Colonic Microbiota Research Articles

The protein ingredient quality of infant formula influences colonic physiology and microbiota and the serum metabolomic profile in neonatal mini-piglets

The protein ingredient quality of infant formula influences colonic physiology and microbiota and the serum metabolomic profile in neonatal mini-piglets

Comparison of nasal microbiota between preterm and full-term infants in early life.

The respiratory microbiota influences infant immune system maturation. Little is known about how perinatal, physiological, and environmental exposures impact the nasal microbiota in preterm infants after discharge, or nasal microbiota differences between preterm and healthy full-term infants. Nasal swabs (from 136 preterm and 299 full-term infants at mean postmenstrual age of 45 weeks from the prospective Basel-Bern Infant Lung Development cohort) were analyzed by 16S-rRNA gene amplification and sequencing (Illumina MiSeq). Associations were tested with multivariable linear regression and principal coordinate analysis. Presence of older siblings in preterm infants was associated with β-diversity (PERMANOVA p = 0.001) and an increased abundance of Moraxella and Haemophilus. The nasal microbiota of preterm infants exhibited a distinct composition compared to that of full-term infants (PERMANOVA, R2 = 0.014, p = 0.001), characterized by a reduced abundance of the Moraxella and Dolosigranulum genera (ANCOM-BC, p < 0.05). Our results indicate that, despite both infant groups having similar nasal microbiota patterns, there are some disparities which suggest that prematurity influences the initial microbiota colonization. In preterm infants the presence of older siblings had an effect on the nasal microbiota, whereas perinatal and early postnatal factors did not show significant effects. Presence of older siblings affected the nasal microbiota of preterm infants. This study demonstrated that microbiota composition differs between full-term and preterm infants, with a lower abundance of Moraxella and Dolosigranulum in preterm infants. Examining the differences in nasal microbiota between preterm and full-term infants may contribute to understanding the trajectory of the bacterial component of the nasal microbiota of preterm infants.

Probiotics Application in the Treatment of Autoimmune Diseases and Enhancement of Efficacy Through Genetic Engineering

The development of multidrug resistance in most pathogenic microorganisms and the rapidly increasing prevalence of non-communicable diseases are becoming major health concerns worldwide. Among non-communicable diseases, autoimmune diseases are caused mainly by imbalances in the gut microbiota (dysbiosis). Gut microbiota colonization and immune system establishment started in the early years of life. A defect in the gut microbiota predominantly affects the proper functioning of immune cells. Hence, restoring gut dysbiosis has received considerable attention for the last few decades as a potential therapeutic option. In this regard, probiotics have been the focus of research during recent decades because of their safe history of use along with fermented foods and beverages. Currently, advanced research is being conducted on the use of probiotics as immunomodulatory mediators and for the amelioration of gut dysbiosis as therapeutic adjuncts in the treatment of autoimmune diseases. In addition, probiotics are genetically engineered to enhance treatment efficacy and to develop live biotherapeutics (LBP). In this review, research articles summarizing findings in autoimmune disease treatment via probiotic strains, emphasizing type 1 diabetes, rheumatoid arthritis, Graves&amp;apos; disease, systemic lupus erythematosus and inflammatory bowel disease in both clinical trials and animal models, were reviewed. Finally, promising results of genetic engineering of probiotics for use as biosensors, delivery of therapeutic proteins, and diagnosis of infections were reported.

Bacillus velezensis HBXN2020 alleviates Salmonella Typhimurium infection in mice by improving intestinal barrier integrity and reducing inflammation

Bacillus velezensis is a species of Bacillus that has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies on B. velezensis have focused on the biocontrol of plant diseases, with few reports on antagonizing Salmonella Typhimurium infections. In this investigation, it was discovered that B. velezensis HBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly, B. velezensis HBXN2020 did not cause any adverse side effects in mice when administered at various doses (1×107, 1×108, and 1×109 CFU) for 14 days. Supplementing B. velezensis HBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels of S. Typhimurium ATCC14028 in the mice’s feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementing B. velezensis HBXN2020 spores significantly regulated cytokine levels (Tnfa, Il1b, Il6, and Il10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, adding B. velezensis HBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (Lactobacillus and Akkermansia). All together, B. velezensis HBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection by S. Typhimurium.

Bacillus velezensis HBXN2020 alleviates Salmonella Typhimurium infection in mice by improving intestinal barrier integrity and reducing inflammation.

Bacillus velezensis is a species of Bacillus that has been widely investigated because of its broad-spectrum antimicrobial activity. However, most studies on B. velezensis have focused on the biocontrol of plant diseases, with few reports on antagonizing Salmonella Typhimurium infections. In this investigation, it was discovered that B. velezensis HBXN2020, which was isolated from healthy black pigs, possessed strong anti-stress and broad-spectrum antibacterial activity. Importantly, B. velezensis HBXN2020 did not cause any adverse side effects in mice when administered at various doses (1×107, 1×108, and 1×109 CFU) for 14 days. Supplementing B. velezensis HBXN2020 spores, either as a curative or preventive measure, dramatically reduced the levels of S. Typhimurium ATCC14028 in the mice's feces, ileum, cecum, and colon, as well as the disease activity index (DAI), in a model of infection caused by this pathogen in mice. Additionally, supplementing B. velezensis HBXN2020 spores significantly regulated cytokine levels (Tnfa, Il1b, Il6, and Il10) and maintained the expression of tight junction proteins and mucin protein. Most importantly, adding B. velezensis HBXN2020 spores to the colonic microbiota improved its stability and increased the amount of beneficial bacteria (Lactobacillus and Akkermansia). All together, B. velezensis HBXN2020 can improve intestinal microbiota stability and barrier integrity and reduce inflammation to help treat infection by S. Typhimurium.

Sanguinarine chloride hydrate mitigates colitis symptoms in mice through the regulation of the intestinal microbiome and metabolism of short-chain fatty acids

Sanguinarine constitutes the main components of Macleaya cordata, and exhibits diverse biological and pharmacological activities. This study investigated the effects of sanguinarine chloride hydrate (SGCH) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. Five groups were designed to investigate the effects of SGCH on the pathological symptoms, the mRNA expression levels of inflammatory cytokines, colonic mucosal barrier damage, microbiota composition, and SCFAs metabolism in UC mice. The administration of SGCH in DSS-induced UC mice resulted in the amelioration of pathological symptoms, as evidenced by an increase in body weight, a decrease in disease activity index score, elongation of colon length, reduction in spleen index, and improvement in colon injury. SGCH can regulate the expression of inflammatory cytokines (IL-6, TNF-α, IL-1β and IL-10) and tight junction proteins (ZO-1 and Occludin) associated with UC. SGCH exhibited a significant decrease in NF-κB P65 mRNA expression levels, accompanied by a significantly reduced protein level of NF-κB P-P65/P65. Further studies revealed SGCH effectively reversed the decrease in intestinal microbiota diversity induced by UC, thereby promoting the growth of beneficial bacteria such as Akkermansia, Alistipes, and norank_o_Clostridia_UCG-014. Correlation analysis demonstrated a positive association between butanoic acid, propanoic acid, isobutyric acid, isovaleric acid, valeric acid, hexanoic acid with Colidextribacter, while Coriobacteriaceae_UCG-002 exhibited a negative correlation with butanoic acid, acetic acid and propanoic acid. In conclusion, the administration of SGCH can ameliorate clinical symptoms in UC mice, regulate the expression of inflammatory cytokines and tight junction proteins, modulate intestinal microbiota metabolism and SCFAs production.

Protective Role of Indole-3-Acetic Acid Against Salmonella Typhimurium: Inflammation Moderation and Intestinal Microbiota Restoration.

Indole-3-acetic acid (IAA), a metabolite derived from microbial tryptophan metabolism, plays a crucial role in regulating intestinal homeostasis. However, the influence and potential applications of IAA in the context of animal pathogen infections remain underexplored. This study investigates the prophylactic effects of IAA pretreatment against Salmonella typhimurium (ST) SL1344 infection, focusing on its ability to attenuate inflammatory responses, enhance intestinal barrier integrity, inhibit bacterial colonization, and restore colonic microbiota dysbiosis. The results demonstrated that IAA ameliorated the clinical symptoms in mice, as evidenced by reduced weight loss and histopathological damage. Furthermore, IAA inhibited the inflammatory response by downregulating the gene expression of pro-inflammatory cytokines IL-17A, TNF-α, IL-1β, and IL-6 in colon, ileum, and liver. IAA also preserved the integrity of the intestinal mucosal barrier and promoted the expression of tight junction proteins. Additionally, 16S rRNA gene sequencing revealed significant alterations in intestinal microbiota structure induced by ST infection following IAA treatment. Notable changes in β diversity and species richness were characterized by the enrichment of beneficial bacteria including Bacteroideaceae, Spirillaceae, and Bacillus. The proliferation of Salmonella enterica subspecies enterica serovar Typhi was significantly inhibited, thereby enhancing the intestinal health of the host. In summary, the oral administration of IAA contributes to the alleviation of inflammation, restoration of the intestinal barrier, and correction of colonic microbiota disturbance in mice challenged with ST.

Dual action tofacitinib-loaded PLGA nanoparticles alleviate colitis in an IBD mouse model.

Inflammatory bowel disease (IBD) affects over 7 million people worldwide and significant side effects are associated with current therapies such as tofacitinib citrate (TFC), which is linked to increased risks of malignancy and congestive heart issues. To mitigate these systemic adverse effects, localised drug delivery via nano-sized carriers to inflamed gut tissues represents a promising approach. Herein, we aimed to optimise the synthesis of nanoparticles (NPs) using a low molecular weight grade of Poly(lactic-co-glycolic acid) (PLGA) 50:50 loaded with TFC. This approach leverages the dual anti-inflammatory action of TFC and the local production of anti-inflammatory short-chain fatty acids from the degradation of PLGA by colonic gut microbiota. NPs were produced by nanoprecipitation and characterised for their drug release profile in vitro. The efficacy of the enhanced PLGA-TFC NPs was then tested in a C57BL/6 DSS colitis mouse model. The release profile of TFC from the enhanced PLGA NPs showed a 40% burst release within the first hour, followed by up to 80% drug release in the colonic environment. Notably, the degradation of PLGA by colonic gut microbiota did not significantly influence TFC release. In the mouse model, neither PLGA NPs alone nor TFC alone showed significant effects on weight loss compared to the TFC-loaded PLGA NPs, emphasising the enhanced efficacy potential of the combined formulation. Altogether, these results suggest a promising role of NP delivery systems in enhancing TFC efficacy, marking a significant step towards reducing dosage and associated side effects in IBD treatment. This study underscores the potential of PLGA-TFC NPs in providing targeted and effective therapy for IBD.

Mobile genetic elements: the hidden puppet masters underlying infant gut microbiome assembly?

The gut microbiota is important for healthy infant development. Part of the initial colonizing microbial strains originate from the maternal gut, and undergo a selective event, termed the “colonization bottleneck”. While vertical mother-to-infant inheritance and subsequent colonization of bacteria have previously been studied, the role of mobile genetic elements (MGEs) in the infant gut microbiota assembly is unclear. In this perspective article, we discuss how horizontally and vertically transmitted phages and conjugative elements potentially have important roles in infant gut microbiota assembly and colonization through parasitic and mutualistic interactions with their bacterial hosts. While some of these MGEs are likely to be detrimental to their host survival, in other contexts, they may help bacteria colonize new niches, antagonize other bacteria, or protect themselves from other parasitic MGEs in the infant gut. As a result, the horizontal transfer of MGEs likely occurs at high rates in the infant gut, contributing to gene transfer between bacteria and affecting which bacteria can pass the colonization bottleneck. We conclude by highlighting the potential in silico , in vitro , and in vivo methodological approaches that could be employed to study the transmission and colonization dynamics of MGEs and bacteria in the infant gut.

Shrimp Intestinal Microbiota Homeostasis: Dynamic Interplay Between the Microbiota and Host Immunity

ABSTRACTThe shrimp intestine harbors a microbiota that has pivotal roles for host's physiology. Imbalance of shrimp intestinal microbiota has been shown closely related to the occurrence of diseases. The morphological and biological features of the shrimp intestine are considered suboptimal for stable microbial colonization, making the intestinal microbiota composition highly susceptible to the impact of environmental changes or stressors, and particularly unstable. Therefore, the relative unsteadiness of the microbiota composition represents a continuous threat to host survival. Shrimp intestinal microbiota homeostasis is achieved through a dynamic interplay between the microbiota and the host's innate immunity. The shrimp intestine possesses effective innate immune mechanisms that can suppress the uncontrolled proliferation of microbiota components, and simultaneously protect the microbiota from elimination. The mechanism(s) by which the microbial components and the intestinal innate immunity interact with each other to achieve homeostasis represents an interesting interplay between host and microbiota. This review summarizes the current knowledge about intestinal microbiota colonization in shrimp, as well as the intricate mechanisms employed by the intestinal immune system to regulate this microbiota. Moreover, the potential intervention strategies to promote and protect shrimp intestinal homeostasis by modulating the microbiota are also discussed. Thus, this review seeks to comprehensively analyze the current information and contribute to a deeper understanding of the complex interplay between the shrimp intestinal microbiota and innate immunity in maintaining shrimp intestinal homeostasis and overall health. This enhanced understanding may potentially open new avenues for aquaculture management and disease mitigation strategies, ultimately benefiting the shrimp farming industry.

Poria cocos polysaccharides alleviate dextran sulphate sodium-induced ulcerative colitis in mice by modulating intestinal inflammatory responses and microbial dysbiosis

Poria cocos polysaccharide (PCP), one of the main active components of P. cocos, is extensively used worldwide and exhibits strong pharmacological effects. However, whether PCP can attenuate inflammatory bowel disease remains unclear. In this study, we assessed the effects of PCP supplementation on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice. We found that PCP supplementation mitigated UC symptoms in DSS-treated mice, as evidenced by reductions in body weight loss, colon length shortening and disease activity index score. Importantly, PCP supplementation enhanced colonic barrier integrity by increasing tight junction protein abundance and exerted anti-inflammatory effects by suppressing nuclear factor-κB (NF-κB) activation in DSS-treated mice. Furthermore, PCP supplementation reversed DSS-induced dysbiosis in colonic microbiota by increasing the colonic abundance of beneficial bacteria (e.g. Akkermansiaceae) and decreasing the colonic abundance of harmful bacteria (e.g. Erysipelotrichaceae) in DSS-treated mice. Although PCP supplementation failed to ameliorate DSS-induced UC in antibiotic-treated mice, faecal microbiota transplantation from PCP-administered mice ameliorated DSS-induced UC in antibiotic-treated mice. In summary, PCP alleviates UC in mice by attenuating intestinal inflammation via the inhibition of NF-κB activation and modulating the intestinal microbiota.

PREBIOTIC EFFICACY OF DEFATTED FENUGREEK SEED FLAKES (FENUFLAKESTM): A SHORT-TERM COLONIC SIMULATION STUDY

Objective: To investigate the prebiotic effects of defatted fenugreek seed flakes (Fenuflakes™) using a 48-hour colonic simulation model. Methods: Fecal samples from three healthy adult human donors were exposed to treatment conditions of blank (medium control), Fenuflakes, or inulin (fiber control). The effects on microbial fermentation (pH and gas production), metabolite production [Short Chain Fatty Acid (SCFAs), Branched-Chain Fatty Acid (BCFA), ammonium and lactate production], and microbial community composition were evaluated at 0, 6, 24, and 48 h. Results: In comparison to inulin, Fenuflakes demonstrated a significant reduction in gas production. Both inulin and Fenuflakes significantly increased beneficial SCFAs, but no significant change was observed in BCFA. Ammonium production increased upon Fenuflakes treatment due to a residual protein fraction reaching the colon, in contrast to inulin, which is in a protein-depleted state. The lactate levels significantly increased for Fenuflakes and inulin. The presence of Fenuflakes and inulin resulted in favorable fermentation by the colonic gut microbiota, indicating an increase in species enrichment and alpha diversity in the microbial community composition. Conclusion: Fenuflakes exhibit prebiotic potential by increasing SCFA and promoting the enrichment of several beneficial colonic bacteria while maintaining normal colonic pH and producing less gas than inulin.

Mutual Interactions of Silymarin and Colon Microbiota in Healthy Young and Healthy Elder Subjects.

This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects. An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50µgmL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003. This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.

The influence of modulation of intestinal microbiota on clinical and immunological parameters and oxytocin levels in children with autism spectrum disorders

Autism spectrum disorders are associated with an imbalance of immune and neurological disorders, starting after the age of two. The study is devoted to studying the role of specialized strains of bacteria Lactobacillus reuteri, which mediate the synthesis of oxytocin in humans and influence inflammation indicators. Bacteria of this strain were part of the biologically active additive “Panbiolact Mental”, developed and presented by NPO ArtLife (Tomsk). The purpose of the work was to assess the effect of specialized strains of bacteria Lactobacillus reuteri on changes in the composition of the intestinal microbiota, oxytocin levels, and immune parameters of children with ASD. The study included 43 children with autism spectrum disorders who took Panbiolact Mental for 90 days. The study materials included venous blood samples and fecal samples. The concentrations of cytokines (IL-4, IL-10, TNF, IFN), immunoglobulins (IgE, IgG, IgA, IgM) and the neuropeptide oxytocin were determined in the blood serum. Fecal samples were used to assess the qualitative and quantitative composition of the colon microbiota. Clinical symptoms of the disease associated with quality of life were assessed using the standard ATEC test scale (Autism Treatment Evaluation Checklist), expressed in scores corresponding to the severity of clinical and neurological parameters of the disease. In children with autism spectrum disorders, after 90 days of regular use of Panbiolact Mental, the number of bacteria of the genera Acinetobacter decreased, the number of Bacteroides species pluralis, Akkermansia muciniphila, Eubacterium rectale, Prevotella species pluralis and Methanobrevibacter smithii increased. Increases in the concentration of oxytocin, the protolerogenic coefficient IL-10/TNFα, immunoglobulins M and G, and a decrease in the concentrations of TNFα and IL-10 were recorded. The results of the study support the hypothesis of a significant role of gut microbiota diversity in the neuro-immune pathogenesis of autism spectrum disorders. “Panbiolact Mental” is presented as a potentially effective remedy for an integrated approach to the correction of ASD in children. These data may form the basis for further research in the field of probiotic therapy, as well as for the development of new strategies based on modulation of the intestinal microbiota.

The dynamic crosslinking between gut microbiota and inflammation during aging: reviewing the nutritional and hormetic approaches against dysbiosis and inflammaging.

The early-life gut microbiota (GM) is increasingly recognized for its contributions to human health and disease over time. Microbiota composition, influenced by factors like race, geography, lifestyle, and individual differences, is subject to change. The GM serves dual roles, defending against pathogens and shaping the host immune system. Disruptions in microbial composition can lead to immune dysregulation, impacting defense mechanisms. Additionally, GM aids digestion, releasing nutrients and influencing physiological systems like the liver, brain, and endocrine system through microbial metabolites. Dysbiosis disrupts intestinal homeostasis, contributing to age-related diseases. Recent studies are elucidating the bacterial species that characterize a healthy microbiota, defining what constitutes a 'healthy' colonic microbiota. The present review article focuses on the importance of microbiome composition for the development of homeostasis and the roles of GM during aging and the age-related diseases caused by the alteration in gut microbial communities. This article might also help the readers to find treatments targeting GM for the prevention of various diseases linked to it effectively.

Delving the depths of 'terra incognita' in the human intestine - the small intestinal microbiota.

The small intestinal microbiota has a crucial role in gastrointestinal health, affecting digestion, immune function, bile acid homeostasis and nutrient metabolism. The challenges of accessibility at this site mean that our knowledge of the small intestinal microbiota is less developed than of the colonic or faecal microbiota. Here, we summarize the features and fluctuations of the microbiota along the small intestinal tract, focusing on humans, and discuss physicochemical factors and assessment methods, including the technical challenges of investigating the low microbial biomass of the proximal small bowel. We highlight the essential protective mechanisms of the small intestine, including motility, the paracellular barrier and mucus, and secretory immunity, to show their roles in limiting excessive exposure of host tissues to microbial metabolites. We address current knowledge gaps, particularly the variability among individuals, the effects of dysbiosis of the small intestinal microbiota on health and how different taxa in small intestinal microbiota could compensate for each other functionally.

From colon wall to tumor niche: Unraveling the microbiome's role in colorectal cancer progression.

Colorectal cancer (CRC) is influenced by perturbations in the colonic microbiota, characterized by an imbalance favoring pathogenic bacteria over beneficial ones. This dysbiosis contributes to CRC initiation and progression through mechanisms such as carcinogenic metabolite production, inflammation induction, DNA damage, and oncogenic signaling activation. Understanding the role of external factors in shaping the colonic microbiota is crucial for mitigating CRC progression. This study aims to elucidate the gut microbiome's role in CRC progression by analyzing paired tumor and mucosal tissue samples obtained from the colon walls of 17 patients. Through sequencing of the V3-V4 region of the 16S rRNA gene, we characterized the tumor microbiome and assessed its association with clinical variables. Our findings revealed a significant reduction in alpha diversity within tumor samples compared to paired colon biopsy samples, indicating a less diverse microbial environment within the tumor microenvironment. While both tissues exhibited dominance of similar bacterial phyla, their relative abundances varied, suggesting potential colon-specific effects. Fusobacteriota enrichment, notably in the right colon, may be linked to MLH1 deficiency. Taxonomy analysis identified diverse bacterial genera, with some primarily associated with the colon wall and others unique to this region. Conversely, several genera were exclusively expressed in tumor tissue. Functional biomarker analysis identified three key genes with differential abundance between tumor microenvironment and colon tissue, indicating distinct metabolic activities. Functional biomarker analysis revealed three key genes with differential abundance: K11076 (putrescine transport system) and K10535 (nitrification) were enriched in the tumor microenvironment, while K11329 (SasA-RpaAB circadian timing mediator) dominated colon tissue. Metabolic pathway analysis linked seven metabolic pathways to the microbiome. Collectively, these findings highlight significant gut microbiome alterations in CRC and strongly suggest that long-term dysbiosis profoundly impacts CRC progression.

MIIST305 mitigates gastrointestinal acute radiation syndrome injury and ameliorates radiation-induced gut microbiome dysbiosis.

High-dose radiation exposure results in gastrointestinal (GI) acute radiation syndrome identified by the destruction of mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses. In addition, radiation causes gut microbiome dysbiosis characterized by diminished microbial diversity, reduction in the abundance of beneficial commensal bacteria, and the spread of bacterial pathogens that trigger the recruitment of immune cells and the production of pro-inflammatory factors that lead to further GI tissue damage. Currently, there are no FDA-approved countermeasures that can treat radiation-induced GI injury. To meet this critical need, Synedgen Inc., has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract which acts by intercalating into the mucus layer and the glycocalyx of intestinal epithelial cells that could potentially ameliorate the deleterious effects of radiation. Male C57BL/6J adult mice were exposed to 13 Gy total body X-irradiation with 5% bone marrow shielding and MIIST305 was administered on days 1, 3, and 5 post-irradiation. Approximately 85% of the animals survived the irradiation exposure and were apparently healthy until the end of the 30-day study period. In contrast, no control, vehicle-treated animals survived past day 10 at this radiation dose. We show that MIIST305 improved intestinal epithelial barrier function and suppressed systemic inflammatory response mediated by radiation-induced pro-inflammatory cytokines. Taxonomic profiling and community structure of the fecal and colonic mucosa microbiota demonstrated that MIIST305 treatment increased microbial diversity and restored abundance of beneficial commensal bacteria, including Lactobacillus and Bifidobacterium genera, while suppressing potentially pathogenic bacteria compared with vehicle-treated animals. In summary, MIIST305 is a novel GI-targeted therapeutic that greatly enhances survival in mice exposed to lethal radiation and protects the GI tract from injury by restoring a balanced gut microbiota and effectively reducing proinflammatory responses. Further development of this drug as an FDA-approved medical countermeasure will be of critical importance in the event of a radiation public health emergency.

Regular Exercise Training Induces More Changes on Intestinal Glucose Uptake from Blood and Microbiota Composition in Leaner Compared to Heavier Individuals in Monozygotic Twins Discordant for BMI.

Obesity impairs intestinal glucose uptake (GU) (intestinal uptake of circulating glucose from blood) and alters gut microbiome. Exercise improves intestinal insulin-stimulated GU and alters microbiome. Genetics influence the risk of obesity and gut microbiome. However, the role of genetics on the effects of exercise on intestinal GU and microbiome is unclear. Twelve monozygotic twin pairs discordant for BMI (age 40.4 ± 4.5 years, BMI heavier 36.7 ± 6.0, leaner 29.1 ± 5.7, 8 female pairs) performed a six-month-long training intervention. Small intestine and colonic insulin-stimulated GU was studied using [18F]FDG-PET and microbiota from fecal samples with 16s rRNA. Ten pairs completed the intervention. At baseline, heavier twins had lower small intestine and colonic GU (p < 0.05). Response to exercise differed between twins (p = 0.05), with leaner twins increasing colonic GU. Alpha and beta diversity did not differ at baseline. During the intervention, beta diversity changed significantly, most prominently at the mid-point (p < 0.01). Beta diversity changes were only significant in the leaner twins when the twin groups were analyzed separately. Exercise was associated with changes at the phylum level, mainly at the mid-point (pFDR < 0.05); at the genus level, several microbes increased, such as Lactobacillus and Sellimonas (pFDR < 0.05). In type 1 analyses, many genera changes were associated with exercise, and fewer, such as Lactobacillus, were also associated with dietary sugar consumption (p < 0.05). Obesity impairs insulin-stimulated intestinal GU independent of genetics. Though both twin groups exhibited some microbiota changes, most changes in insulin-stimulated colon GU and microbiota were significant in the leaner twins.

The reverse transsulfuration pathway affects the colonic microbiota and contributes to colitis in mice

Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth–/– mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth–/– mice compared to both WT and Slc7a11–/– mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.