Extra-intestinal Effects Research Articles

Butyric acid and prospects for creation of new medicines based on its derivatives: a literature review.

The widespread use of antimicrobials causes antibiotic resistance in bacteria. The use of butyric acid and its derivatives is an alternative tactic. This review summarizes the literature on the role of butyric acid in the body and provides further prospects for the clinical use of its derivatives and delivery methods to the animal body. Thus far, there is evidence confirming the vital role of butyric acid in the body and the effectiveness of its derivatives when used as animal medicines and growth stimulants. Butyric acid salts stimulate immunomodulatory activity by reducing microbial colonization of the intestine and suppressing inflammation. Extraintestinal effects occur against the background of hemoglobinopathy, hypercholesterolemia, insulin resistance, and cerebral ischemia. Butyric acid derivatives inhibit histone deacetylase. Aberrant histone deacetylase activity is associated with the development of certain types of cancer in humans. Feed additives containing butyric acid salts or tributyrin are used widely in animal husbandry. They improve the functional status of the intestine and accelerate animal growth and development. On the other hand, high concentrations of butyric acid stimulate the apoptosis of epithelial cells and disrupt the intestinal barrier function. This review highlights the biological activity and the mechanism of action of butyric acid, its salts, and esters, revealing their role in the treatment of various animal and human diseases. This paper also discussed the possibility of using butyric acid and its derivatives as surface modifiers of enterosorbents to obtain new drugs with bifunctional action.

A Pilot Study of Exercise Training for Children and Adolescents With Inflammatory Bowel Disease: An Evaluation of Feasibility, Safety, Satisfaction, and Efficacy.

Children with inflammatory bowel disease (IBD) experience extraintestinal side effects including altered body composition, impaired muscle strength, and aerobic capacity. Exercise training may remedy these issues. To assess the feasibility, safety, participant satisfaction, and efficacy of a training program for youth with IBD. Children with IBD completed 16weeks of training (2 supervised + 1 home sessions per week). Feasibility was assessed by tracking recruitment, adherence, and compliance rates. Safety was assessed by tracking symptoms and adverse events. Posttraining interviews gauged satisfaction. Circulating inflammatory markers, body composition, muscle strength, aerobic fitness, and habitual physical activity were measured at baseline, midtraining (8wk), and posttraining. Eleven youth were recruited and 10 completed the study. Participants adhered to 28 (1) of 32 prescribed supervised sessions and 8 (4) of 16 prescribed home sessions. There were no adverse events, and overall feedback on training was positive. Posttraining, we observed an increase in lean mass (+2.4 [1.1]kg), bone density (+0.0124 [0.015] g·cm-2), aerobic fitness (+2.8 [5.7] mL·kgLM-1·min-1), and vigorous physical activity levels (+13.09 [8.95]min·h-1) but no change in inflammation or muscle strength. Supervised exercise training is feasible, safe, and effective for youth with IBD and should be encouraged.

Moonlighting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein of Lactobacillus gasseri attenuates allergic asthma via immunometabolic change in macrophages

BackgroundThe extra-intestinal effects of probiotics for preventing allergic diseases are well known. However, the probiotic components that interact with host target molecules and have a beneficial effect on allergic asthma remain unknown. Lactobacillus gasseri attenuates allergic airway inflammation through the activation of peroxisome proliferator- activated receptor γ (PPARγ) in dendritic cells. Therefore, we aimed to isolate and investigate the immunomodulatory effect of the PPARγ activation component from L. gasseri.MethodsCulture supernatants of L. gasseri were fractionated and screened for the active component for allergic asthma. The isolated component was subjected to in vitro functional assays and then cloned. The crystal structure of this component protein was determined using X-ray crystallography. Intrarectal inoculation of the active component-overexpressing Clear coli (lipopolysaccharide-free Escherichia coli) and intraperitoneal injection of recombinant component protein were used in a house dust mite (HDM)-induced allergic asthma mouse model to investigate the protective effect. Recombinant mutant component proteins were assayed, and their structures were superimposed to identify the detailed mechanism of alleviating allergic inflammation.ResultsA moonlighting protein, glycolytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH), LGp40, that has multifunctional effects was purified from cultured L. gasseri, and the crystal structure was determined. Both intrarectal inoculation of LGp40-overexpressing Clear coli and intraperitoneal administration of recombinant LGp40 protein attenuated allergic inflammation in a mouse model of allergic asthma. However, CDp40, GAPDH isolated from Clostridium difficile did not possess this anti-asthma effect. LGp40 redirected allergic M2 macrophages toward the M1 phenotype and impeded M2-prompted Th2 cell activation through glycolytic activity that induced immunometabolic changes. Recombinant mutant LGp40, without enzyme activity, showed no protective effect against HDM-induced airway inflammation.ConclusionsWe found a novel mechanism of moonlighting LGp40 in the reversal of M2-prompted Th2 cell activation through glycolytic activity, which has an important immunoregulatory role in preventing allergic asthma. Our results provide a new strategy for probiotics application in alleviating allergic asthma.

L-Cell Expression of Melanocortin-4-Receptor Is Marginal in Most of the Small Intestine in Mice and Humans and Direct Stimulation of Small Intestinal Melanocortin-4-Receptors in Mice and Rats Does Not Affect GLP-1 Secretion.

The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5–6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014—an often used MC4R antagonist, which we found to be a partial agonist—did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.

In vivo bioavailability and in vitro toxicological evaluation of the new butyric acid releaser N-(1-carbamoyl-2-phenyl-ethyl) butyramide

A large body of evidence suggests that supplementation of butyric acid exerts beneficial intestinal and extra-intestinal effects. Unfortunately, unpleasant sensorial properties and unfavourable physico-chemical properties strongly limit its use in food supplements and foods for medicinal purposes. N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) is a new butyric acid releaser in solid form with neutral sensorial properties. The aim of this investigation is to provide preliminary information on its pharmacokinetic and toxicological properties through the study of a) in vivo bioavailability of FBA administered by oral gavage to male and female Swiss CD1 mice in comparison with sodium butyrate, b) the influence of digestion on FBA stability through an in vitro simulated oro-gastro-duodenal digestion process, and c) in vitro toxicological profile by means of the Ames Test and Micronucleus Test. The results reveal that FBA is a good butyric acid releaser, being able to increase butyrate serum concentration in a dose and time dependent manner in both male and female mice with a pharmacokinetic profile similar to that obtained from sodium butyrate as such. These data are confirmed by investigating the influence of digestion on FBA, which undergoes extensive hydrolysis following oro-gastro-duodenal digestion, especially in duodenal conditions, with a residual concentration of less than 10% of the initial FBA concentration. Finally, in the Ames and Micronucleus Tests, FBA does not show any in vitro genotoxicity as it is non mutagenic in the Ames Test and results to be unable to induce chromosome breaks in the Micronucleus Test. In conclusion, FBA is a new butyric acid releaser that can overcome the disadvantages of butyric acid while maintaining the same pharmacokinetic properties and safety profile, as shown by the results of the preliminary in vitro toxicological studies performed in this investigation.

High fat diet, gut microbiome and gastrointestinal cancer.

Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.

Extra-Intestinal Effects of C. difficile Toxin A and B: An In Vivo Study Using the Zebrafish Embryo Model

C.difficile infection (CDI) is not a merely “gut-confined” disease as toxemia could drive the development of CDI-related extra-intestinal effects. These effects could explain the high CDI-associated mortality, not just justified by diarrhea and dehydration. Here, the extra-intestinal effects of toxin A (TcdA) and B (TcdB) produced by C. difficile have been studied in vivo using the zebrafish embryo model. Noteworthy, protective properties of human serum albumin (HSA) towards toxins-induced extra-intestinal effects were also addressed. Zebrafish embryos were treated with TcdA, TcdB and/or HSA at 24 h post-fertilization. Embryos were analyzed for 48 h after treatment to check vital signs and morphological changes. Markers related to cardio-vascular damage and inflammation were evaluated by Real-Time quantitative PCR and/or western blotting. Both toxins induced cardiovascular damage in zebrafish embryos by different mechanisms: (i) direct toxicity (i.e., pericardial edema, cardiac chambers enlargement, endothelial alteration); (ii) increased hormonal production and release (i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), (iii) alteration of the vascular system through the increase of the vascular endothelial growth factor (VEGF-A) levels, as well as of its receptors, (iv) pro-inflammatory response through high cytokines production (i.e., CXCL8, IL1B, IL6 and TNFα) and (v) cell-mediated damage due to the increase in neutrophils number. In addition to cardiovascular damage, we observe skin alteration and inflammation. Finally, our data indicate a protective effect of HSA toward the toxins induced extra-intestinal effects. Together, our findings can serve as a starting point for humans’ studies to substantiate and understand the extra-intestinal effects observed in CDI patients.

Gut-organ axis: a microbial outreach and networking.

Human gut microbiota (GM) includes a complex and dynamic population of microorganisms that are crucial for well-being and survival of the organism. It has been reported as diverse and relatively stable with shared core microbiota, including Bacteroidetes and Firmicutes as the major dominants. They are the key regulators of body homeostasis, involving both intestinal and extra-intestinal effects by influencing many physiological functions such as metabolism, maintenance of barrier homeostasis, inflammation and hematopoiesis. Any alteration in GM community structures not only trigger gut disorders but also influence other organs and cause associated diseases. In recent past, the GM has been defined as a 'vital organ' with its involvement with other organs; thus, establishing a link or a bi- or multidirectional communication axis between the organs via neural, endocrine, immune, humoral and metabolic pathways. Alterations in GM have been linked to several diseases known to humans; although the exact interaction mechanism between the gut and the organs is yet to be defined. In this review, the bidirectional relationship between the gut and the vital human organs was envisaged and discussed under several headings. Furthermore, several disease symptoms were also revisited to redefine the communication network between the gut microbes and the associated organs.

Across the "Sweetest" Properties of Human Breast Milk: Focus on Oligosaccharides.

Breast Milk (BM), containing nutrients and bioactive components, represents the best source for neonatal nutrition and determines short- and long- term benefits. Human milk oligosaccharides (HMOs) play an active role in these pathophysiological mechanisms. In fact, they influence the shaping of breastfed infant's gut microbiota, promote intestinal development, confer protection against intestinal or systemic infections modulating immune system; moreover, HMOs determine extra-intestinal effects on several target organs, i.e reducing necrotizing enterocolitis rate or improving brain development. In this review, we analyze the great inter- and intra-individual variability of BM HMOs, investigating maternal, genetic and environmental factors modulating their composition. Moreover, we provide an update regarding HMOs' unique properties, underlining their complex interaction with intestinal microbiota and host-derived metabolites. The possible HMOs' influence on extraintestinal bacterial communities, potentially influencing newborns' and even lactating mothers' health, have been hypothesized. Finally, recognized HMOs' crucial role, we underline the promising opportunities showed by their addition in formula milk, to make it more similar to maternal milk itself.

Intestinal parasitic infection alters bone marrow derived dendritic cell inflammatory cytokine production in response to bacterial endotoxin in a diet-dependent manner.

Giardia lamblia is a common intestinal parasitic infection that although often acutely asymptomatic, is associated with debilitating chronic intestinal and extra-intestinal sequelae. In previously healthy adults, a primary sporadic Giardia infection can lead to gut dysfunction and fatigue. These symptoms correlate with markers of inflammation that persist well after the infection is cleared. In contrast, in endemic settings, first exposure occurs in children who are frequently malnourished and also co-infected with other enteropathogens. In these children, Giardia rarely causes symptoms and associates with several decreased markers of inflammation. Mechanisms underlying these disparate and potentially enduring outcomes following Giardia infection are not presently well understood. A body of work suggests that the outcome of experimental Giardia infection is influenced by the nutritional status of the host. Here, we explore the consequences of experimental Giardia infection under conditions of protein sufficiency or deficiency on cytokine responses of ex vivo bone marrow derived dendritic cells (BMDCs) to endotoxin stimulation. We show that BMDCs from Giardia- challenged mice on a protein sufficient diet produce more IL-23 when compared to uninfected controls whereas BMDCs from Giardia challenged mice fed a protein deficient diet do not. Further, in vivo co-infection with Giardia attenuates robust IL-23 responses in endotoxin-stimulated BMDCs from protein deficient mice harboring enteroaggregative Escherichia coli. These results suggest that intestinal Giardia infection may have extra-intestinal effects on BMDC inflammatory cytokine production in a diet dependent manner, and that Giardia may influence the severity of the innate immune response to other enteropathogens. This work supports recent findings that intestinal microbial exposure may have lasting influences on systemic inflammatory responses, and may provide better understanding of potential mechanisms of post-infectious sequelae and clinical variation during Giardia and enteropathogen co-infection.

P131 CHARACTERIZING THE MICROBIOTA-GUT-BRAIN AXIS IN A MURINE MODEL OF PEDIATRIC INFLAMMATORY BOWEL DISEASE

Inflammatory bowel diseases (IBD) are chronic intestinal diseases affecting over 1.4 million Americans. Children and adolescents typically have more severe disease and are more likely to display extra-intestinal effects, including psychosocial deficits, compared to adult patients. Unfortunately, the mechanism(s) through which these extra-intestinal deficits develop is unknown and murine models of pediatric IBD do not exist. Our overall goal was to develop a model of pediatric IBD and assess the microbiota-gut-brain axis in adolescent mice. We hypothesized that induction of colitis at weaning would lead to long-lasting effects on the microbiota-gut-brain axis, including behavior. Colonic inflammation was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen with anticoagulant properties known to cause colitis in rodents. DSS (2% w/v) was given to weanling mice (P21) in drinking water for 5 days and then allowed to recover, modeling acute colitis. Behavior (cognition and anxiety) and inflammation (colon and hippocampus) was assessed at 6-8 weeks of age. In adult mice anxiety (light/dark box) and cognition (novel object recognition [NOR] task) were performed, and tissue samples collected for analysis by qPCR. Compared to control mice, DSS-treated mice showed impaired object recognition and increased anxiety-like behaviors. Gene expression was assessed in the colon and showed increased expression of the pattern recognition receptors nucleotide-binding oligomerization domain Nod1 andNod2 (as well as increased expression of the anti-inflammatory cytokine, interleukin 10 (Il10), and genes involved in NF-κB signaling (IκB) in DSS-treated mice compared to controls. Finally, gene expression in the hippocampus showed increased expression of nod1, nod2, and brain derived neurotropic factor (Bdnf) in DSS-treated mice compared to sham-treated controls. Taken together, these results indicate that acute DSS-induced colitis in early adolescence can have long-lasting effects on the microbiota-gut-brain axis in adulthood.

Probiotics: a new or an old concept?

Probiotics are an agent renewable from the outside that is capable of delivering active factors (metabolites, regulatory molecules, etc.) to target points of the gastrointestinal tract, and ensure the formation of a regulatory impact source for extraintestinal effects (target points). The uniqueness of probiotics lies in the fact that the microbial cell is simultaneously a proper transport container, a delivery system with a specific distribution in the gastrointestinal tract and a factory for reproduction of effector molecules.The modern Probiotics 2.0 concept implies not only the development of bioengineering strains, but the use of probiotics for the maximally proven indications. Conducting research in the most promising areas of probiotics usage, on the one hand, and the development of evidence base for a particular strain in a relatively narrow spectrum of clinically significant effects, on the other hand, significantly reduces the financial and time costs to bring new products to market. An example is a strain of Bifidobacterium longum longum 35624® that was authorized for the treatment of patients with irritable bowel syndrome. However, the “old” probiotics are no less important, especially if the original strain compliance with the “10 golden rules for probiotic therapy” is high.

Apical Membrane Alterations in Non-intestinal Organs in Microvillus Inclusion Disease.

Microvillus inclusion disease (MVID) is a severe form of neonatal diarrhea, caused mainly by mutations in MYO5B. Inactivating mutations in MYO5B causes depolarization of enterocytes in the small intestine, which gives rise to chronic, unremitting secretory diarrhea. While the pathology of the small intestine in MVID patients is well described, little is known about extraintestinal effects of MYO5B mutation. We examined stomach, liver, pancreas, colon, and kidney in Navajo MVID patients, who share a single homozygous MYO5B-P660L (1979C>T p.Pro660Leu, exon 16). Sections were stained for markers of the apical membrane to assess polarized trafficking. Navajo MVID patients showed notable changes in H/K-ATPase-containing tubulovesicle structure in the stomach parietal cells. Colonic mucosa was morphologically normal, but did show losses in apical ezrin and Syntaxin 3. Hepatocytes in the MVID patients displayed aberrant canalicular expression of the essential transporters MRP2 and BSEP. The pancreas showed small fragmented islets and a decrease in apical ezrin in pancreatic ducts. Kidney showed normal primary cilia. These findings indicate that the effects of the P660L mutation in MYO5B in Navajo MVID patients are not limited to the small intestine, but that certain tissues may be able to compensate functionally for alterations in apical trafficking.

Clostridium difficile Toxins A and B: Insights into Pathogenic Properties and Extraintestinal Effects.

Clostridium difficile infection (CDI) has significant clinical impact especially on the elderly and/or immunocompromised patients. The pathogenicity of Clostridium difficile is mainly mediated by two exotoxins: toxin A (TcdA) and toxin B (TcdB). These toxins primarily disrupt the cytoskeletal structure and the tight junctions of target cells causing cell rounding and ultimately cell death. Detectable C. difficile toxemia is strongly associated with fulminant disease. However, besides the well-known intestinal damage, recent animal and in vitro studies have suggested a more far-reaching role for these toxins activity including cardiac, renal, and neurologic impairment. The creation of C. difficile strains with mutations in the genes encoding toxin A and B indicate that toxin B plays a major role in overall CDI pathogenesis. Novel insights, such as the role of a regulator protein (TcdE) on toxin production and binding interactions between albumin and C. difficile toxins, have recently been discovered and will be described. Our review focuses on the toxin-mediated pathogenic processes of CDI with an emphasis on recent studies.

Gut microbiota-bone axis

ABSTRACTThe gut microbiota (GM) is an important regulator of body homeostasis, including intestinal and extra-intestinal effects. This review focuses on the GM-bone axis, which we define as the effect of the gut-associated microbial community or the molecules they synthesize, on bone health. While research in this field is limited, findings from preclinical studies support that gut microbes positively impact bone mineral density and strength parameters. Moreover, administration of beneficial bacteria (probiotics) in preclinical models has demonstrated higher bone mineralization and greater bone strength. The preferential bacterial genus that has shown these beneficial effects in bone is Lactobacillus and thus lactobacilli are among the best candidates for future clinical intervention trials. However, their effectiveness is dependent on stage of development, as early life constitutes an important time for impacting bone health, perhaps via modulation of the GM. In addition, sex-specific difference also impacts the efficacy of the probiotics. Although auspicious, many questions regarding the GM-bone axis require consideration of potential mechanisms; sex-specific efficacy; effective dose of probiotics; and timing and duration of treatment.

Effects of two whole-grain barley varieties on caecal SCFA, gut microbiota and plasma inflammatory markers in rats consuming low- and high-fat diets

Mixed-linkage β-glucans are fermented by the colon microbiota that give rise to SCFA. Propionic and butyric acids have been found to play an important role in colonic health, as well as they may have extraintestinal metabolic effects. The aim of the present study was to investigate how two whole-grain barley varieties differing in dietary fibre and β-glucan content affected caecal SCFA, gut microbiota and some plasma inflammatory markers in rats consuming low-fat (LF) or high-fat (HF) diets. Barley increased the caecal pool of SCFA in rats fed the LF and HF diets compared with those fed the control diet, and the effect was generally dependent on fibre content, an exception was butyric acid in the LF setting. Furthermore, whole-grain barley reduced plasma lipopolysaccharide-binding protein and monocyte chemoattractant protein-1, increased the caecal abundance of Lactobacillus and decreased the Bacteroides fragilis group, but increased the number of Bifidobacterium only when dietary fat was consumed at a low level. Fat content influenced the effects of barley: rats fed the HF diets had a higher caecal pool of acetic and propionic acids, higher concentrations of amino acids and higher amounts of lipids in the portal plasma and liver than rats fed the LF diets; however, less amounts of butyric acid were generally formed. Interestingly, there was an increase in the caecal abundance of Akkermansia and the caecal pool of succinic acid, and a decrease in the proportion of Bifidobacterium and the Clostridium leptum group. In summary, whole-grain barley decreased HF diet-induced inflammation, which was possibly related to the formation of SCFA and changes in microbiota composition. High β-glucan content in the diet was associated with reduced plasma cholesterol levels.

Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis.

Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model. Using a chemically induced trinitrobenzene sulfonic acid murine model of colitis, we compared the efficacy of oral and intraperitoneal (i.p.) delivery of the PHDi; AKB-4924 in preventing colitis, as measured by endoscopy, histology, barrier integrity, and immune profiling. Furthermore, we measured potential off-target effects, examining HIF and HIF target genes in the heart and kidney, as well as erythropoietin and hematocrit levels. Oral administration of AKB-4924 exhibited mucosal protection comparable i.p. dosing. Oral delivery of PHDi led to reduced colonic epithelial HIF stabilization compared with i.p. delivery, but this was still sufficient to induce transcription of downstream HIF targets. Furthermore, oral delivery of PHDi led to reduced stabilization of HIF and activation of HIF targets in extraintestinal organs. Oral delivery of PHDi therapies to this intestinal mucosa protects against colitis in animal models and represents a potential therapeutic strategy for inflammatory bowel disease, which also precludes unwanted extraintestinal effects.

Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis.

ABSTRACTThere is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection. Entamoeba histolytica is a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensal Clostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolytica infection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB+ to an SFB− mouse was sufficient to provide protection against E. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells.

Exclusive antagonism of the α4β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates

Biological therapies that antagonize specific molecules have demonstrated efficacy in inflammatory bowel diseases, but infections resulting from systemic immunosuppression underscore the need for safer therapies. The objective of this investigation was to determine if antagonism of the α(4) β(7) integrin would exclusively yield gut-selective antiinflammatory activity in primates. A series of experiments were conducted to investigate potential intra- and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the α(4) β(7) -exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP-02) for 4, 13, and 26 weeks. No adverse clinical effects of vedolizumab were observed in healthy cynomolgus monkeys up to the highest doses tested (100 mg/kg). Histomorphologic analyses indicated a reduction in the frequency of leukocytes in gastrointestinal tissue, but not other organs. A significant (P < 0.05) decrease in the frequency of β 7+ lymphocytes in gastrointestinal tissues corresponded to a significant (P < 0.05) increase in α(4) β 7+ memory helper T lymphocytes in peripheral blood. This elevation was specific to α(4) β 7+ memory helper T lymphocytes; levels of other leukocyte subsets remained unaffected. Systemic opportunistic infections were not observed, and vedolizumab did not inhibit adaptive or innate immune responses systemically. These data demonstrate that blocking the α(4) β(7) integrin exclusively yields gut-selective antiinflammatory activity in primates.

A novel facet to consider for the effects of butyrate on its target cells. Focus on “The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein”

short-chain fatty acids (SCFAs), acetate, propionate, and butyrate are produced by bacterial fermentation of dietary fiber in the colonic lumen. In the normal human large intestine, SCFA concentrations range from 70 to 100 mM; these SCFAs account for ∼80% of the anions present in the lumen ([5][1