effects of DON on tight junctions (TJP1, OCLN), innate epithelial defenses (PTGS2, CD14, TLR4, TLR5), and absorptive cell functions (CA2, VIL1, NHE3, CFTR). In contrast, butyrate did not prevent the toxic effects of DON on mitochondrial metabolism, proliferation and goblet cell functions. Taken together, our results demonstrate that the bacterial metabolite butyrate is able to reduce DON-induced epithelial barrier disruption.

Numerous studies have established that prebiotic ingredients in foods and dietary supplements may play a role in supporting human health. Over the three decades that have passed since prebiotics were first defined as a concept, research has revealed a complex universe of prebiotic-induced changes to the human microbiota. There are strong indications of a direct link between these prebiotic-induced changes and specific health benefits. However, at the present time, the EU has not permitted use of the term 'prebiotic' in connection with an approved health claim. This paper is the outcome of a workshop organized on the 25 October 2023 by the European branch of the International Life Science Institute (ILSI). It provides an overview of the regulatory requirements for authorized health claims in the EU, key areas of prebiotic research, and findings to date in relation to prebiotics and digestive, immune, metabolic and cognitive health. Research gaps and documentation challenges are then explored and a roadmap proposed for achieving authorization of 'prebiotic' in the wording of future EU health claims.

Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase toward the end of pregnancy and comprise reduced α-diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in mice carrying an intestinal epithelial deletion of the Crohn's disease risk gene . Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between wildtype and pregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as , , , and . Changes partially recovered after lactation. Additionally, metagenomic and metabolomic analyses suggest an increased capacity for chitin degradation, resulting in higher levels of free N-acetyl-glucosamine products in feces, alongside reduced glucose and myo-inositol levels in serum around the time of delivery. On the host side, we found that the immunological response of mice is characterized by higher colonic mRNA levels of TNFα and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improve precision care for managing pregnancies in IBD patients.

Association between ileal colonization by Adherent-Invasive (AIEC) and Crohn's disease (CD) has been widely described in high-incidence Western countries but remains unexplored in Asian countries with a fast increase in CD incidence. In the PACIFIC study, we compared the characteristics of AIEC pathobionts retrieved from ileal biopsies of CD patients enrolled in France (FR) and Hong Kong (HK). The prevalence of AIEC was similar in France (24.5%, 25/102) and Hong Kong (30.0%, 18/60) ( = 0.44). No difference was observed between the two populations of AIEC regarding adhesion and invasion levels. When tested for antibiotic resistance, the proportion of AIEC strains resistant to ampicillin, piperacillin, tobramycin, and gentamicin was significantly higher in HK AIEC strains compared to French strains. AIEC strains from FR or HK population were both able to persist in the mice intestine (DSS-treated CEABAC10 mice model). Moreover, genomic analysis of 25 FR and 17 hK AIEC strains using next-generation sequencing revealed the co-existence of several virulence factors associated with enteric pathotypes, although no single virulence factor was significantly associated with either country of origin or AIEC status. , all AIEC strains (FR and HK) were sensitive to the EcoActive™ phage cocktail, suggesting that it could be a promising option to target AIEC in CD across the world.

The Western diet is associated with gastrointestinal dysbiosis, an active contributor to the pathophysiology of obesity and its comorbidities. Gastrointestinal dysbiosis is strongly linked to increased adiposity, low-grade inflammation, dyslipidaemia, and insulin resistance in individuals with morbid obesity. Bariatric bypass surgery remains the most effective treatment for achieving significant weight loss and alleviating obesity-related comorbidities. A growing body of evidence indicates that traditional Roux-en-Y Gastric Bypass (RYGB) improves the disrupted gut microbiota linked with obesity, potentially contributing to sustained weight loss and reduction of comorbidities. One Anastomosis Gastric Bypass (OAGB), a relatively new and technically simpler bariatric procedure, has shown both safety and efficacy in promoting weight loss and improving comorbidities. Few studies have investigated the impact of OAGB on gut microbiota. This review provides insights into the pathogenesis of obesity, current treatment strategies and our current understanding of the gut microbiota in health and disease, including modulating the gut microbiota as a promising and novel way to alleviate the burden of obesity and cardiometabolic conditions. By exploring the impact of gastric bypass surgery on gut microbiota-host interactions, we aim to shed light on this evolving field of research and uncover potential therapeutic targets for elevating outcomes in bariatric surgery.

Gut microbiota exert functions of high importance in the intestine. Furthermore, there is increasing evidence for its role in immune regulation and maintenance of homeostasis in many physiological processes taking place in distant tissues. In particular, in this review, we explore the impact of metabolites produced by the gut microbiota on the development of atopic dermatitis (AD). Probiotics and prebiotics balance the microbiota and promote the generation of bacterial metabolites, such as short-chain fatty acids and tryptophan derivates, which promote the regulation of the exacerbated AD immune response through regulatory T cells and IL-10 and TGF-β cytokines. Metabolites also have a direct action on keratinocytes once they reach the bloodstream. Besides, probiotics decrease the levels of metabolites associated with AD onset, such as phenols. Understanding all these crosstalk processes between the gut and the skin reveals a number of possibilities, mainly through the manipulation of the gut microbiome, which may represent therapeutic strategies that can contribute to the standard treatments of AD patients to improve their quality of life.

infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during induced carcinogenesis, the transgenic mouse, which is prone to -induced gastric cancer, was utilized. mice and mice were infected with a cag type 4 secretion system (T4SS) positive strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in -infected mice compared to mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after infection.

Metagenomic research faces a persistent challenge due to the low concordance across studies. While matching host confounders can mitigate the impact of individual differences, the influence of factors such as genetics, environment, and lifestyle habits on microbial profiles makes it exceptionally challenging to create fully matched cohorts. The microbial metabolic background, which modulates microbial composition, reflects a cumulative impact of host confounders, serving as an ideal baseline for microbial sample matching. In this study, we introduced miMatch, an innovative metagenomic sample-matching tool that uses microbial metabolic background as a comprehensive reference for host-related variables and employs propensity score matching to build case-control pairs, even in the absence of host confounders. In the simulated datasets, miMatch effectively eliminated individual metabolic background differences, thereby enhancing the accuracy of identifying differential microbial patterns and reducing false positives. Moreover, in real metagenomic data, miMatch improved result consistency and model generalizability across cohorts of the same disease. A user-friendly web server (https://www.biosino.org/iMAC/mimatch) has been established to promote the integration of multiple metagenomic cohorts, strengthening causal relationships in metagenomic research.

Sulfate- and sulfite-reducing bacteria (SRB) are a group of strict anaerobes found within the human gut. , a sulfite-reducing bacterium which produces hydrogen sulfide (HS) from taurine and isethionate respiration, is a common member of the healthy commensal human gut microbiota but has been implicated in several disease states including inflammatory bowel disease and colorectal cancer. , one of the most prominent gut bacteria, has sulfatases which release sulfate, serving as a potential substrate for sulfate-reducing bacteria. Here, we showed that when and were in co-culture, there was a significant increase in 's growth and in HS production by . Differential gene expression analysis revealed increased expression of 's complex in co-culture, which delivers electrons for sulfite reduction to HS. This was accompanied by a decreased expression of genes associated with taurine, sulfolactate, and thiosulfate respiration, indicating that may provide an alternative source of sulfite to . We hypothesized adenosine 5'-phosphosulfate (APS) to be this intermediate. Indeed, was able to grow using APS or sulfite as electron acceptors. Endometabolomic and transcriptomic analyses revealed decreased production of indole by in co-culture with due to enhanced tryptophan utilization by . The results of this microbe-microbe interaction could have significant pro-inflammatory effects in the human gut environment.

Arabinoxylo-oligosaccharides (AXOS) are non-digestible dietary fibers that potentially confer a health benefit by stimulating beneficial bacteria in the gut. Still, a detailed overview of the diversity of gut bacteria and their specificity to utilize structurally different AXOS has not been provided to date and was aimed for in this study. Moreover, we assessed the genetic information of summarized bacteria, and we extracted genes expected to encode for enzymes that are involved in AXOS hydrolysis (based on the CAZy database). The taxa involved in AXOS fermentation in the gut display a large variety of AXOS-active enzymes in their genome and consequently utilize AXOS to a highly different extent. Clostridia and Bacteroidales are generalists that consume many structurally diverse AXOS, whereas are specialists that specifically consume AXOS with a low degree of polymerization. Further complexity is evident from the fact that the exact bacterial species, and in some cases even the bacterial strains (e.g. in ) that are stimulated, highly depend on the specific AXOS molecular structure. Furthermore, certain species in and are active as cross-feeders and consume monosaccharides and unbranched short xylo-oligosaccharides released from AXOS. Our review highlights the possibility that (enzymatic) fine-tuning of specific AXOS structures leads to improved precision in targeting growth of specific beneficial bacterial species and strains in the gut.

Understanding the interrelationship between the gut microbiota and host physiology, although still in its relative infancy, has taken important steps forward over the past decade. In the context of brain disorders including those characterized by neurodevelopmental and neurodegenerative changes there have been important advances. However, initially research involved correlational analyses, had limited translational scope, and lacked functional assessments. Thus, largescale longitudinal clinical investigations that assess causation and underlying mechanisms via in depth analysis methods are needed. In neurodegeneration research, strong causal evidence now links the gut microbiome to Alzheimer's (AD), and Parkinson's Disease (PD), as supported by human-to-animal transplantation studies. Longitudinal interventions are being conducted in AD, PD, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Neurodevelopmental research has also seen a boon in microbiome-related clinical research including in autism, Attention-deficit/hyperactivity disorder, and schizophrenia, which is confirming prior animal model work regarding the key time-windows in the gut microbiome important for infant cognition. While recent research advances represent important progress, fundamental knowledge gaps and obstacles remain. Knowing how and why the gut microbiome changes at the extremes of life will develop our mechanistic understanding and help build the evidence base as we strive toward counteracting microbial missteps with precision therapeutic interventions.

Human noroviruses (HuNoVs) are a major cause of diarrheal disease, yet critical aspects of their biology, including cellular tropism, remain unclear. Although research has traditionally focused on the intestinal epithelium, the hypothesis that HuNoV infects macrophages has been recurrently discussed and is investigated here using a zebrafish larval model. Through single-cell RNA sequencing of dissected zebrafish intestines, we unbiasedly identified macrophages as host cells for HuNoV replication, with all three open reading frames mapped to individual macrophages. Notably, HuNoV preferentially infects actively phagocytosing inflammatory macrophages. HuNoV capsid proteins and double-stranded RNA colocalized within intestinal macrophages of infected zebrafish larvae, and the negative-strand RNA intermediate was detected within FACS-sorted macrophages. Flow cytometry confirmed viral replication within these macrophages, constituting approximately 23% of HuNoV's host cells. Identifying macrophages as host cells prompts a reevaluation of their role in HuNoV pathogenesis, offering new directions for understanding and controlling this infection.

The human intestinal tract is densely colonized by a microbial community that is subject to intense competition. Bacteria in this complex habitat seek to outcompete their neighbors for nutrients and eliminate competitors with antibacterial toxins. Antagonism can be mediated by diverse effectors including toxic proteins and small molecule inhibitors that are released extracellularly or delivered by specialized secretion systems to targeted cells. Two prototypical microbiota-derived enterotoxins, colibactin and tilimycin, and the newly discovered family of indolimines represent an expanding group of non-proteinaceous small molecules which specifically target DNA. In addition to cell killing, they generate mutations and genome instability in intoxicated microbes and host cells alike. They have been studied in detail because of their direct toxicity to human cells and important etiological roles in intestinal pathologies. Increasing evidence, however, reveals that these commensal genotoxins are also mediators of interbacterial antagonism, which impacts gut microbial ecology. In this review, we illustrate the functional versatility of commensal genotoxins in the gut ecosystem.

The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite -cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood-brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. and mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk of long COVID has been associated with the depletion or over-abundance of specific taxa within the gut microbiome. However, the microbial mechanisms mediating these effects are not yet known. We hypothesized that altered microbial production of tryptophan and its downstream derivatives might contribute to inappropriate immune responses to viral infection. In patients hospitalized with COVID-19 ( = 172), serum levels of tryptophan and indole-3-propionate (IPA) negatively correlated with serum levels of many proinflammatory mediators (including C-reactive protein and Serum amyloid A), while C-glycosyltryptophan (C-Trp), indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA) levels were positively correlated with levels of acute phase proteins, proinflammatory cytokines, alarmins and chemokines. A similar pattern was observed in long COVID patients ( = 20) where tryptophan and IPA were negatively associated with a large number of serum cytokines, while C-Trp and IAA were positively associated with circulating cytokine levels. Metagenomic analysis of the fecal microbiota showed the relative abundance of genes encoding the microbial enzymes required for tryptophan production (e.g. anthranilate synthase) and microbial tryptophan metabolism was significantly lower in patients hospitalized with COVID-19 ( = 380) compared to healthy controls ( = 270). Microbial tryptophan metabolites reduced innate cell proinflammatory responses to cytosolic DNA sensor Stimulator of interferon genes (STING), toll-like receptor (TLR)-3 and TLR-4 stimulation , while IL-10 secretion was enhanced. Microbial tryptophan metabolites also modified human lymphocyte responses by limiting the production of TH1 and TH17 associated cytokines, while enhancing secretion of IL-22. These data suggest that lower levels of tryptophan production and tryptophan metabolism by gut microbes may increase the risk of severe and chronic outcomes to SARS-CoV-2 infection due to impaired innate and adaptive responses to infection. Screening patients for lower-level microbiome capacity for tryptophan metabolism may help identify at-risk individuals.

A rising corpus of research has shown the beneficial effects of probiotic on human health, contributing to the growing popularity of these microorganisms in recent decades. The gastrointestinal and urinary tracts are home to these bacteria, which play a vital role in the microbial flora of both humans and animals. The probiotic, i.e, , are highly recognized for their remarkable probiotic qualities. The current study aims to highlight the beneficial effects of probiotics in different health conditions, point out the research gap, and highlight the future directives for the safe use of these probiotics in several health issues. Most importantly, we have added the most recent literature related to the characteristics and usage of these probiotics in clinical and pre-clinical settings. Based on the above statement, we believe that this is the first report on the application of probiotics in human diseases. By providing a deeper knowledge of the complex functions these probiotics play in both human and animal health, our analysis will direct future studies and developments in this rapidly developing field.

Intestinal mucins play a crucial role in the mucosal barrier, serving as the body's initial defense against microorganisms. However, how the host regulates the secretion and glycosylation of these mucins in response to bacterial invasion remains unclear. Our study demonstrates that when exposed to (), a gut pathobiont, the host mucosa promptly adjusts the behavior of specialized goblet cells (GCs) located in the middle of the crypts. A subset of these cells undergoes a remodeling, becoming intercrypt goblet cells (icGCs), which do not detach from the surface but instead migrate along intercrypt spaces while secreting a mucus impermeable to bacterial pathogens. Significantly, a non-piliated mutant unable to bind to mucus fails to induce icGCs, allowing its translocation through the mucosa and submucosa. Interestingly, a closely related nonpathogenic bacterium, , able to bind to mucus, also triggers the differentiation of GCs into icGCs. This discovery opens new avenues for treating patients with a "leaky gut" as observed in intestinal diseases such as inflammatory bowel diseases and metabolic disorders, but also patients with a history of repeated antibiotic use. Utilizing mucus-adherent probiotics to induce icGCs represents a promising strategy for reinforcing the mucosal barrier.

We investigate the role of homeostatic mechanisms involved in acute, postprandial nutrient metabolism and nutrient-induced systemic inflammation in CKD presence and progression in Metabolic dysfunction-associated steatohepatitis (MASH). We assessed postprandial incretins (GLP-1 and GIP), intestinotropic hormone GLP-2, endotoxin LPS, Zonulin (a marker of intestinal permeability), hepatokines, adipokines and NF-kB activation in circulating MNCs during a meal tolerance test in 52 biopsy proven MASH patients randomized to curcumin Meriva or placebo and 26 matched controls. At baseline, MASH-CKD had a lower GLP-2 response and a 2-fold higher postprandial LPS and NF-kB activation in MNCs than MASH patients without CKD, but similar remaining postprandial or fasting parameters. Postprandial IAUC GLP-2 predicted the presence of CKD in MASH (OR = 0.43, 95%CI:0.32-0.80,  = 0.008) independently of liver histology and traditional risk factors. After 72 weeks, changes in IAUC GLP-2 independently predicted the presence of CKD (OR = 0.49, 95%CI:0.21-0.73,  = 0.010) and eGFR changes [β(SE) = 0.510(0.007,  = 0.006] at end-of-treatment, In MASH, an impaired GLP-2 response to meals is associated with intestinal barrier dysfunction, endotoxemia and NF-kB-mediated systemic inflammation and may promote renal dysfunction and CKD. These data provide the rationale for evaluating GLP-2 analogues in MASH-related CKD.