Modulation Of Microbiota Composition Research Articles

Dietary Moringa oleifera leaf powder improves jejunal permeability and digestive function by modulating the microbiota composition and mucosal immunity in heat stressed rabbits.

Heat stress (HS) has detrimental effects on intestinal health by altering digestive and immune responses in animals. Dietary Moringa oleifera leaf powder (MOLP) has been implicated in ameliorating the impact of HS, but its effects in terms of intestinal function improvement under HS remain poorly characterized. Therefore, the current study investigated the impact of HS and MOLP supplementation on tight junction barriers, intestinal microbiota (jejunal digesta), and differentially expressed genes (DEGs) in jejunal mucosa of heat-stressed rabbits by using the next-generation sequencing techniques. A total of 21 male New Zealand White rabbits (32weeks old mean body weight of 3318 ± 171g) were divided into three groups (n = 7/group) as control (CON, 25°C), heat stress (HS, 35°C for 7h daily), and HS with MOLP supplementation (HSM, 35°C for 7h daily) gavage at 200mg/kg body weight per day for 4weeks. The results indicated that MOLP supplementation increased mRNA expression of tight junction proteins and glutathione transferase activity, while the malonaldehyde concentration was decreased in the jejunal mucosa compared to HS group (P < 0.05). Furthermore, MOLP decreased the concentrations of lipopolysaccharide, pro-inflammatory cytokines, and myeloperoxidase compared with HS group (P < 0.05). Intestinal microbiota analysis revealed that at phyla level, the relative abundance of Bacteroidetes was higher in HSM group compared to CON and HS groups. MOLP supplementation also resulted in higher abundance of putatively health-associated genera such as Christensenellaceae R-7 gut group, Ruminococcaceae NK4A214 group, Ruminococcus 2, Lachnospiraceae NK4A136 group, and Lachnospiraceae unclassified along with higher butyrate levels in HSM group as compared to HS group. The analysis of DEGs revealed that MOLP reversed inflammatory response by downregulation of genes, such as TNFRSF13C, LBP, and COX2 in enriched KEGG pathway of NF-kβ pathway. MOLP supplementation also significantly upregulated the expression of genes in protein digestion and absorption pathway, including PRSS2, LOC100349163, CPA1, CPB1, SLC9A3, SLC1A1, and SLC7A9 in HSM group. Three genes of fibrillar collagens, i.e., COL3A1, COL5A3, and COL12A1 in protein digestion were also down-regulated in HSM group. In conclusion, MOLP supplementation could improve jejunal permeability and digestive function, positively modulate microbiota composition and mucosal immunity in heat-stressed rabbits.

Dietary supplementation with Pediococcus pentosaceus enhances the innate immune response in and promotes growth of Litopenaeus vannamei shrimp.

To reach the sustainable development goals on health management in Litopenaeus vannamei shrimp culture, Pediococcus pentosaceus AB01 was supplemented in shrimp diet. In this study, the control diet and three experimental diets containing P.pentosaceus AB01 (108 , 109 , 1010 CFU/g) were separately introduced to L.vannamei for a 28 days feeding trial. After the feeding trial, percent weight gain, feeding efficiency, and feed conversion ratio (FCR) were significantly elevated in L.vannamei administered with P.pentosaceus AB01 at 109 and 1010 colony-forming unit (CFU)/g. Protease, amylase, and trypsin were found at higher levels in the probiotic-supplied groups. The feeding of shrimps with P.pentosaceus AB01 significantly increased innate immune response and levels of related biochemical parameters in the haemolymph. After the white spot syndrome virus (WSSV) challenge, supplementation of P.pentosaceus AB01 had significant positive effects (p < .05) on survival rate, compared to that of the control diet. The higher resistance of L.vannamei to WSSV might have been due to alterations in the gut microbiome composition and upregulation of the Toll-Like Receptor (TLR) signalling pathway. Hence, P.pentosaceus AB01 may be a promising alternative feed to promote growth rate, modulate microbiota composition, and enhance immunity in L.vannamei shrimp.

Effects of dietary montmorillonite supplementation on the growth performance, antioxidant capacity, intestinal barrier and microbiota composition in Marsupenaeus japonicus

Traditionally, montmorillonite (Mt) was used as a pelletizing aid in the production of feed pellets, or absorbents for aflatoxin B1 and heavy metal in aquaculture. The physiological metabolism influence of Mt. on aquatic animals has been long neglected. Therefore, this study aimed to investigate the influence of dietary Mt. supplementation (0%, 0.05%, 0.1%, 0.4% and 1% Mt) on the growth performance, antioxidant capacity, intestinal barrier and microbiota composition in Marsupenaeus japonicus. The results showed that although growth performance was not influenced by the dietary Mt. supplementation, shrimp fed with 0.05% Mt. significantly increased antioxidant enzymes (superoxide dismutase and glutathione in the hepatopancreas) activities and genes expression (superoxide dismutase 5, peroxiredoxin and catalase) in the hepatopancreas and intestine. Moreover, intestinal barrier function was significantly influenced, which was identified by the increased villus height and width, upregulated barrier-related genes (fascicilin II and integrin) expression. The relative abundance of intestinal probiotic (Lactobacillus, Bacteroidales S24–7 group, Ruegeria and Faecalibacterium) were increased when shrimp fed with 0.05% and 1% Mt. In addition, shrimp fed with 0.05% Mt. significantly increased the relative abundance of Alloprevotella and decreased the relative abundance of Escherichia-Shigella, while the relative abundance of Vibrio was increased when Mt. supplementation level reached at 1%. Overall, these results indicated that dietary appropriate Mt. supplementation (0.05%) could improve antioxidant capacity, intestinal barrier and modulate microbiota composition in M. japonicus. These findings might provide partial theoretical evidence for the effects of dietary Mt. supplementation on the physiological metabolism in M. japonicus.

Defective Humoral Immunity Disrupts Bile Acid Homeostasis which Promotes Inflammatory Disease of the Small Bowel

Abstract Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. Here, we use a CD19−/− mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in bile acid homeostasis, and gluten-sensitive enteropathy of the small intestine. The gluten-sensitive small intestine enteropathy that develops in CD19−/− mice is associated with alterations to luminal bile acid composition in the SI, marked by significant reductions in the abundance of conjugated bile acids. Manipulation of bile acid availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase activity all influence the severity of small intestine enteropathy in CD19−/− mice. Collectively, results from our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial BA metabolism. J.L.K. was supported by a NIAID K22 Award (AI123481), a Jeffrey Modell Network Specific Diseases Research Award, a University of South Carolina ASPIRE-I Award, a pilot project award through the University of South Carolina Center for Alternative Medicine COBRE program (P20GM103641; awarded to Drs. Mitzi and Prakash Nagarkatti), an R21 (AI142409), and 1R01AI155887.

Defective humoral immunity disrupts bile acid homeostasis which promotes inflammatory disease of the small bowel

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. Here, we use a CD19−/− mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in bile acid homeostasis, and gluten-sensitive enteropathy of the small intestine. The gluten-sensitive small intestine enteropathy that develops in CD19−/− mice is associated with alterations to luminal bile acid composition in the SI, marked by significant reductions in the abundance of conjugated bile acids. Manipulation of bile acid availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase activity all influence the severity of small intestine enteropathy in CD19−/− mice. Collectively, results from our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial BA metabolism.

Could Candida Overgrowth Be Involved in the Pathophysiology of Autism?

The purpose of this review is to summarize the current acquiredknowledge of Candida overgrowth in the intestine as a possible etiology of autism spectrum disorder (ASD). The influence of Candida sp. on the immune system, brain, and behavior of children with ASD isdescribed. The benefits of interventions such as a carbohydrates-exclusion diet, probiotic supplementation, antifungal agents, fecal microbiota transplantation (FMT), and microbiota transfer therapy (MTT) will be also discussed. Our literature query showed that the results of most studies do not fully support the hypothesis that Candida overgrowth is correlated with gastrointestinal (GI) problems and contributes to autism behavioral symptoms occurrence. On the one hand, it was reported that the modulation of microbiota composition in the gut may decrease Candida overgrowth, help reduce GI problems and autism symptoms. On the other hand, studies on humans suggesting the beneficial effects of a sugar-free diet, probiotic supplementation, FMT and MTT treatment in ASD are limited and inconclusive. Due to the increasing prevalence of ASD, studies on the etiology of this disorder are extremely needed and valuable. However, to elucidate the possible involvement of Candida in the pathophysiology of ASD, more reliable and well-designed research is certainly required.

Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics.

Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics.

Orally Administered Natural Lipid Nanoparticle-Loaded 6-Shogaol Shapes the Anti-Inflammatory Microbiota and Metabolome.

The past decade has seen increasing interest in microbiota-targeting therapeutic strategies that aim to modulate the gut microbiota’s composition and/or function to treat chronic diseases, such as inflammatory bowel disease (IBD), metabolic symptoms, and obesity. While targeting the gut microbiota is an innovative means for treating IBD, it typically requires an extended treatment time, hampering its potential application. Herein, using an established natural-lipid nanoparticle (nLNP) platform, we demonstrate that nLNPs encapsulated with the drug candidate 6-shogaol (6S/nLNP) distinctly altered microbiota composition within one day of treatment, significantly accelerating a process that usually requires five days using free 6-shogaol (6S). In addition, the change in the composition of the microbiota induced by five-day treatment with 6S/nLNP was maintained for at least 15 days (from day five to day 20). The consequent alteration in the fecal metabolic profile stemming from this compositional change manifested as functional changes that enhanced the in vitro anti-inflammatory and wound-healing efficacy of macrophage cells (Raw 264.7) and epithelial cells (Caco-2 BBE1), respectively. Further, this metabolic compositional change, as reflected in an altered metabolic profile, promoted a robust anti-inflammatory effect in a DSS-induced mouse model of acute colitis. Our study demonstrates that, by near-instantly modulating microbiota composition and function, an nLNP-based drug-delivery platform might be a powerful tool for treating ulcerative colitis.

Effects of a Postbiotic and Prebiotic Mixture on Suckling Rats' Microbiota and Immunity.

Human milk serves as a model for infant formula providing nutritional solutions for infants not able to receive enough mother’s milk. Infant formulas aim to mimic the composition and functionality of human milk by providing ingredients reflecting those of the latest human milk insights, such as prebiotics, probiotics and postbiotics. The aim of this study was to examine the effects of the supplementation with a postbiotic (LactofidusTM) and its combination with the prebiotics short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS) in a preclinical model of healthy suckling rats. Pups were supplemented daily with LactofidusTM (POST group) and/or scGOS/lcFOS (P+P and PRE groups, respectively). Body weight and fecal consistency were analyzed. At the end of the study, immunoglobulin (Ig) profile, intestinal gene expression, microbiota composition and short chain fatty acid (SCFA) proportion were quantified. The supplementation with all nutritional interventions modulated the Ig profile, but the prebiotic mixture and the postbiotic induced differential effects: whereas scGOS/lcFOS induced softer feces and modulated microbiota composition and SCFA profile, Lactofidus™ upregulated Toll-like receptors gene expression. The use of the combination of scGOS/lcFOS and Lactofidus™ showed the effects observed for the oligosaccharides separately, as well as showing a synergistic impact on animal growth. Thus, the combined use of both products seems to be a good strategy to modulate immune and microbial features in early life.

Bacteriophage-Bacteria Interactions in the Gut: From Invertebrates to Mammals.

Bacteria and their viruses (bacteriophages or phages) interact antagonistically and beneficially in polymicrobial communities such as the guts of animals. These interactions are multifaceted and are influenced by environmental conditions. In this review, we discuss phage-bacteria interactions as they relate to the complex environment of the gut. Within the mammalian and invertebrate guts, phages and bacteria engage in diverse interactions including genetic coexistence through lysogeny, and phages directly modulate microbiota composition and the immune system with consequences that are becoming recognized as potential drivers of health and disease. With greater depth of understanding of phage-bacteria interactions in the gut and the outcomes, future phage therapies become possible.

Higher fiber complementary food alters Fecal microbiota composition and normalizes stool form in Malawian children: A randomized trial

Dietary fiber favorably modulates gut microbiota and may be protective against diarrhea in sub-Saharan Africa where rates in infants and young children are high. Soybean hull is high in fiber and accessible in rural Africa; however, its use in complementary feeding has not been evaluated. The objective of this study was to determine the acceptability and feasibility of a soybean, soy hull fiber, and maize (SFM) blend food; the primary outcome was compliance to the feeding protocol. Secondary outcomes were stool form and frequency, fecal microbiota composition, growth and dietary intake. In a parallel, single-blind study, children 6-36 months of age from the Lilongwe district of Malawi were randomized to receive daily SFM (n=69) or maize only(n=10) porridge(phala) for 6 months. Anthropometrics were measured monthly, and compliance, stool frequency,and stool form, weekly. At baseline, 3-month,and 6-month (study end) time points, dietary intake (24-h recall) was assessed,and fecal samples were collected. Fecal DNA was analyzed by Real-Time polymerase chain reaction (PCR) for microbes of interest and 16S rRNA gene amplicon sequencing. Mothers accessed the acceptability and feasibility of the study foods at study end. Mothers reported excellent compliance to feeding the SFM porridge, rated it more acceptable than maize,and noted improved appetite, weight, and stool consistency of their children. Stool frequency at baseline (2±1 stools/d) was unchanged with intervention; however, there were significantly fewer diarrhea-type stools reported during study months 4-6 vs.1-3 for the SFM group, whereas no improvement was seen for the maize group. At study end, the fecal abundance ofAkkermansia muciniphila was enriched in children receiving the SFM, compared to maize (p&lt;0.05), and a trend for increased Faecalibacterium prausnitzii (p=0.07) was seen. A comparison of fecal microbiota composition using linear discriminant analysis effect size (LEfSe)showed notable differences in numerous taxa in the SFM group compared to baseline, whereas the maize comparator exhibited fewer changes. Fiber intake was higher for the SFMgroup, compared to maize at 6 months (13.7±3.8 vs. 8.4±4.5 g/day, p&lt;0.01). Weight-for-height and BMI-for-age Z-scores were significantly higher for the SFM group. In young Malawian children, feeding a blend of soybean, soy hulls and maize reduced diarrhea-type stools and increased the abundance of Akkermansia muciniphila, a bacterial species involved in maintaining intestinal health, and thus may provide a feasible means of improving wellness in children in resource-poor settings through the modulation of microbiota composition.

Prolyl Endopeptidase Gene Disruption Improves Gut Dysbiosis and Non-alcoholic Fatty Liver Disease in Mice Induced by a High-Fat Diet

The gut-liver axis is increasingly recognized as being involved in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). Prolyl endopeptidase (PREP) plays a role in gut metabolic homeostasis and neurodegenerative diseases. We investigated the role of PREP disruption in the crosstalk between gut flora and hepatic steatosis or inflammation in mice with NAFLD. Wild-type mice (WT) and PREP gene knocked mice (PREPgt) were fed a low-fat diet (LFD) or high-fat diet (HFD) for 16 or 24 weeks. Murine gut microbiota profiles were generated at 16 or 24 weeks. Liver lipogenesis-associated molecules and their upstream mediators, AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1), were detected using RT-PCR or western blot in all mice. Inflammatory triggers and mediators from the gut or infiltrated inflammatory cells and signal mediators, such as p-ERK and p-p65, were determined. We found that PREP disruption modulated microbiota composition and altered the abundance of several beneficial bacteria such as the butyrate-producing bacteria in mice fed a HFD for 16 or 24 weeks. The level of butyrate in HFD-PREPgt mice significantly increased compared with that of the HFD-WT mice at 16 weeks. Interestingly, PREP disruption inhibited p-ERK and p-p65 and reduced the levels of proinflammatory cytokines in response to endotoxin and proline-glycine-proline, which guided macrophage/neutrophil infiltration in mice fed a HFD for 24 weeks. However, at 16 weeks, PREP disruption, other than regulating hepatic inflammation, displayed improved liver lipogenesis and AMPK/SIRT1 signaling. PREP disruption may target multiple hepatic mechanisms related to the liver, gut, and microbiota, displaying a dynamic role in hepatic steatosis and inflammation during NAFLD. PREP might serve as a therapeutic target for NAFLD.

Defective Humoral Immunity Disrupts Bile Acid Homeostasis Which Promotes Inflammatory Disease of the Small Bowel

Abstract Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Whether and how mucosal antibody responses influence gut health through modulation of microbiota composition is unclear. One critical metabolic function carried out exclusively by bacteria in the gut is bio-transformation of host bile acids (BAs), and dysregulation of BAs metabolism has been linked to numerous inflammatory and metabolic diseases in humans. Here, we use a CD19−/− mouse model of antibody-deficiency to demonstrate that a relationship exists between dysbiosis, defects in BA homeostasis, and enteropathy of the small intestine (SI). SI enteropathy that develops in CD19−/− mice is associated with alterations to the luminal BA pool in the SI, marked by significant reductions in the abundance of conjugated BAs. Manipulation of BA availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase (bsh) activity all influence the severity of SI enteropathy in CD19−/− mice. Collectively, results from our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial BA metabolism.

A grass carp model with an antibiotic-disrupted intestinal microbiota

Intestinal microbiota has increasingly been recognized as a major determinant of host health due to its critical role in the maintenance of immune homeostasis. An experimental fish model with disrupted intestinal microbiota allows us to identify potential strategies for restoring or modulating microbiota composition. The aim of this study was to develop a reliable grass carp model with disrupted intestinal microbiota by treatment with an antibiotic cocktail consisting of vancomycin, enrofloxacin, florfenicol, and metronidazole at different concentrations. To identify the appropriate concentration and exposure time of antibiotic treatment required to disrupt intestinal microbiota, five antibiotic regimens were compared in terms of their effects on intestinal microbiota composition, growth and health status, and histological changes in the intestine, hepatopancreas, and spleen. Antibiotic-induced changes in the expression of inflammation- and apoptosis-related genes in grass carp intestines were also examined. The results revealed that the highest antibiotic concentration over a 28 day period was required to disrupt both luminal and mucosal microbiota through significant expansion of Proteobacteria and suppression of Fusobacteria. Treatment with this regimen induced significant down-regulation of caspase-8, MLCK, ZO-1, IL-17N, and IL-23R, and up-regulation of IL-1β and IL-6 in the intestine, suggesting possible effects on intestinal epithelial tight junction and inflammatory conditions. This treatment did not produce substantial histopathological changes, and was not directly detrimental to growth and health. Therefore, this antibiotic regimen may provide a suitable option to disrupt intestinal microbiota in grass carp. In addition, our study also implies that fish may serve as a promising model for investigating growth-promoting effects of antibiotics, when treated with antibiotics in low doses.

Contribution of Infectious Agents to the Development of Celiac Disease.

The ingestion of wheat gliadin (alcohol-soluble proteins, an integral part of wheat gluten) and related proteins induce, in genetically predisposed individuals, celiac disease (CD), which is characterized by immune-mediated impairment of the small intestinal mucosa. The lifelong omission of gluten and related grain proteins, i.e., a gluten-free diet (GFD), is at present the only therapy for CD. Although a GFD usually reduces CD symptoms, it does not entirely restore the small intestinal mucosa to a fully healthy state. Recently, the participation of microbial components in pathogenetic mechanisms of celiac disease was suggested. The present review provides information on infectious diseases associated with CD and the putative role of infections in CD development. Moreover, the involvement of the microbiota as a factor contributing to pathological changes in the intestine is discussed. Attention is paid to the mechanisms by which microbes and their components affect mucosal immunity, including tolerance to food antigens. Modulation of microbiota composition and function and the potential beneficial effects of probiotics in celiac disease are discussed.

Lactobacillus fermentum CECT5716 ameliorates high fat diet-induced obesity in mice through modulation of gut microbiota dysbiosis

Obesity is one of the main features of metabolic syndrome, where a low-grade chronic inflammation and gut dysbiosis contribute to the development of the related metabolic dysfunctions. Different probiotics have demonstrated beneficial effects on this condition, increasing the interest in the development of probiotic treatments. Lactobacillus fermentum CECT5716 has shown anti-inflammatory effects and capacity to modulate microbiota composition in different experimental models. In this study, L. fermentum CECT5716 was evaluated in a model of high fat diet-induced obesity in mice. It exerts anti-obesity effects, associated with its anti-inflammatory properties and amelioration of endothelial dysfunction and gut dysbiosis. The probiotic restores Akkermansia sp. abundance and reduced Erysipelotrichi class and Clostridium spp presence as well as increased Bacteroides proportion. In conclusion, this probiotic represents a very interesting approach. Our findings describe, for the first time, the ability of this probiotic to ameliorate experimental obesity through microbiome modulation, affecting different bacteria that have been reported to play a key role in the pathogenesis of obesity. Therefore, this suggests a potential use of L. fermentum CECT5716 in clinical practice, also taking into account that probiotic treatments have demonstrated to be relatively safe and well tolerated.

Mediterranean Diet for the Prevention of Gestational Diabetes in the Covid-19 Era: Implications of Il-6 In Diabesity.

The aim of this review is to highlight the influence of the Mediterranean Diet (MedDiet) on Gestational Diabetes Mellitus (GDM) and Gestational Weight Gain (GWG) during the COVID-19 pandemic era and the specific role of interleukin (IL)-6 in diabesity. It is known that diabetes, high body mass index, high glycated hemoglobin and raised serum IL-6 levels are predictive of poor outcomes in coronavirus disease 2019 (COVID-19). The immunopathological mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection include rising levels of several cytokines and in particular IL-6. The latter is associated with hyperglycemia and insulin resistance and could be useful for predicting the development of GDM. Rich in omega-3 polyunsaturated fatty acids, vitamins, and minerals, MedDiet improves the immune system and could modulate IL-6, C reactive protein and Nuclear Factor (NF)-κB. Moreover, polyphenols could modulate microbiota composition, inhibit the NF-κB pathway, lower IL-6, and upregulate antioxidant enzymes. Finally, adhering to the MedDiet prior to and during pregnancy could have a protective effect, reducing GWG and the risk of GDM, as well as improving the immune response to viral infections such as COVID-19.

A polysaccharide from natural Cordyceps sinensis regulates the intestinal immunity and gut microbiota in mice with cyclophosphamide-induced intestinal injury.

A polysaccharide from Cordyceps sinensis (NCSP) was reported to attenuate intestinal injury and regulate the balance of T helper (Th)1/Th2 cells in immunosuppressed mice. However, whether it influences Th17 and regulatory T (Treg) cells as well as gut ecology remains unknown. In the present study, the intestinal injury mouse model was also established by intraperitoneal injection of cyclophosphamide (Cy) for three consecutive days. NCSP was found to increase the number of CD4+ T cells, stimulate the secretion of interleukins (IL)-17 and IL-21, and the expression of transcription factor (retinoic acid-related orphan receptor (ROR)-γt). The levels of transforming growth factor (TGF)-β3 and transcription factor (forkhead box (Fox)p-3) were increased in NCSP-treated groups. Moreover, NCSP upregulated the mRNA expression of toll like receptors (TLR-2, -6 and -9), while it downregulated the TLR-4 expression. In addition, NCSP modulated the intestinal microbiota composition and increased the levels of SCFAs. These findings indicated that NCSP may enhance intestinal immunity and have the potential to become a prebiotic to regulate intestinal microbiota.

S‐Allylcysteine Inhibits PhIP/DSS‐Induced Colon Carcinogenesis through Mitigating Inflammation, Targeting Keap1, and Modulating Microbiota Composition in Mice

ScopeThe objective of the present study is to investigate whether edible S‐allylcysteine (SAC) has chemoprophylactic effects on inflammation‐associated colon carcinogenesis induced in mice through 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) exposure and promoted by dextran sodium sulfate (DSS) and whether its cancer‐prevention effects are related to the modulation of gut microbiota composition.Methods and resultsDietary administration of 0.05% SAC in mice for 18 weeks prevents shortening of the colon length and reduces the number of colon polyps. The SAC supplementation markedly decreases PhIP/DSS‐induced plasma and colon tissue pro‐inflammatory cytokines. These changes are accompanied by the suppression of inducible nitric oxide synthase, COX‐2, and MMP‐2 protein expression in colon tissue. In addition, the dietary administration of SAC increases heme oxygenase‐1 expression through activation of the NF‐E2‐related factor 2 pathway, thus abating PhIP/DSS‐induced colitis. The 16S rRNA gene sequence data indicate that SAC counteracted the PhIP/DSS‐induced gut dysbiosis, resulting in a microbiota composition similar to the control group.ConclusionThe results indicate that SAC can suppress PhIP/DSS‐induced colorectal carcinogenesis. Hence, SAC may merit further clinical investigation as a chemoprevention strategy for retarding colitis‐associated colon cancer in humans.

Dietary Adaptation of Microbiota in Drosophila Requires NF-κB-Dependent Control of the Translational Regulator 4E-BP

Dietary nutrients shape complex interactions between hosts and their commensal gut bacteria, further promoting flexibility in host-microbiota associations that can drive nutritional symbiosis. However, it remains less clear if diet-dependent host signaling mechanisms also influence these associations. Using Drosophila, we show here that nuclear factor κB (NF-κB)/Relish, an innate immune transcription factor emerging as a signaling node linking nutrient-immune-metabolic interactions, is vital to adapt gut microbiota species composition to host diet macronutrient composition. We find that Relish is required within midgut enterocytes to amplify host-Lactobacillus associations, an important bacterial mediator of nutritional symbiosis, and thus modulate microbiota composition in response to dietary adaptation. Relish limits diet-dependent transcriptional inducibility of the cap-dependent translation inhibitor 4E-BP/Thor to control microbiota composition. Furthermore, maintaining cap-dependent translation in response to dietary adaptation is critical to amplify host-Lactobacillus associations. These results highlight that NF-κB-dependent host signaling mechanisms, in coordination with host translation control, shape diet-microbiota interactions.