Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity.

Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.

Potentially probiotic Limosilactobacillus reuteri from human milk strengthens the gut barrier in T84 cells and a murine enteroid model.

AIMS: At conception, the infant gut barrier is immature, gradually developing with regular intake of maternal milk. This study addressed whether the barrier-strengthening effect of breast feeding might be attributable, at least in part, to autochthonous beneficial human milk bacteria. METHODS AND RESULTS: Twelve bacterial strains from the breast milk of Pakistani mothers who underwent cesarean delivery (NPL-88, NPL-157, NPL-179, NPL-181, NPL-388 (Limosilactobacillus reuteri), NPL-76, NPL-495, NPL-504 (Limosilactobacillus fermentum), NPL-415 (Lactobacillus pentosus), NPL-412, NPL-416 (Lactiplantibacilllus plantarum) and NPL-374 (Bifidobacterium longum) were shortlisted based on their tolerance to acidic pH (2.8-4.2) and bile (0.1-0.3%). The effect of these bacteria on gut barrier function in the presence and absence of pathogens was assessed as changes in transepithelial electrical resistance (TEER) in the human T84 colonic epithelial cell line and in murine enteroid-derived monolayers (EDMs). The TEER of T84 cells monolayers rose in the presence of most of the human milk strains, being most pronounced in case of L. reuteri NPL-88 (34% within five h), exceeding the effect of the well-known probiotic L. acidophilus (20%). qRT-PCR, western blot and immunofluorescent staining associated the increase in TEER with enhanced expression of tight junction proteins. Pretreatment of murine EDMs with NPL-88 also largely prevented the ability of the pathogen, Salmonella, to decrease TEER (87 ± 1.50%; P < 0.0001, n = 4). CONCLUSIONS: Human milk lactic acid bacteria are potential probiotics that can strengthen gut barrier function and protect breastfed neonates against enteric infections.

Lactobacillus fermentum (MTCC-5898) based fermented whey renders prophylactic action against colitis by strengthening the gut barrier function and maintaining immune homeostasis.

Nutritional intervention using probiotic fermented dairy product has emerged as a promising prophylactic strategy to curb inflammatory bowel diseases. Under present investigation, the potential of fermented whey prepared with probiotic Lactobacillus fermentum (LF:MTCC-5898) was investigated on dextran sodium sulfate (DSS) induced impaired intestinal barrier function in mice. Probiotic fermented whey (PFW) consumption improved the symptoms of colitis-associated with intestinal inflammation by significantly (p < 0.01) diminishing the percent loss in body weight, disease activity index and spleen index with improved colon length besides hematological and histopathological score. Likewise, pre-treatment with PFW improved the barrier integrity (p < 0.01) in contrast to leaky condition induced by DSS administration which increased the FITC-dextran permeability across gut epithelium. PFW consumption also provided the gut immune protection through significantly increased (p < 0.05) TLR-2 expression and stimulated T-regulatory response by producing TGF-ß (p < 0.01) and, potently suppressed (p < 0.01) inflammatory response (TNF-α, IL-4 and C-reactive protein). Further, PFW intake significantly enhanced (p < 0.05) immunoglobulin (sIgA) secretion and concomitantly restored the Occludin, ZO-1 (p < 0.01) and Claudin-1(p < 0.05) transcriptional expression as compared to colitis mice. Additionally, immune-fluorescence further established the presence of intact actin cytoskeleton and tight junction proteins (claudin-1, occludin and ZO-1) after PFW consumption. Thus, PFW rectified the impaired and leaky barrier junctions not only through modulation of transcriptional expression of tight junction genes but also with reduced secretion of inflammatory mediators and helped in ameliorating the colitis. Hence, probiotic fermented whey prepared with L.fermentum (MTCC-5898) could be used as potential prophylactic functional food in the prevention of gut ailments.

Enteroendocrine System and Gut Barrier in Metabolic Disorders.

With the continuous rise in the worldwide prevalence of obesity and type 2 diabetes, developing therapies regulating body weight and glycemia has become a matter of great concern. Among the current treatments, evidence now shows that the use of intestinal hormone analogs (e.g., GLP1 analogs and others) helps to control glycemia and reduces body weight. Indeed, intestinal endocrine cells produce a large variety of hormones regulating metabolism, including appetite, digestion, and glucose homeostasis. Herein, we discuss how the enteroendocrine system is affected by local environmental and metabolic signals. These signals include those arising from unbalanced diet, gut microbiota, and the host metabolic organs and their complex cross-talk with the intestinal barrier integrity.

Identifying the Components of Acidosis in Patients With Severe Plasmodium falciparum Malaria Using Metabolomics.

BACKGROUND: Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. METHODS: A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. RESULTS: We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. CONCLUSIONS: These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria. CLINICAL TRIALS REGISTRATION: NCT02451904.

Ligilactobacillus animalis 506 Protects the Intestinal Barrier from the Damaging Effects of Enteric Pathogens and Deoxynivalenol.

This study investigated the impact of L. animalis 506 on gut barrier integrity and regulation of inflammation in vitro using intestinal epithelial cell lines. Caco-2 or HT29 cell monolayers were challenged with enterotoxigenic E. coli (ETEC) or a ruminant isolate of Salmonella Heidelberg in the presence or absence of one of six probiotic Lactobacillus spp. strains. Among these, L. animalis 506 excelled at exerting protective effects by significantly mitigating the decreased transepithelial electrical resistance (TEER) as assessed using area under the curve (AUC) (p < 0.0001) and increased apical-to-basolateral fluorescein isothiocyanate (FITC) dextran translocation (p < 0.0001) across Caco-2 cell monolayers caused by S. Heidelberg or ETEC, respectively. Similarly, L. animalis 506 and other probiotic strains significantly attenuated the S. Heidelberg- and ETEC-induced increase in IL-8 from HT29 cells (p < 0.0001). Moreover, L. animalis 506 significantly counteracted the TEER decrease (p < 0.0001) and FITC dextran translocation (p < 0.0001) upon challenge with Clostridium perfringens. Finally, L. animalis 506 significantly attenuated DON-induced TEER decrease (p < 0.01) and FITC dextran translocation (p < 0.05) and mitigated occludin and zona occludens (ZO)-1 redistribution in Caco-2 cells caused by the mycotoxin. Collectively, these results demonstrate the ability of L. animalis 506 to confer protective effects on the intestinal epithelium in vitro upon challenge with enteric pathogens and DON known to be of particular concern in farm animals.

Prebiotic Potential of Goji Berry (Lycium barbarum) in Improving Intestinal Integrity and Inflammatory Profiles via Modification of the Gut Microbiota in High-Fat Diet-Fed Rats.

Background: Imbalances in gut microbiota and subsequent destabilization of intestinal barrier equilibrium have been related to the evolution of metabolic disorders. Goji berries (Lycium barbarum; GB) and their fermented counterpart (FGB) have been identified for their prebiotic capacity in managing intestinal barrier functions and inflammatory profiles Consequently, this research was designed to investigate the effects of supplementing GB and FGB on intestinal integrity, inflammation, and changes in the composition of gut microbiota in high-fat (HF)-fed rats. Materials and Methods: Thirty-two male Sprague-Dawley rats (6 weeks old, 8 per group) were divided into four categories based on their weight and provided with either respective diets over a 6-week period: low-fat (LF; 10% of calories from fat), HF (45% of calories from fat), and HF diets supplemented with either GB or FGB at a 2% (w/w). Results: Supplementation of GB and FGB resulted in compositional changes in the gut microbiota, denoted by a distinct abundance of Faecalibacterium prausnitzii with GB and Akkermansia muciniphila species with FGB, which have been linked to ameliorated obesity phenotypes and metabolic parameters. These alterations were correlated with enhancements in gut barrier integrity, thereby protecting against local and systemic inflammation induced by a HF diet. Supplementation with GB and FGB also mitigated lipopolysaccharide-induced inflammation through inhibition of its downstream pathway. Conclusion: These findings indicate that both GB and FGB supplementation can improve gut barrier function and inflammatory profiles in HF-fed rats via modulation of the microbial composition of the gut, supporting the potential application of GB and FGB in improving gut barrier function and managing inflammation amid metabolic challenges.

2-(3,4-dihydroxyphenyl)ethyl 3-hydroxybutanoate (HTHB) ameliorates cognitive dysfunction via modulating gut microbiota in aged senescence-accelerated mouse prone 8 (SAMP8) mice.

Numerous studies have indicated a close association between gut microbiota dysbiosis, inflammation, and cognitive impairment, highlighting their crucial role in the aging process. 2-(3,4-Dihydroxyphenyl)ethyl 3-hydroxybutanoate (HTHB), a novel derivative of hydroxytryrosol (HT), known for its metabolic and anti-inflammatory properties, was investigated for its effects on memory, inflammation, and gut microbiota in senescence-accelerated mouse prone 8 (SAMP8) mice. The study employed behavioral testing, biochemical detection and 16S RNA analysis. Results revealed that HTHB mitigated memory decline and lymphocyte aberrance, reduced inflammation in the brain cortex, intestine and peripheral system, and modulated gut microbiota dysbiosis. Interestingly, the cognitive function and serum inflammation of mice significantly correlated with differences in gut microbiota in SAMP8 mice. Furthermore, HTHB treatment exhibited an enhancement of gut barrier integrity in colon tissue in SAMP8 mice. In vitro experiments using HCT116 and DLD1 cells further evidenced that HTHB rescued the tight junction protein levels impaired by lipopolysaccharide (LPS). These finding demonstrate that HTHB effectively ameliorates cognitive dysfunction in aged mice, might by modulating gut microbiota, suppressing inflammation and promoting intestinal barrier integrity. This highlights the potential of HTHB as a therapeutic agent for age-related cognitive loss.

Deciphering Microbiome, Transcriptome, and Metabolic Interactions in the Presence of Probiotic Lactobacillus acidophilus against Salmonella Typhimurium in a Murine Model.

Salmonella enterica serovar Typhimurium (S. Typhimurium), a foodborne pathogen that poses significant public health risks to humans and animals, presents a formidable challenge due to its antibiotic resistance. This study explores the potential of Lactobacillus acidophilus (L. acidophilus 1.3251) probiotics as an alternative strategy to combat antibiotic resistance associated with S. Typhimurium infection. In this investigation, twenty-four BALB/c mice were assigned to four groups: a non-infected, non-treated group (CNG); an infected, non-treated group (CPG); a group fed with L. acidophilus but not infected (LAG); and a group fed with L. acidophilus and challenged with Salmonella (LAST). The results revealed a reduction in Salmonella levels in the feces of mice, along with restored weight and improved overall health in the LAST compared to the CPG. The feeding of L. acidophilus was found to downregulate pro-inflammatory cytokine mRNA induced by Salmonella while upregulating anti-inflammatory cytokines. Additionally, it influenced the expression of mRNA transcript, encoding tight junction protein, oxidative stress-induced enzymes, and apoptosis-related mRNA expression. Furthermore, the LEfSe analysis demonstrated a significant shift in the abundance of critical commensal genera in the LAST, essential for maintaining gut homeostasis, metabolic reactions, anti-inflammatory responses, and butyrate production. Transcriptomic analysis revealed 2173 upregulated and 506 downregulated differentially expressed genes (DEGs) in the LAST vs. the CPG. Functional analysis of these DEGs highlighted their involvement in immunity, metabolism, and cellular development. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis indicated their role in tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), chemokine, Forkhead box O (FOXO), and transforming growth factor (TGF-ß) signaling pathway. Moreover, the fecal metabolomic analysis identified 929 differential metabolites, with enrichment observed in valine, leucine, isoleucine, taurine, glycine, and other metabolites. These findings suggest that supplementation with L. acidophilus promotes the growth of beneficial commensal genera while mitigating Salmonella-induced intestinal disruption by modulating immunity, gut homeostasis, gut barrier integrity, and metabolism.

Lactobacillus delbrueckii CIDCA 133 fermented milk modulates inflammation and gut microbiota to alleviate acute colitis.

Lactobacillus delbrueckii subsp. lactis CIDCA 133 is a health-promoting bacterium that can alleviate gut inflammation and improve the epithelial barrier in a mouse model of mucositis. Despite these beneficial effects, the protective potential of this strain in other inflammation models, such as inflammatory bowel disease, remains unexplored. Herein, we examined for the first time the efficacy of Lactobacillus delbrueckii CIDCA 133 incorporated into a fermented milk formulation in the recovery of inflammation, epithelial damage, and restoration of gut microbiota in mice with dextran sulfate sodium-induced colitis. Oral administration of Lactobacillus delbrueckii CIDCA 133 fermented milk relieved colitis by decreasing levels of inflammatory factors (myeloperoxidase, N-acetyl-ß-D-glucosaminidase, toll-like receptor 2, nuclear factor-κB, interleukins 10 and 6, and tumor necrosis factor), secretory immunoglobulin A levels, and intestinal paracellular permeability. This immunobiotic also modulated the expression of tight junction proteins (zonulin and occludin) and the activation of short-chain fatty acids-related receptors (G-protein coupled receptors 43 and 109A). Colonic protection was effectively associated with acetate production and restoration of gut microbiota composition. Treatment with Lactobacillus delbrueckii CIDCA 133 fermented milk increased the abundance of Firmicutes members (Lactobacillus genus) while decreasing the abundance of Proteobacteria (Helicobacter genus) and Bacteroidetes members (Bacteroides genus). These promising outcomes influenced the mice's mucosal healing, colon length, body weight, and disease activity index, demonstrating that this immunobiotic could be explored as an alternative approach for managing inflammatory bowel disease.

Impacts of gut microbiota alteration on age-related chronic liver diseases.

The gut microbiome and its metabolites are involved in developing and progressing liver disease. Various liver illnesses, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and hepatocellular carcinoma, are made worse and have worse prognoses with aging. Dysbiosis, which occurs when the symbiosis between the microbiota and the host is disrupted, can significantly negatively impact health. Liver disease is linked to qualitative changes, such as an increase in hazardous bacteria and a decrease in good bacteria, as well as quantitative changes in the overall amount of bacteria (overgrowth). Intestinal gut microbiota and their metabolites may lead to chronic liver disease development through various mechanisms, such as increasing gut permeability, persistent systemic inflammation, production of SCFA, bile acids, and alteration in metabolism. Age-related gut dysbiosis can disrupt the communication between gut microbiota and the host, impacting the host's health and lifespan. With aging, a gradual loss of the ability to maintain homeostasis because of structural alteration and gut dysbiosis leads to the disease progression in end-stage liver disease. Recently chronic liver disease has been identified as a global problem. A large number of patients are receiving liver transplants yearly. Thereby gut microbiome ecology is changing in the patients of the gut due to the changes in pathophysiology during the preoperative stage. The present review summarises the age-associated dysbiosis of gut microbial composition and its contribution to chronic liver disease. This review also provides information about the impact of liver transplant on the gut microbiome and possible disadvantageous effects of alteration in gut microbiota.

Postnatal intestinal mucosa and gut microbial composition develop hand in hand: A mouse study.

BACKGROUND: During the early postnatal life, gut microbiota development experiences dynamic changes in their structural and functional composition. The postnatal period is the critical window to develop a host defense mechanism. The maturation of intestinal mucosal barrier integrity is one of the essential defense mechanisms to prevent the entry of pathogens. However, the co-development of intestinal microbial colonization, formation of barrier integrity, and intestinal epithelial cell layer is not entirely understood. METHODS: We studied the gut microbial composition and diversity using 16S rRNA marker gene-based sequencing in mice to understand postnatal age-dependent association kinetics between gut microbial and intestinal development. Next, we assessed the intestinal development by in vivo gut permeability assay, mRNA gene expression of different tight junction proteins and intestinal epithelial cell markers, goblet cells population, villus length, and cecal IgA quantification. RESULTS: Our results showed a significant shift in gut microbial structural and functional composition from postnatal day 14 onwards with early life Proteobacteria abundance. Relative abundance of Verrucomicrobia was maximum at postnatal day 14 and showed a gradual decrease over time. We also observed an age-dependent biphasic pattern in barrier integrity improvement and differentiation of intestinal epithelial cells (IECs). A significant improvement in barrier integrity between days 1 and 7 showed the host factor contribution, while that beyond day 14 revealed an association with changes in microbiota composition. Our temporal correlation analysis associated Bacteroidetes phylum with the mucosal barrier formation during postnatal development. CONCLUSIONS: The present study revealed the importance and interplay of host factors and the microbiome in gut development and intestinal mucosal homeostasis.

Loss of Gut Barrier Integrity In Lupus.

Systemic Lupus Erythematosus is a complex autoimmune disease and its etiology remains unknown. Increased gut permeability has been reported in lupus patients, yet whether it promotes or results from lupus progression is unclear. Recent studies indicate that an impaired intestinal barrier allows the translocation of bacteria and bacterial components into systemic organs, increasing immune cell activation and autoantibody generation. Indeed, induced gut leakage in a mouse model of lupus enhanced disease characteristics, including the production of anti-dsDNA antibody, serum IL-6 as well as cell apoptosis. Gut microbiota dysbiosis has been suggested to be one of the factors that decreases gut barrier integrity by outgrowing harmful bacteria and their products, or by perturbation of gut immune homeostasis, which in turn affects gut barrier integrity. The restoration of microbial balance eliminates gut leakage in mice, further confirming the role of microbiota in maintaining gut barrier integrity. In this review, we discuss recent advances on the association between microbiota dysbiosis and leaky gut, as well as their influences on the progression of lupus. The modifications on host microbiota and gut integrity may offer insights into the development of new lupus treatment.

Exercise protects intestinal epithelial barrier from high fat diet- induced permeabilization through SESN2/AMPKα1/HIF-1α signaling.

Over-nutrition and a sedentary lifestyle are associated with increased intestinal permeability. This condition promotes obesity and associated metabolic disorders. Sestrin2 (SESN2) is a stress-inducible protein thought to promote the survival and recovery of epithelial cells and act as a positive regulator in exercise-induced improvements of glycolipid metabolism. Here we aimed to test the hypothesis that chronic exercise can protect intestinal barrier function against high-fat diet induced permeabilization through SESN2. WT and SESN2-/- mice were randomly assigned to five groups, fed with either normal chow or high fat diet (HFD), and provided with or without exercise training for 15-week. Metabolic parameters, fecal microbiota composition, and intestinal barrier integrity were assessed. The role of the gut microbiota was investigated by administering a mixture of broad-spectrum antibiotics (ABX). Fifteen-week HFD feeding induced dysmetabolism, dysbiosis and gut barrier dysfunctions in the WT mice. These effects were exaggerated in SESN2-/- mice. Chronic aerobic exercise significantly reversed HFD-induced pathologic changes, while SESN2 ablation weakened the protective effects of exercise. ABX did not abolish the differences in gut barrier function between WT and SESN2-/- mice. We speculated that SESN2 may protect intestinal integrity partly independent of gut microbiome. Combining ex vivo and in vivo approaches, we demonstrated that SESN2/pAMPK-Thr172/HIF-1α pathway may play an important role in exercise- improved intestinal permeability. Taken together, our study demonstrated that HFD and SESN2-KO have synergistic effects on intestinal homeostasis. SESN2 is crucial in exercise-improved intestinal permeability.

Gut barrier disruption and chronic disease.

The intestinal barrier protects the host against gut microbes, food antigens, and toxins present in the gastrointestinal tract. However, gut barrier integrity can be affected by intrinsic and extrinsic factors, including genetic predisposition, the Western diet, antibiotics, alcohol, circadian rhythm disruption, psychological stress, and aging. Chronic disruption of the gut barrier can lead to translocation of microbial components into the body, producing systemic, low-grade inflammation. While the association between gut barrier integrity and inflammation in intestinal diseases is well established, we review here recent studies indicating that the gut barrier and microbiota dysbiosis may contribute to the development of metabolic, autoimmune, and aging-related disorders. Emerging interventions to improve gut barrier integrity and microbiota composition are also described.

Apigenin remodels the gut microbiota to ameliorate ulcerative colitis.

Introduction: Ulcerative colitis (UC), a chronic non-specific colorectal inflammatory disease with unclear etiology, has long plagued human health. Gut microbiota dysbiosis destroy homeostasis of the colon, which is closely related to ulcerative colitis progress. Apigenin, a flavonoid widely present in celery, has been found to improve ulcerative colitis. However, the potential molecular mechanism of apigenin ameliorating ulcerative colitis through protecting intestinal barrier and regulating gut microbiota remains undefined. Methods: Dextran sodium sulfate (DSS)-induced colitis mouse model was conducted to evaluate the effect of apigenin on UC. Disease activity index score of mice, colon tissue pathological, cytokines analysis, intestinal tight junction proteins expression, and colonic content short-chain fatty acids (SCFAs) and 16S rRNA gene sequencing were conducted to reflect the protection of apigenin on UC. Results: The results indicated that apigenin significantly relieved the intestinal pathological injury, increased goblet cells quantity and mucin secretion, promoted anti-inflammatory cytokines IL-10 expression, and inhibited the expression of proinflammatory cytokines, TNF-α, IL-1ß, IL-6 and MPO activity of colon tissue. Apigenin increased ZO-1, claudin-1 and occludin expressions to restore the integrity of the intestinal barrier. Moreover, apigenin remodeled the disordered gut microbiota by regulating the abundance of Akkermansia, Turicibacter, Klebsiella, Romboutsia, etc., and its metabolites (SCFAs), attenuating DSS-induced colon injury. We also investigated the effect of apigenin supplementation on potential metabolic pathways of gut microbiota. Conclusion: Apigenin effectively ameliorated DSS-induced UC via balancing gut microbiome to inhibit inflammation and protect gut barrier. With low toxicity and high efficiency, apigenin might serve as a potential therapeutic strategy for the treatment of UC via regulating the interaction and mechanism between host and microorganism.

The Gut Microbiome of Children during the COVID-19 Pandemic.

The gut microbiome has been shown to play a critical role in maintaining a healthy state. Dysbiosis of the gut microbiome is involved in modulating disease severity and potentially contributes to long-term outcomes in adults with COVID-19. Due to children having a significantly lower risk of severe illness and limited sample availability, much less is known about the role of the gut microbiome in children with COVID-19. It is well recognized that the developing gut microbiome of children differs from that of adults, but it is unclear if this difference contributes to the different clinical presentations and complications. In this review, we discuss the current knowledge of the gut microbiome in children with COVID-19, with gut microbiome dysbiosis being found in pediatric COVID-19 but specific taxa change often differing from those described in adults. Additionally, we discuss possible mechanisms of how the gut microbiome may mediate the presentation and complications of COVID-19 in children and the potential role for microbial therapeutics.

Oral sodium butyrate supplementation ameliorates paclitaxel-induced behavioral and intestinal dysfunction.

Paclitaxel (PTX) is one of the most broadly used chemotherapeutic agents for the treatment of several tumor types including ovarian, breast, and non-small cell lung cancer. However, its use is limited by debilitating side effects, involving both gastrointestinal and behavioral dysfunctions. Due to growing evidence showing a link between impaired gut function and chemotherapy-associated behavioral changes, the aim of this study was to identify a novel therapeutic approach to manage PTX-induced gut and brain comorbidities. Mice were pre-treated with sodium butyrate (BuNa) for 30 days before receiving PTX. After 14 days, mice underwent to behavioral analysis and biochemical investigations of gut barrier integrity and microbiota composition. Paired evaluations of gut functions revealed that the treatment with BuNa restored PTX-induced altered gut barrier integrity, microbiota composition and food intake suggesting a gut-to-brain communication. The treatment with BuNa also ameliorated depressive- and anxiety-like behaviors induced by PTX in mice, and these effects were associated with neuroprotective and anti-inflammatory outcomes. These results propose that diet supplementation with this safe postbiotic might be considered when managing PTX-induced central side effects during cancer therapy.

Supplementation of Bacillus sp. DU-106 Alleviates Antibiotic-Associated Diarrhea in Association with the Regulation of Intestinal Microbiota in Mice.

Bacillus sp. DU-106, a potential probiotic, has been proved to activate innate immunity, reduce hypercholesterolemia, and regulate the gut microbiota of mice. In the present study, we investigated the therapeutic effect of strain DU-106 in antibiotic-associated diarrhea (AAD) via analyzing the changes in gut microbial composition in mice. The results indicated that supplementation of strain DU-106 alleviated gastrointestinal symptoms, improved gut barrier integrity and immunoglobulin-A level of mice with AAD. A 16S rRNA sequencing showed that antibiotics decreased bacterial diversity and the abundances of Alistipes, Roseburia, Hungatella, Eubacterium-xylanophilum, Lachnospiraceae-UCG-001, Intestinimonas, and Lachnospiraceae-NK4A136, but increased the abundance of Klebsiella, Bacteroidota, and Verrucomicrobiota. However, strain DU-106 treatment reversed these alternations in mice with AAD. In conclusion, strain DU-106 could alleviate AAD in association with the regulation of intestinal microbiota and could be used as an alternative treatment for AAD.

A diet enriched in omega-3 PUFA and inulin prevents type 1 diabetes by restoring gut barrier integrity and immune homeostasis in NOD mice.

Introduction: The integrity of the gut barrier (GB) is fundamental to regulate the crosstalk between the microbiota and the immune system and to prevent inflammation and autoimmunity at the intestinal level but also in organs distal from the gut such as the pancreatic islets. In support to this idea, we recently demonstrated that breakage of GB integrity leads to activation of islet-reactive T cells and triggers autoimmune Type 1 Diabetes (T1D). In T1D patients as in the NOD mice, the spontaneous model of autoimmune diabetes, there are alterations of the GB that specifically affect structure and composition of the mucus layer; however, it is yet to be determined whether a causal link between breakage of the GB integrity and occurrence of autoimmune T1D exists. Methods: Here we restored GB integrity in the NOD mice through administration of an anti-inflammatory diet (AID- enriched in soluble fiber inulin and omega 3-PUFA) and tested the effect on T1D pathogenesis. Results: We found that the AID prevented T1D in NOD mice by restoring GB integrity with increased mucus layer thickness and higher mRNA transcripts of structural (Muc2) and immunoregulatory mucins (Muc1 and Muc3) as well as of tight junction proteins (claudin1). Restoration of GB integrity was linked to reduction of intestinal inflammation (i.e., reduced expression of IL-1ß, IL-23 and IL-17 transcripts) and expansion of regulatory T cells (FoxP3+ Treg cells and IL-10+ Tr1 cells) at the expenses of effector Th1/Th17 cells in the intestine, pancreatic lymph nodes (PLN) and intra-islet lymphocytes (IIL) of AID-fed NOD mice. Importantly, the restoration of GB integrity and immune homeostasis were associated with enhanced concentrations of anti-inflammatory metabolites of the ω3/ω6 polyunsaturated fatty acids (PUFA) and arachidonic pathways and modifications of the microbiome profile with increased relative abundance of mucus-modulating bacterial species such as Akkermansia muciniphila and Akkermansia glycaniphila. Discussion: Our data provide evidence that the restoration of GB integrity and intestinal immune homeostasis through administration of a tolerogenic AID that changed the gut microbial and metabolic profiles prevents autoimmune T1D in preclinical models.