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Antibiotics can cause weight loss by impairing gut microbiota in mice and the potent benefits of lactobacilli

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Abstract

This study assessed whether antibiotics could alter gut microbiota to affect host growth and the possibility of alleviation by lactobacilli. We divided four-week-old BABL/c mice into control (Ctrl), antibiotic exposure (Abx), Lactobacillus plantarum PC-170 (PC), and Lactobacillus rhamnosus GG (LGG) group and the Abx, LGG, and PC group received an one-week antibiotic/antibiotic + probiotic treatment. The fecal microbiota and the expression of splenic cytokines were determined. Following the ceftriaxone treatment, the body weight gain of Abx was delayed compared with others. The ceftriaxone treatment significantly decreased the alpha-diversity of the fecal microbiota and altered the fecal microbiota but LGG and PC can partly alleviate the effect. At the end of the study, the microbial community of LGG and PC group were more similar to Ctrl compared with Abx group. The results indicated that ceftriaxone could significantly alter intestinal microbiota. Lactobacilli might alleviate the side effects of antibiotics by stabilizing the intestinal microbiota.

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... In intervention groups, the current study found a substantial decline in food-water intake and response to weight gain but not FBG and insulin resistance (HOMA-IR). Many studies reported similar findings concerning food-water intake and response to weight gain [19,21,28]. This could be attributed at least partially to dysbiosis of gut microbiota, which is of potential in insulin sensitivity, body weight, and appetite regulation [29]. ...
... Interestingly, Ceftriaxone dysbiosis was also led to significant tearing and damage of the jejunum villi, which similar to the findings of Cheng et al. [20] and Guo et al. [21] studies. In line with our study, Miao et al. [28] and Cheng et al. [20] studies found that the villi depth was significantly reduced in the jejunum of Ceftriaxone-received rats. Interestingly, I found a slight tearing and damage in jejunum villi of diabetic control, which is in line with the Shan et al. study [30]. ...
... Interestingly, there was a marked increase in the LMR in dysbiotic groups, however, it is not significant, which is in line with the histopathology findings. In dysbiotic groups, the low SCFAs [23][24][25][26] and the histopathological changes [18][19][20]25,28] together with gut dysbiosis [16][17][18]20,21] could significantly affect gut permeability. SCFAs, in particular, butyrate improve gut permeability by increasing tight junction protein expression and decreasing the low-grade inflammation [32]. ...
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Currently, several studies propose that the dominant intestinal bacteria are core flora. Besides keeping the homeostasis of the intestinal environment, the intestinal microflora also plays a role in body metabolism, production of some vitamins, and control of barrier function. The study aimed to investigate the jejunum microbiota in diabetic rats as well as it’s the relationship with Ceftriaxone sodium-mediated gut dysbiosis, diabetic parameters, and intestinal permeability. Thirty-two Wistar rats (Male) were enrolled and divided into four groups (A, B, C, and D; N = 8). Subsequently, T2DM was induced in C and D groups by HFD/STZ model and then gut dysbiosis in B and D groups via intragastric administration of Ceftriaxone sodium for two weeks. The food-water intake, body weight, fasting blood glucose, plasma insulin, HOMA-IR, intestinal permeability, and jejunum microbiota and it’s histology were investigated. In this study, T2DM was associated with a significant decrease in the richness and diversity of jejunum microbiota, elevation in the intestinal permeability, and higher abundance of some opportunistic pathogens. Ceftriaxone sodium-induced gut dysbiosis declined food-water intake, damagedthe villi of jejunum tissue, increased intestinal permeability, and affected the diversity of jejunum microbiota. In diabetic rats, Ceftriaxone sodium-mediated gut dysbiosis also declined the abundance of someSCFAs bacteria and raised the abundant of some opportunistic bacteria such as Staphylococcus_sciuri. Interestingly, we found that several bacteria were negatively correlated with HOMA-IR, fasting blood glucose, body weight, and intestinal permeability. Overall, the study highlighted the jejunum microflora alterations in HFD/STZ diabetic rats and assessed the effect of Ceftriaxone sodium-induced gut dysbiosis on diabetic parameters, jejunum microbiota and histology, and intestinal permeability, which are of potential for further studies.
... Ceftriaxone administration caused significant weight loss in the study. This is consistent with the previous finding that the weight gain of mice was delayed significantly following the ceftriaxone treatment (Miao et al., 2020). However, it was contradictory with previous findings that antibiotics result in weight gain in the animal production system (Angelakis, 2017). ...
... The gut microbiota of mice was altered greatly in quantity and quality by the oral administration of ceftriaxone in this study. Similar to the result, other studies confirmed that oral ceftriaxone significantly decreased the quantity of fecal microbiota (Cheng et al., , 2019Guo et al., 2017;Miao et al., 2020). At the phylum level, the microbiota diversity of the AB group decreased, Proteobacteria became a dominant phylum, and the abundance of Bacteroidetes, Firmicutes, Actinobacteria, and Deferribacteres decreased. ...
... At the phylum level, the microbiota diversity of the AB group decreased, Proteobacteria became a dominant phylum, and the abundance of Bacteroidetes, Firmicutes, Actinobacteria, and Deferribacteres decreased. This result is supported by studies that ceftriaxone could characteristically decrease the alpha-diversity of the fecal microbiota accompanied with more Proteobacteria and less Bacteroidetes (Cheng et al., , 2019Miao et al., 2020). In some dysbiosis and related diseases, an increased Proteobacteria is perceived as a diagnostic characteristic since it is closely related to colon epithelial oxygenation as well as the disruption of the gut anaerobic environment (Zhu et al., 2013;Shin et al., 2015;Miao et al., 2020). ...
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Background: Growing evidence points out that a disturbance of gut microbiota may also disturb the gut–brain communication. However, it is not clear to what extent the alteration of microbiota composition can modulate brain function, affecting host behaviors. Here, we investigated the effects of gut microbiota depletion on emotional behaviors. Methods: Mice in the experimental group were orally administered ceftriaxone sodium solution (250 mg/ml, 0.2 ml/d) for 11 weeks. The open-field test and tail-suspension test were employed for the neurobehavioral assessment of the mice. Fecal samples were collected for 16s rDNA sequencing. The serum levels of cytokines and corticosterone were quantified using enzyme-linked immunosorbent assays. The immunohistochemistry method was used for the detection of brain-derived neurotrophic factor (BDNF) and c-Fos protein. Results: The gut microbiota for antibiotic-treated mice showed lower richness and diversity compared with normal controls. This effect was accompanied by increased anxiety-like, depression-like, and aggressive behaviors. We found these changes to be possibly associated with a dysregulation of the immune system, abnormal activity of the hypothalamic-pituitary-adrenal axis, and an alteration of neurochemistry. Conclusions: The findings demonstrate the indispensable role of microbiota in the gut–brain communication and suggest that the absence of conventional gut microbiota could affect the nervous system, influencing brain function.
... However, sexual dimorphism in response to broad-spectrum antibiotics has been observed in laboratory mice (Fujisaka et al., 2016). It was shown that antibiotics can change the body mass of mice due to changes in gut microbiota (Miao et al., 2019). To avoid possible confounding effects of body mass of males on the mating preference of females, we tested the sexual attractiveness of female mice to males using low-dose oral administration of a combination of broad-spectrum antibiotics vancomycin and neomycin sulfate and showed that gut dysbiosis potentially reduced sexual attractiveness of mouse female. ...
... Despite gut microbiota dysbiosis, the antibiotic-treated males, like the control males, consistently preferred the control females over the antibiotic-treated females. It has been evidenced that antibiotics can cause body weight loss (Miao et al., 2019); however, we can rule out the potential influence of body weight on the sexual attractiveness of females to males, because antibiotic treatment did not significantly change the body weight of female mice in our study (Independent t-test: t = 0.357, df = 18, P = 0.718; Supplementary Figure 5). These observations suggest that antibiotic-induced gut microbiota dysbiosis strikingly modified gut bacterial composition and then reduced the sexual attractiveness of females to males. ...
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Increasing evidence has shown that the gut microbiome has significant effects on mate preferences of insects; however, whether gut microbiota composition affects sexual attractiveness and mate preference in mammals remains largely unknown. Here, we showed that antibiotic treatment significantly restructured the gut microbiota composition of both mouse males and females. Males, regardless of antibiotic treatment, exhibited a higher propensity to interact with the control females than the antibiotic-treated females. The data clearly showed that gut microbiota dysbiosis reduced the sexual attractiveness of females to males, implying that commensal gut microbiota influences female attractiveness to males. The reduced sexual attractiveness of the antibiotic-treated females may be beneficial to discriminating males by avoiding disorders of immunity and sociability in offspring that acquire maternal gut microbiota via vertical transmission. We suggest further work should be oriented to increase our understanding of the interactions between gut microbiota dysbiosis, sexual selection, and mate choice of wild animals at the population level.
... For example, butyrate has both intestinal and systemic anti-inflammatory, pro-inflammatory, immunomodulatory, and anti-oxidant effects [27][28][29][30]. ABX pretreatment has been shown to cause dysbiosis in mice with significant effects in normal health and disease conditions [31][32][33]. A deficiency of gut microbiota in mice affects the distribution and maturation of microglia and impairs the innate immune responses in the brain [34]. ...
... PBX are defined as live microorganisms conferring a health benefit on the host when administered in adequate amounts [58], and VSL#3 is a medical grade probiotic mixture that contains 8 different strains of "good" bacteria within the orders Lactobacillales or Bifidobacteriales [9,59,60]. In this study, 16S rRNA sequencing identified significant compositional changes that occur in the gut microbiome secondary to ABX or PBX administration and these findings are consistent with previously published findings in mice with ABX or PBX [33]. A markedly separated distribution (beta diversity) of microbiota confirmed that the various treatments created unique bacterial communities within each group as evidenced by the distinct clustering patterns visualized on the PCoA plot. ...
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Objective Antibiotics (ABX) are widely used for life-threatening infections and also for routine surgical operations. Compelling evidence suggests that ABX-induced alterations of gut microbiota composition, termed dysbiosis, are linked with diverse disease states including neurological and neurodegenerative conditions. To combat the consequences of dysbiosis, probiotics (PBX) are widely used. ABX-induced dysbiosis is reported to impair neurological function after spinal cord injury. Traumatic peripheral nerve injury (TPNI) results in profound neurologic impairment and permanent disability. It is unknown whether ABX treatment-induced dysbiosis has any impact on TPNI-induced functional recovery, and if so, what role medical-grade PBX could have on TPNI recovery. Results In this study, ABX-induced dysbiosis and PBX-induced microbiota enrichment models were used to explore the potential role of gut microbiome in TPNI. Stool analysis with 16S ribosomal RNA (rRNA) gene sequencing confirmed ABX-induced dysbiosis and revealed that ABX-induced changes could be partially restored by PBX administration with an abundance of butyrate producing bacteria. Pre-injury ABX significantly impaired, but pre-injury PBX significantly improved post-TPNI functional recovery. Importantly, post-injury PBX protected against pre-injury ABX-induced functional impairment. These findings demonstrate that reestablishment of gut microbiota composition with butyrate producing PBX during ABX-induced dysbiosis could be a useful adjuvant therapy for TPNI.
... This argument is supported by the recent data concerning ceftriaxone influences on α-diversity, as indicated twice by Cheng et al. [115,116]. Bacteroidetes almost entirely disappear from the feces following exposure to ceftriaxone as per Miao et al. [117], which is consistent with data disseminated by Cheng et al. [118]. Maternal antibiotic treatment (MAT) lowered the relative abundance of Bacteroidetes and Firmicutes in parallel with a proliferation of Proteobacteria. ...
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Background: Antenatal depression (AND) and post-partum depression (PPD) are long-term debilitating psychiatric disorders that significantly influence the composition of the gut flora of mothers and infants that starts from the intrauterine life. Not only does bacterial ratio shift impact the immune system, but it also increases the risk of potentially life-threatening disorders. Material and methods: Therefore, we conducted a narrative mini-review aiming to gather all evidence published between 2018-2022 regarding microflora changes in all three stages of pregnancy. Results: We initially identified 47 potentially eligible studies, from which only 7 strictly report translocations; 3 were conducted on rodent models and 4 on human patients. The remaining studies were divided based on their topic, precisely focused on how probiotics, breastfeeding, diet, antidepressants, exogenous stressors, and plant-derived compounds modulate in a bidirectional way upon behavior and microbiota. Almost imperatively, dysbacteriosis cause cognitive impairments, reflected by abnormal temperament and personality traits that last up until 2 years old. Thankfully, a distinct technique that involves fecal matter transfer between individuals has been perfected over the years and was successfully translated into clinical practice. It proved to be a reliable approach in diminishing functional non- and gastrointestinal deficiencies, but a clear link between depressive women's gastrointestinal/vaginal microbiota and clinical outcomes following reproductive procedures is yet to be established. Another gut-dysbiosis-driving factor is antibiotics, known for their potential to trigger inflammation. Fortunately, the studies conducted on mice that lack microbiota offer, without a shadow of a doubt, insight. Conclusions: It can be concluded that the microbiota is a powerful organ, and its optimum functionality is crucial, likely being the missing puzzle piece in the etiopathogenesis of psychiatric disorders.
... In this study, lincomycin exposure decreased bodyweight gain of mice, in tandem with a previous study [16]. This could have been due to lincomycin-induced reduction in jejunum villus height, crypt depth, and colon muscular layer width, which might have caused a reduction in contact area between nutrients and intestines as well as affected intestinal peristalsis to reduce nutrient absorption. ...
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The adverse effects of short-term megadose of antibiotics exposure on the gastrointestinal and liver tissue reactions in young children have been reported. Antibiotic-induced intestinal and liver reactions are usually unpredictable and present a poorly understood pathogenesis. It is, therefore, necessary to develop strategies for reducing the adverse effects of antibiotics. Studies on the harm and rescue measures of antibiotics from the perspective of the gut–liver system are lacking. Here, we demonstrate that lincomycin exposure reduced body weight, disrupted the composition of gut microbiota and intestinal morphology, triggered immune-mediated injury and inflammation, caused liver dysfunction, and affected lipid metabolism. However, baicalin administration attenuated the lincomycin-induced changes. Transcriptome analysis showed that baicalin improved immunity in mice, as evidenced by the decreased levels of intestinal inflammatory cytokines and expression of genes that regulate Th1, Th2, and Th17 cell differentiation, and inhibited mucin type O-glycan biosynthesis pathways. In addition, baicalin improved liver function by upregulating the expression of genes involved in bile acid secretion and lipid degradation, and downregulating genes involved in lipid synthesis in lincomycin-treated mice. Bile acids can regulate intestinal immunity and strengthen hepatoenteric circulation. In addition, baicalin also improved anti-inflammatory bacteria abundance (Blautia and Coprobacillus) and reduced pathogenic bacteria abundance (Proteobacteria, Klebsiella, and Citrobacter) in lincomycin-treated mice. Thus, baicalin can ameliorate antibiotic-induced injury and its associated complications such as liver disease.
... When it comes to antibiotics, studies in humans have been contradictory, showing that children treated with antibiotics are more likely to develop obesity and diabetes in a dose-dependent manner [86][87][88], while in mice at least, antibiotics treatment-induced improved gut barrier, insulin sensitivity and weight loss [89]. Furthermore, gram-positive bacteria-targeted antibiotic treatment of mice with systemic lupus erythematosus reduced bacterial growth in mesenteric lymph nodes and the liver [90]. ...
Article
Despite the strongly accumulating evidence for microbial signatures in metabolic tissues, including the blood, suggesting a novel paradigm for metabolic disease development, the notion of a core blood bacterial signature in health and disease remains a contentious concept. Recent studies clearly demonstrate that under a strict contamination-free environment, methods such as 16 S rRNA gene sequencing, fluorescence in-situ hybridization, transmission electron microscopy, and several more, allied with advanced bioinformatics tools, allow unambiguous detection and quantification of bacteria and bacterial DNA in human tissues. Bacterial load and compositional changes in the blood have been reported for numerous disease states, suggesting that bacteria and their components may partially induce systemic inflammation in cardiometabolic disease. This concept has been so far primarily based on measurements of surrogate parameters. It is now highly desirable to translate the current knowledge into diagnostic, prognostic, and therapeutic approaches. This review addresses the potential clinical relevance of a blood bacterial signature pertinent to cardiometabolic diseases and outcomes and new avenues for translational approaches. It discusses pitfalls related to research in low bacterial biomass while proposing mitigation strategies for future research and application approaches.
... This association was observed independently of antibiotic spectrum and was dose dependent 14 . In contrast, in adults, certain antibiotic treatments induce weight loss, insulin sensitivity and improved inflammation and gut permeability 15,16 . It is possible that this discrepancy in the effects of antibiotics could stem from deleterious effects of microbiota depletion on gut development in children 17 . ...
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Human-associated microorganisms play a vital role in human health, and microbial imbalance has been linked to a wide range of disease states. In this Review, we explore recent efforts to progress from correlative studies that identify microorganisms associated with human disease to experiments that establish causal relationships between microbial products and host phenotypes. We propose that successful efforts to uncover phenotypes often follow a chain of evidence that proceeds from (1) association studies; to (2) observations in germ-free animals and antibiotic-treated animals and humans; to (3) fecal microbiota transplants (FMTs); to (4) identification of strains; and then (5) molecules that elicit a phenotype. Using this experimental ‘funnel’ as our guide, we explore how the microbiota contributes to metabolic disorders and hypertension, infections, and neurological conditions. We discuss the potential to use FMTs and microbiota-inspired therapies to treat human disease as well as the limitations of these approaches. This Review article explores how uncovering phenotypes linked to the human microbiome often progresses from correlative studies to studies in germ-free animals and fecal microbiota transplants and, finally, to identification of strains and molecules.
... As far as it is known that gut microbes were altered by non-antibiotics drugs but now it is found out that gut microbes can also affect the drugs by enzymatically disfiguring the structure of drug and change its bioavailability [66]. The commensal bacteria obtain the antibiotic resistance genes can moderate protection of pathogens from bactericidal effects of antibiotics [67]. The antibiotic named ceftraixone modulate the gut microbiota and Lactobacillus reduces the side effects of antibiotics by maintaining steadiness of intestinal micro biota [68]. ...
... Our previous study identified that short-term use of ceftriaxone can damage the intestinal microbiota in young mice [22]. Therefore, this study was conducted to determine whether the short-term antibiotic and/or probiotic exposure in early life could affect the construction of the intestinal microbiota and the possible long-term effects of these treatments on host metabolism. ...
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Background Accumulating evidence have shown that the intestinal microbiota plays an important role in prevention of host obesity and metabolism disorders. Recent studies also demonstrate that early life is the key time for the colonization of intestinal microbes in host. However, there are few studies focusing on possible association between intestinal microbiota in the early life and metabolism in adulthood. Therefore the present study was conducted to examine whether the short term antibiotic and/or probiotic exposure in early life could affect intestinal microbes and their possible long term effects on host metabolism. Results A high-fat diet resulted in glucose and lipid metabolism disorders with higher levels of visceral fat rate, insulin-resistance indices, and leptin. Exposure to ceftriaxone in early life aggravated the negative influences of a high-fat diet on mouse physiology. Orally fed TMC3115 protected mice, especially those who had received treatment throughout the whole study, from damage due to a high-fat diet, such as increases in levels of fasting blood glucose and serum levels of insulin, leptin, and IR indices. Exposure to ceftriaxone during the first 2 weeks of life was linked to dysbiosis of the fecal microbiota with a significant decrease in the species richness and diversity. However, the influence of orally fed ceftriaxone on the fecal microbiota was limited to 12 weeks after the termination of treatment. Of note, at week 12 there were still some differences in the composition of intestinal microbiota between mice provided with high fat diet and antibiotic exposure and those only fed a high fat diet. Conclusions These results indicated that exposure to antibiotics, such as ceftriaxone, in early life may aggravate the negative influences of a high-fat diet on the physiology of the host animal. These results also suggest that the crosstalk between the host and their intestinal microbiota in early life may be more important than that in adulthood, even though the same intestinal microbes are present in adulthood.
... Similar to GP-treated mice, antibiotic treated mice showed weight loss and a bloom in A. muciniphila (59). We previously noted reduced α-diversity but unchanged total bacterial load in the gut microbiome of GP-treated mice, suggesting GPs may exert an antimicrobial effect on certain microbial members while providing an expanded niche for A. muciniphila (4,8). ...
Article
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A Western Diet (WD) low in fiber but high in fats and sugars contributes to obesity and non-alcoholic fatty liver disease (NAFLD). Supplementation with grape polyphenols (GPs) rich in B-type proanthocyanidins (PACs) can attenuate symptoms of cardiometabolic disease and alter the gut microbiota and its metabolites. We hypothesized that GP-mediated metabolic improvements would correlate with altered microbial metabolites such as short chain fatty acids (SCFAs). To more closely mimic a WD, C57BL/6J male mice were fed a low-fiber diet high in sucrose and butterfat along with 20% sucrose water to represent sugary beverages. This WD was supplemented with 1% GPs (WD-GP) to investigate the impact of GPs on energy balance, SCFA profile, and intestinal metabolism. Compared to WD-fed mice, the WD-GP group had higher lean mass along with lower fat mass, body weight, and hepatic steatosis despite consuming more calories from sucrose water. Indirect and direct calorimetry revealed that reduced adiposity in GP-supplemented mice was likely due to their greater energy expenditure, which resulted in lower energy efficiency compared to WD-fed mice. GP-supplemented mice had higher abundance of Akkermansia muciniphila, a gut microbe reported to increase energy expenditure. Short chain fatty acid measurements in colon content revealed that GP-supplemented mice had lower concentrations of butyrate, a major energy substrate of the distal intestine, and reduced valerate, a putrefactive SCFA. GP-supplementation also resulted in a lower acetate:propionate ratio suggesting reduced hepatic lipogenesis. Considering the higher sucrose consumption and reduced butyrate levels in GP-supplemented mice, we hypothesized that enterocytes would metabolize glucose and fructose as a replacement energy source. Ileal mRNA levels of glucose transporter-2 (GLUT2, SLC2A2) were increased indicating higher glucose and fructose uptake. Expression of ketohexokinase (KHK) was increased in ileum tissue suggesting increased fructolysis. A GP-induced increase in intestinal carbohydrate oxidation was supported by: (1) increased gene expression of duodenal pyruvate dehydrogenase (PDH), (2) a decreased ratio of lactate dehydrogenase a (LDHa): LDHb in jejunum and colon tissues, and (3) decreased duodenal and colonic lactate concentrations. These data indicate that GPs protect against WD-induced obesity and hepatic steatosis by diminishing portal delivery of lipogenic butyrate and sugars due to their increased intestinal utilization.
... More recent studies have focused on CTX-and cocaine-induced alterations in the mGluR2 versus the GLT1 (Logan et al., 2020). Logan et al. (2020) demonstrated that CTX attenuates reinstatement of cocaine selfadministration, and a Glu2 receptor antagonist injected directly into the NAc blocks the effect of CTX. 4. Most studies highlighted in Tables 1-4 administered high doses of CTX (200 mg/kg is the most common dose) for 5-12 days prior to tests of reinstatement, a course of treatment known to significantly alter the composition of the gut microbiome in humans (Burdet et al., 2019) and animals alike (Luo et al., 2016;Connelly et al., 2017;Chakraborty et al., 2018;Luo et al., 2018;Holota et al., 2019;Miao et al., 2020). It is also interesting that the original report on CTXmediated neuroprotection used the same course of treatment in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis (Rothstein et al., 2005), a mouse that is now known to have a leaky intestine and an impaired gut microbiome (Wu et al., 2015). ...
Article
The gut microbiome modulates neuro-chemical function and behavior and has been impli-cated in numerous central nervous system (CNS) diseases, including developmental, neurodegenerative, and psychiatric disorders. Substance use disorders (SUDs) remain a serious threat to the public well-being, yet gut microbiome involvement in drug abuse has received very little attention. Studies of the mechanisms underlying SUDs have naturally focused on CNS reward circuits. However, a significant body of research has accumulated over the past decade that has unwittingly provided strong support for gut microbiome participation in drug reward. β-Lactam antibiotics have been employed to increase glutamate transporter expression to reverse relapse-induced release of glutamate. Sodium butyrate has been used as a histone deacetylase inhibitor to prevent drug-induced epigenetic alterations. High-fat diets have been used to alter drug reward because of the extensive overlap of the circuitry mediating them. This review article casts these approaches in a different light and makes a compelling case for gut microbiome modulation of SUDs. Few factors alter the structure and composition of the gut microbiome more than antibiotics and a high-fat diet, and butyrate is an endogenous product of bacterial fermentation. Drugs such as cocaine, alcohol, opiates, and psychostimulants also modify the gut microbiome. Therefore, their effects must be viewed on a complex background of cotreatment-induced dysbiosis. Consideration of the gut microbiome in SUDs should have the beneficial effects of expanding the understanding of SUDs and aiding in the design of new therapies based on opposing the effects of abused drugs on the host’s commensal bacterial community. © 2021, American Society for Pharmacology and Experimental Therapy. All rights reserved.
... In the current study, the administration of two commonly prescribed antibiotics, clindamycin and amoxicillin, influenced We checked whether our experimental condition itself affected normal body weight gain throughout the time course of experiment. There has been a disagreement with previous studies related to the effect of antibiotics on body weight: some reports noted that antibiotic administration causes weight loss [24,49], whereas others imply that antibiotic-induced GM dysbiosis causes obesity [50,51]. The discrepancy can be explained by various factors (age of treatment group, duration of treatment, method of administration, dose of antibiotics, and type of antibiotics). ...
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Gut microbiota (GM) plays a critical role in health maintenance. Previous reports connected GM with metabolic, immunologic and neurologic pathways. The main purpose of the current investigation was to study whether antibiotic-induced disturbances of GM affects psychological or behavioral conditions on mice as animal model. Mice were exposed to clindamycin or amoxicillin, and their behaviors were evaluated. Antibiotic-treated groups displayed reduced recognition memory and increased depression. No significant changes in the locomotor activity and anxiety were observed. Our data suggested that changes in GM composition by antibiotics may lead to the cognitive and behavioral deficit.
... In the current study, the administration of two commonly prescribed antibiotics, clindamycin and amoxicillin, influenced We checked whether our experimental condition itself affected normal body weight gain throughout the time course of experiment. There has been a disagreement with previous studies related to the effect of antibiotics on body weight: some reports noted that antibiotic administration causes weight loss [24,49], whereas others imply that antibiotic-induced GM dysbiosis causes obesity [50,51]. The discrepancy can be explained by various factors (age of treatment group, duration of treatment, method of administration, dose of antibiotics, and type of antibiotics). ...
... For the genus level, it has been reported that Lactobacillus and Blautia are probiotics in the intestine. Lactobacillus can inhibit or reduce the invasion of pathogenic bacteria and the production of intestinal inflammatory factors through adhesion and competition [42]. Blautia is an important Gram-positive bacterium that maintains intestinal homeostasis and can produce butyric acid and other beneficial metabolites and prevent inflammation by upregulating the proliferation of intestinal Treg cells [25]. ...
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In this study, a knee osteoarthritis (KOA) rat model induced by monosodium iodoacetate (MIA) was used to study the effect of moxibustion on improving knee cartilage damage and its effect on the intestinal flora. The experimental rats were divided into the normal group (N), model group (M), moxibustion treatment group (MS), and diclofenac sodium treatment group (DS). After 4 weeks, cartilage pathological damage in the knee joint was evaluated using hematoxylin-eosin and safranin O-fast green staining analysis. ELISAs and Western blots were used to detect the expression levels of IL-1β and TNF-α in the serum and cartilage, respectively. The total DNA of the fecal samples was extracted and subjected to high-throughput sequencing of the V3-V4 region of the 16S rRNA gene to analyze the changes in the intestinal flora. In the model group, the cartilage was obviously damaged, the expression levels of IL-1β and TNF-α in the serum and cartilage were increased, and the abundance and diversity of the intestinal flora were decreased. Moxibustion treatment significantly improved the cartilage damage and reduced the concentration of inflammatory factors in the serum and cartilage. The high-throughput sequencing results showed that compared to the model group, the moxibustion treatment regulated some specific species in the intestinal microorganisms rather than the α diversity. In conclusion, our findings suggest that moxibustion treatment may work through two aspects in rats. On one hand, it directly acts on knee cartilage to promote repair, and on the other hand, it regulates the composition of the intestinal flora and reduces the production of inflammatory factors.
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Burkholderia mallei, the causative agent of glanders, is principally a disease of equines, although it can also infect humans and is categorized by the U.S. Centers for Disease Control and Prevention as a category B biological agent. Human cases of glanders are rare and thus there is limited information on treatment. It is therefore recommended that cases are treated with the same therapies as used for melioidosis, which for prophylaxis, is co-trimoxazole (trimethoprim/sulfamethoxazole) or co-amoxiclav (amoxicillin/clavulanic acid). In this study, the fluoroquinolone finafloxacin was compared to co-trimoxazole as a post-exposure prophylactic in a murine model of inhalational glanders. BALB/c mice were exposed to an aerosol of B. mallei followed by treatment with co-trimoxazole or finafloxacin initiated at 24 h post-challenge and continued for 14 days. Survival at the end of the study was 55% or 70% for mice treated with finafloxacin or co-trimoxazole, respectively, however, this difference was not significant. However, finafloxacin was more effective than co-trimoxazole in controlling bacterial load within tissues and demonstrating clearance in the liver, lung and spleen following 14 days of therapy. In summary, finafloxacin should be considered as a promising alternative treatment following exposure to B. mallei.
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Atopic dermatitis (AD) is a highly prevalent inflammatory skin disease worldwide. Recent studies have suggested an important role for association with the gut and skin microbiome axis in AD development. Paeonia lactiflora Pallas extract (PL) is commonly used for the treatment of inflammatory diseases. However, the possible mechanisms by which PL can alleviate AD by regulating the gut microbiota have not been investigated. In this study, we aimed to investigate the therapeutic effects and underlying mechanism of PL in mice with antibiotic cocktail (ABX)-induced AD. The effects of PL were evaluated in bone marrow-derived macrophages (BMDMs) and ABX and dinitrochlorobenzene (DNCB) mouse models. PL suppressed inflammatory cytokine and NO production in LPS-treated BMDMs. Moreover, PL attenuated scoring atopic dermatitis (SCORAD) scores, epidermal thickness, white blood cell counts and the disease activity index (DAI) in ABX-induced AD mice. Meanwhile, PL decreased IL-17A production, induced Foxp3 expression and improved intestinal barrier integrity by especially increasing the expression of tight junction proteins such as ZO-1 and occludin. Additionally, PL partially increased the diversity of the gut microbiota and changed the microbial composition. Our findings suggest that PL may be a potential natural product that can ameliorate atopic dermatitis symptoms by suppressing inflammatory cytokine production, inducing Foxp3 expression, increasing intestinal barrier integrity and changing the gut microbiota composition.
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Background 7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Godmania , Tridax , and Primula species that confers protection against high-fat diet (HFD) induced metabolic pathologies selectively in female mice. We have previously reported that this metabolic protection is associated with early and stable remodeling of the intestinal microbiome, evident in female but not male DHF-supplemented mice. Early changes in the gut microbiome in female DHF-fed mice were highly predictive of subsequent metabolic protection, suggesting a causative association between the gut microbiome and the metabolic effects of DHF. Objective To investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation. Materials and methods Age-matched male and female C57Bl6/J mice were given ad libitum access to HFD and drinking water containing vehicle or DHF for 12 weeks. For antibiotic (Abx) treatment, female mice were given drinking water containing a cocktail of antibiotics for 2 weeks prior to HFD feeding and throughout the feeding period. Metabolic phenotyping consisted of longitudinal assessments of body weights, body composition, food, and water intake, as well as measurement of energy expenditure, glucose tolerance, and plasma and hepatic lipids. Protein markers mediating the cellular effects of DHF were assessed in brown adipose tissue (BAT) and skeletal muscle. Results Metabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial “activation” of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity. Conclusion These results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects.
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Background Although animal experiments found that antibiotic exposure during early life increased adiposity, limited human epidemiological evidence is available for the effects of veterinary antibiotic exposure on children's growth and development. Objective This study was conducted to examine the body burden of fluoroquinolones in northern Chinese children and assess its association with growth and development. Methods After recruiting 233 children aged 0–15 years from 12 different sites in northern China in 2020, we measured urinary concentrations of 5 respective fluoroquinolones (fleroxacin, ofloxacin, norfloxacin, ciprofloxacin, and enrofloxacin) by high performance liquid chromatography. Categories of children's growth and development were identified based on the Z score of body mass index. The health risks of individual and combined antibiotic exposure were estimated by the hazard quotient (HQ) and hazard index (HI), respectively. The association between children's growth and development with antibiotic concentrations was evaluated via multiple logistic regression analysis. Results In total, 4 antibiotics, fleroxacin, ofloxacin, ciprofloxacin, and enrofloxacin, were found in urine samples of northern Chinese children at an overall frequency of 57.08%. Due to diet and economic differences, antibiotic concentrations in urine samples differed by study area, and the highest concentrations were found in Tianjin, Henan, and Beijing. The percentage of the participants with HQ > 1 caused by ciprofloxacin exposure was 20.61%, and the HI values in 23.18% of samples exceeded 1, suggesting potential health risks. The odds ratio (95% confidence interval) of overweight or obesity risk of tertile 2 of enrofloxacin was 3.01 (1.12, 8.11), indicating an increase in overweight or obesity risk for children with middle-concentration enrofloxacin exposure. Conclusion This is the first study to show a positive association of enrofloxacin internal exposure with overweight or obesity risk in children, demonstrating that more attention should be given to the usage and disposal of fluoroquinolones to safeguard children's health.
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Bronchopulmonary dysplasia is a relatively common and severe complication of prematurity, and its pathogenesis remains ambiguous. Revolutionary advances in microbiological analysis techniques, together with the growing sophistication of the gut–lung axis hypothesis, have resulted in more studies linking gut microbiota dysbiosis to the occurrence and development of bronchopulmonary dysplasia. The present article builds on current findings to examine the intrinsic associations between gut microbiota and bronchopulmonary dysplasia. Gut microbiota dysbiosis may insult the intestinal barrier, triggering inflammation, metabolic disturbances, and malnutrition, consequences of which might impact bronchopulmonary dysplasia by altering the gut–lung axis. By evaluating the potential mechanisms, new therapeutic targets and potential therapeutic modalities for bronchopulmonary dysplasia can be identified from a microecological perspective.
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Bronchopulmonary dysplasia is a relatively common and severe complication of prematurity, and its pathogenesis remains ambiguous. Revolutionary advances in microbiological analysis techniques, together with the growing sophistication of the gut-lung axis hypothesis, have resulted in more studies linking gut microbiota dysbiosis to the occurrence and development of bronchopulmonary dysplasia. The present article builds on current findings to examine the intrinsic associations between gut microbiota and bronchopulmonary dysplasia. The gut microbiota affects bronchopulmonary dysplasia via several potential mechanisms including alteration of the gut-lung axis, promotion of inflammation and the ensuing growth effects, therefore these are also investigated. By evaluating the potential mechanisms, new therapeutic targets and potential therapeutic modalities for BPD can be identified from a microecological perspective.
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Owing to an error during typesetting, a number of references were deleted from the Methods reference list. This altered all of the references in the Methods section and some of the references in Extended Data Fig. 5, making them inaccurate. References 121–134 were added back into the Methods reference list, and the references in the Methods section and in Extended Data Fig. 5 were renumbered accordingly. The error has been corrected in the PDF and HTML versions of this article.
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Recent studies have demonstrated that antibiotics/or probiotics administration in early life play key roles on modulating intestinal microbiota and the alterations might cause long-lasting consequences both physiologically and immunologically. We investigated the effects of early life ceftriaxone, vancomycin and Bifidobacterium bifidum TMC3115 (TMC3115) treatment on intestinal microbiota and immunity both in neonates and adults even after termination of antibiotics exposure. We found that ceftriaxone and vancomycin, but not TMC3115, significantly altered the intestinal microbiota, serum total IgE level, and the morphology and function of the intestinal epithelium in the neonatal mice. In the adult stages, the diversity and composition of the intestinal microbiota were significantly different in the antibiotic-treated mice, and ceftriaxone-treated mice exhibited significantly higher serum total IgE and OVA-specific IgE levels. TMC3115 significantly mitigated the alteration of intestinal microbiota caused by ceftriaxone not vancomycin. Antibiotics and TMC3115 can differently modulate intestinal microbiota and SCFAs metabolism, affecting the development and function of the immunity and intestinal epithelium to different degrees in neonatal mice. Neonatal ceftriaxone-induced abnormal intestinal microbiota, immunity and epithelium could last to adulthood partly, which might be associated with the enhancement of host susceptibility to IgE-mediated allergies and related immune responses, TMC3115 may protect against the side effects of antibiotic treatment, at least partly.
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Probiotics confer immunological protection to the host through the regulation, stimulation, and modulation of immune responses. Researchers have shifted their attention to better understand the immunomodulatory effects of probiotics, which have the potential to prevent or alleviate certain pathologies for which proper medical treatment is as yet unavailable. It has been scientifically established that immune cells (T-and B-cells) mediate adaptive immunity and confer immunological protection by developing pathogen-specific memory. However, this review is intended to present the recent studies on immunomodulatory effects of probiotics. In the early section of this review, concepts of probiotics and common probiotic strains are focused on. On a priority basis, the immune system, along with mucosal immunity in the human body, is discussed in this study. It has been summarized that a number of species of Lactobacillus and Bifidobacterium exert vital roles in innate immunity by increasing the cytotoxicity of natural killer cells and phagocytosis of macrophages and mediate adaptive immunity by interacting with enterocytes and dendritic, Th1, Th2, and Treg cells. Finally, immunomodulatory effects of probiotics on proinflammatory and anti-inflammatory cytokine production in different animal models have been extensively reviewed in this paper. Therefore, isolating new probiotic strains and investigating their immunomodulatory effects on cytokine profiles in humans remain a topical issue.
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Background: The effects of probiotic Bifidobacterium animalis subsp. lactis CECT 8145 (Ba8145) and those of its heat-killed form (h-k Ba8145) on human anthropometric adiposity biomarkers are unknown. Objective: To assess the effect of Ba8145 and h-k Ba8145 ingestion on anthropometric adiposity biomarkers. Design: Randomized, parallel, double-blind, placebo-controlled trial with abdominally obese individuals. Participants (n = 135) consumed 1 capsule/day containing 1010 colony forming unit (CFU) of Ba8145, 1010 CFU of h-k Ba8145, or placebo (maltodextrin) for 3 months. Results: Ba8145 ingestion decreased waist circumference, waist circumference/height ratio, and Conicity index (P < 0.05) versus its baseline. Changes versus the placebo group reached significance (P < 0.05) after the h-k Ba8145 treatment. Ba8145 decreased the body mass index compared with baseline and placebo group (P < 0.05). The decrease in visceral fat area after Ba8145 treatments reached significance (P < 0.05) only after h-k Ba8145. When analyses by gender were performed, significance remained only for women. Diastolic blood pressure and HOMA index decreased (P < 0.05) after h-k Ba8145. Gut microbiome analyses showed an increase in Akkermansia spp. after Ba8145 treatment, particularly in the live form, which was inversely related to weight (P = 0.003). Conclusions: In abdominally obese individuals, consumption of Ba8145, both as viable and mainly as heat-killed cells, improves anthropometric adiposity biomarkers, particularly in women. An increase in the gut Akkermansia genus appears as a possible mechanism involved. Our results support Ba8145 probiotic as a complementary strategy in obesity management.
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Current guidelines recommend the use of probiotics to reduce the risk of eczema. It remains unclear which strain(s) to use. We systematically evaluated data on the efficacy of Lactobacillus rhamnosus GG (LGG) supplementation prenatally and/or postnatally for the primary prevention of eczema. The Cochrane Library, MEDLINE, and EMBASE databases were searched up to August 2018, with no language restrictions, for systematic reviews of randomized controlled trials (RCTs) and RCTs published afterwards. The primary outcome was eczema. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. Heterogeneity was explored using the I2 statistics. The GRADE criteria were used to assess the overall quality of evidence supporting the primary outcome. Seven publications reporting 5 RCTs (889 participants) were included. High to moderate certainty in the body of evidence suggests that LGG supplementation (regardless of the timing of administration) did not reduce the risk of eczema. There was also no consistent effect on other allergic outcomes. This meta-analysis shows that LGG was ineffective in reducing eczema. It does not support the general recommendation to use probiotics for preventing eczema, unless specific strains would be indicated.
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Dysbiosis, an imbalance in microbial communities, is linked with disease when this imbalance disturbs microbiota functions essential for maintaining health or introduces processes that promote disease. Dysbiosis in disease is predicted when microbiota differ compositionally from a healthy control population, but only truly defined when these differences are mechanistically related to adverse phenotypes. For the human gut microbiota, dysbiosis varies across diseases. One common manifestation is replacement of the complex community of anaerobes typical of the healthy adult gut microbiome with a community of lower overall microbial diversity and increased facultative anaerobes. Here we review diseases in which low-diversity dysbiosis has been observed and mechanistically linked with disease, with a particular focus on liver disease, inflammatory bowel disease, and Clostridium difficile infection.
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The beneficial effects of the gut microbiota on growth in early life are well known. However, knowledge about the mechanisms underlying regulating intestinal development by the microbiota is limited. p40, a Lactobacillus rhamnosus GG-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells for protecting the intestinal epithelium against injury and inflammation. Here, we developed p40-containing pectin/zein hydrogels for targeted delivery of p40 to the small intestine and the colon. Treatment with p40-containing hydrogels from postnatal day 2 to 21 significantly enhanced bodyweight gain prior to weaning and functional maturation of the intestine, including intestinal epithelial cell proliferation, differentiation, and tight junction formation, and IgA production in early life in wild-type mice. These p40-induced effects were abolished in mice with specific deletion of EGFR in intestinal epithelial cells, suggesting that transactivation of EGFR in intestinal epithelial cells may mediate p40-regulated intestinal development. Furthermore, neonatal p40 treatment reduced the susceptibility to intestinal injury and colitis and promoted protective immune responses, including IgA production and differentiation of regulatory T cells, in adult mice. These findings reveal novel roles of neonatal supplementation of probiotic-derived factors in promoting EGFR-mediated maturation of intestinal functions and innate immunity, which likely promote long-term beneficial outcomes.
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A common adverse effect of antibiotic use is diarrhea. Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) by the normalization of an unbalanced gastrointestinal flora. The objective of this systematic review was to assess the benefits and harms of probiotics used for the prevention of AAD in an outpatient setting. A search of the PubMed database was conducted and yielded a total of 17 RCTs with 3631 participants to be included in the review. A meta-analysis was conducted for the primary outcome: the incidence of AAD. The pooled results found that AAD was present in 8.0% of the probiotic group compared to 17.7% in the control group (RR 0.49, 95% CI 0.36 to 0.66; I² = 58%), and the species-specific results were similar regarding the probiotic strains L. rhamnosus GG and S. boulardii. However, the overall quality of the included studies was moderate. A meta-analysis of the ten trials reporting adverse events demonstrated no statistically significant differences in the incidence of adverse events between the intervention and control group (RD 0.00, 95% CI -0.02 to 0.02, 2.363 participants). The results suggests that probiotic use may be beneficial in the prevention of AAD among outpatients. Furthermore, the use of probiotics appears safe.
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Gut-derived bacterial lipopolysaccharide (LPS) and subsequent hepatic toll-like receptor 4 (TLR4) activation have been recognized to be involved in the onset of diet-induced nonalcoholic fatty liver disease (NAFLD), but little is known about the variation of LPS and TLR4 during the progression of NAFLD. Probiotics were able to inhibit proliferation of harmful bacteria and improve gastrointestinal barrier function. However, it?s unclear whether LPS/TLR4 is involved in the protection effect of probiotics on NAFLD. In this study, we described characteristic of gut microbiota structure in the progression of NAFLD, and we also analyzed the relationship between gut microbiota and LPS/TLR4 in this process. Furthermore, we applied probiotics intervention to investigate the effect of probiotics on gut flora structure, intestinal integrity, serum LPS, liver TLR4 and liver pathology. Our results showed that serum LPS and liver TLR4 were highly increased during progression of NAFLD, with gut flora diversity and gut mircobiological colonization resistance (B/E) declining. Furthermore, probiotics could improve gut microbiota structure and liver pathology. Probiotics could also downregulate serum LPS and liver TLR4. Our results suggested that both gut flora alteration and endotoxemia may be involved in the progression of NAFLD. Probiotics may delay the progression of NAFLD via LPS/TLR4 signaling.
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Antibiotic administration, while facilitating clearance of targeted infections, also perturbs commensal microbial communities. Previous studies have all focused on the effects of short term use of antibiotics. Here, we focus on the effects of long term use of antibiotic on gut microbiota and immunity. BALB/c mice received saline or different doses of ceftriaxone sodium (100, 200 and 400 mg/mL) via daily gavage for 150 days. Alterations of fecal microbiota, small intestine histopathology, body weight, spleen index, serum IgG, mucus SIgA, IFN-γ/IL-4 ratio, CD4/CD8 ratio and CD4+CD25+ cells were evaluated. Long term ceftriaxone sodium administration resulted in gut microbiota dysbiosis, intestine histological lesions, growth inhibition, spleen index reducing. The immune defense ability reduced as serum IgG and mucus SIgA decreased significantly. Not only the immune defense, long term ceftriaxone administration also affected immune regulation. The IFN-γ/IL-4 and CD4/CD8 ratios increased, the CD4+CD25+ cells reduced on days 30 and 60 after ceftriaxone administration. However, after 90 days of ceftriaxone administration, the IFN-γ/IL-4, CD4/CD8 ratios and CD4+CD25+ cells restored, which indicated a new balance of immune regulation had been formed. Overall, these findings contribute to our understanding of long term antibiotic administration influencing gut microbiota and immunity.
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Background Children with high body mass index (BMI) at preschool age are at risk of developing obesity. Early identification of factors that increase the risk of excessive weight gain could help direct preventive actions. The intestinal microbiota and antibiotic use have been identified as potential modulators of early metabolic programming and weight development. To test if the early microbiota composition is associated with later BMI, and if antibiotic use modifies this association, we analysed the faecal microbiota composition at 3 months and the BMI at 5–6 years in two cohorts of healthy children born vaginally at term in the Netherlands (N = 87) and Finland (N = 75). We obtained lifetime antibiotic use records and measured weight and height of all children. Results The relative abundance of streptococci was positively and the relative abundance of bifidobacteria negatively associated with the BMI outcome. The association was especially strong among children with a history of antibiotic use. Bacteroides relative abundance was associated with BMI only in the children with minimal lifetime antibiotic exposure. Conclusions The intestinal microbiota of infants are predictive of later BMI and may serve as an early indicator of obesity risk. Bifidobacteria and streptococci, which are indicators of microbiota maturation in infants, are likely candidates for metabolic programming of infants, and their influence on BMI appears to depend on later antibiotic use. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0245-y) contains supplementary material, which is available to authorized users.
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Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.
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Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.
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Antibiotics have direct effects on the human intestinal microbiota, particularly in infancy. Antibacterial agents promote growth in farm animals by unknown mechanisms, but little is known about their effects on human weight gain. Our aim was to evaluate the impact of antibiotic exposure during infancy on weight and height in healthy Finnish children. The population-based cohort comprised 6114 healthy boys and 5948 healthy girls having primary care weight and height measurements and drug purchase data from birth to 24 months. BMI and height, expressed as z-scores at the median age of 24 months (interquartile range 24 to 26 months), were compared between children exposed and unexposed to antibiotics using analysis of covariance with perinatal factors as covariates. Exposed children were on average heavier than unexposed children (adjusted BMI-for-age z-score difference in boys 0.13 SD [95% confidence interval 0.07 to 0.19, P < .001] and in girls 0.07 SD [0.01 to 0.13, P < .05]). The effect was most pronounced after exposure to macrolides before 6 months of age (boys 0.28 [0.11 to 0.46]; girls 0.23 [0.04 to 0.42]) or >1 exposure (boys 0.20 [0.10 to 0.30]; girls 0.13 [0.03 to 0.22]). Antibiotic exposure before 6 months of age, or repeatedly during infancy, was associated with increased body mass in healthy children. Such effects may play a role in the worldwide childhood obesity epidemic and highlight the importance of judicious use of antibiotics during infancy, favoring narrow-spectrum antibiotics. Copyright © 2015 by the American Academy of Pediatrics.
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Structural disruption of gut microbiota and associated inflammation are considered important etiological factors in high fat diet (HFD)-induced metabolic syndrome (MS). Three candidate probiotic strains, Lactobacillus paracasei CNCM I-4270 (LC), L. rhamnosus I-3690 (LR) and Bifidobacterium animalis subsp. lactis I-2494 (BA), were individually administered to HFD-fed mice (10(8) cells day(-1)) for 12 weeks. Each strain attenuated weight gain and macrophage infiltration into epididymal adipose tissue and markedly improved glucose-insulin homeostasis and hepatic steatosis. Weighted UniFrac principal coordinate analysis based on 454 pyrosequencing of fecal bacterial 16S rRNA genes showed that the probiotic strains shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean mice fed a normal (chow) diet. Redundancy analysis revealed that abundances of 83 operational taxonomic units (OTUs) were altered by probiotics. Forty-nine altered OTUs were significantly correlated with one or more host MS parameters and were designated 'functionally relevant phylotypes'. Thirteen of the 15 functionally relevant OTUs that were negatively correlated with MS phenotypes were promoted, and 26 of the 34 functionally relevant OTUs that were positively correlated with MS were reduced by at least one of the probiotics, but each strain changed a distinct set of functionally relevant OTUs. LC and LR increased cecal acetate but did not affect circulating lipopolysaccharide-binding protein; in contrast, BA did not increase acetate but significantly decreased adipose and hepatic tumor necrosis factor-α gene expression. These results suggest that Lactobacillus and Bifidobacterium differentially attenuate obesity comorbidities in part through strain-specific impacts on MS-associated phylotypes of gut microbiota in mice.
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Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favours C. difficile germination and growth.
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Obesity and diabetes are associated with excess caloric intake and reduced energy expenditure resulting in a negative energy balance. The incidence of diabetes has reached epidemic proportions, and childhood diabetes and obesity are increasing alarmingly. Therefore, it is important to develop safe, easily deliverable, and economically viable treatment alternatives for these diseases. Here, we provide data supporting the candidacy of probiotics as such a therapeutic modality against obesity and diabetes. Probiotics are live bacteria that colonize the gastrointestinal tract and impart beneficial effects for health. However, their widespread prescription as medical therapies is limited primarily because of the paucity of our understanding of their mechanism of action. Here, we demonstrate that the administration of a probiotic, VSL#3, prevented and treated obesity and diabetes in several mouse models. VSL#3 suppressed body weight gain and insulin resistance via modulation of the gut flora composition. VSL#3 promoted the release of the hormone GLP-1, resulting in reduced food intake and improved glucose tolerance. The VSL#3-induced changes were associated with an increase in the levels of a short chain fatty acid (SCFA), butyrate. Using a cell culture system, we demonstrate that butyrate stimulated the release of GLP-1 from intestinal L-cells, thereby providing a plausible mechanism for VSL#3 action. These findings suggest that probiotics such as VSL#3 can modulate the gut microbiota-SCFA-hormone axis. Moreover, our results indicate that probiotics are of potential therapeutic utility to counter obesity and diabetes.
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The intestinal microflora is critical for normal development, with aberrant colonization increasing the risk for necrotizing enterocolitis (NEC). In contrast, probiotic bacteria have been shown to decrease its incidence. Multiple pro- and anti-inflammatory cytokines have been identified as markers of intestinal inflammation, both in human patients with NEC and in models of immature intestine. Specifically, IL-10 signaling attenuates intestinal responses to gut dysbiosis, and disruption of this pathway exacerbates inflammation in murine models of NEC. However, the effects of probiotics on IL-10 and its signaling pathway, remain poorly defined. Real-time PCR profiling revealed developmental regulation of MIP-2, TNF-α, IL-12, IL-10 and the IL-10R2 subunit of the IL-10 receptor in immature murine colon, while the expression of IL-6 and IL-18 was independent of postnatal age. Enteral administration of the probiotic Lactobacillus rhamnosus GG (LGG) down-regulated the expression of TNF-α and MIP-2 and yet failed to alter IL-10 mRNA and protein expression. LGG did however induce mRNA expression of the IL-10R2 subunit of the IL-10 receptor. IL-10 receptor activation has been associated with signal transducer and activator of transcription (STAT) 3-dependent induction of members of the suppressors of cytokine signaling (SOCS) family. In 2 week-old mice, LGG also induced STAT3 phosphorylation, increased colonic expression of SOCS-3, and attenuated colonic production of MIP-2 and TNF-α. These LGG-dependent changes in phosphoSTAT3, SOCS3, MIP-2 and TNF-α were all inhibited by antibody-mediated blockade of the IL-10 receptor. Thus LGG decreased baseline proinflammatory cytokine expression in the developing colon through upregulation of IL-10 receptor-mediated signaling, most likely due to the combined induction of phospho-STAT3 and SOCS3. Furthermore, LGG-dependent increases in IL-10R2 were associated with reductions in TNF-α, MIP-2 and disease severity in a murine model of intestinal injury in the immature colon.
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Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.
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Objectives: To examine the associations of antibiotic exposures during the first 2 years of life and the development of body mass over the first 7 years of life. Design: Longitudinal birth cohort study. Subjects: A total of 11 532 children born at 2500 g in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based study of children born in Avon, UK in 1991-1992. Measurements: Exposures to antibiotics during three different early-life time windows (<6 months, 6-14 months, 15-23 months), and indices of body mass at five time points (6 weeks, 10 months, 20 months, 38 months and 7 years). Results: Antibiotic exposure during the earliest time window (<6 months) was consistently associated with increased body mass (+0.105 and +0.083 s.d. unit, increase in weight-for-length Z-scores at 10 and 20 months, P<0.001 and P=0.001, respectively; body mass index (BMI) Z-score at 38 months +0.067 s.d. units, P=0.009; overweight OR 1.22 at 38 months, P=0.029) in multivariable, mixed-effect models controlling for known social and behavioral obesity risk factors. Exposure from 6 to 14 months showed no association with body mass, while exposure from 15 to 23 months was significantly associated with increased BMI Z-score at 7 years (+0.049 s.d. units, P=0.050). Exposures to non-antibiotic medications were not associated with body mass. Conclusions: Exposure to antibiotics during the first 6 months of life is associated with consistent increases in body mass from 10 to 38 months. Exposures later in infancy (6-14 months, 15-23 months) are not consistently associated with increased body mass. Although effects of early exposures are modest at the individual level, they could have substantial consequences for population health. Given the prevalence of antibiotic exposures in infants, and in light of the growing concerns about childhood obesity, further studies are needed to isolate effects and define life-course implications for body mass and cardiovascular risks.
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Increasing evidence suggests that environmental factors changing the normal colonisation pattern in the gut strongly influence the risk of developing autoimmune diabetes. The aim of this study was to investigate, both during infancy and adulthood, whether treatment with vancomycin, a glycopeptide antibiotic specifically directed against Gram-positive bacteria, could influence immune homeostasis and the development of diabetic symptoms in the NOD mouse model for diabetes. Accordingly, one group of mice received vancomycin from birth until weaning (day 28), while another group received vancomycin from 8 weeks of age until onset of diabetes. Pyrosequencing of the gut microbiota and flow cytometry of intestinal immune cells was used to investigate the effect of vancomycin treatment. At the end of the study, the cumulative diabetes incidence was found to be significantly lower for the neonatally treated group compared with the untreated group, whereas the insulitis score and blood glucose levels were significantly lower for the mice treated as adults compared with the other groups. Mucosal inflammation was investigated by intracellular cytokine staining of the small intestinal lymphocytes, which displayed an increase in cluster of differentiation (CD)4(+) T cells producing pro-inflammatory cytokines in the neonatally treated mice. Furthermore, bacteriological examination of the gut microbiota composition by pyrosequencing revealed that vancomycin depleted many major genera of Gram-positive and Gram-negative microbes while, interestingly, one single species, Akkermansia muciniphila, became dominant. The early postnatal period is a critical time for microbial protection from type 1 diabetes and it is suggested that the mucolytic bacterium A. muciniphila plays a protective role in autoimmune diabetes development, particularly during infancy.
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Epithelial cells of the mammalian intestine are covered with a mucus layer that prevents direct contact with intestinal microbes but also constitutes a substrate for mucus-degrading bacteria. To study the effect of mucus degradation on the host response, germ-free mice were colonized with Akkermansia muciniphila. This anaerobic bacterium belonging to the Verrucomicrobia is specialized in the degradation of mucin, the glycoprotein present in mucus, and found in high numbers in the intestinal tract of human and other mammalian species. Efficient colonization of A. muciniphila was observed with highest numbers in the cecum, where most mucin is produced. In contrast, following colonization by Lactobacillus plantarum, a facultative anaerobe belonging to the Firmicutes that ferments carbohydrates, similar cell-numbers were found at all intestinal sites. Whereas A. muciniphila was located closely associated with the intestinal cells, L. plantarum was exclusively found in the lumen. The global transcriptional host response was determined in intestinal biopsies and revealed a consistent, site-specific, and unique modulation of about 750 genes in mice colonized by A. muciniphila and over 1500 genes after colonization by L. plantarum. Pathway reconstructions showed that colonization by A. muciniphila altered mucosal gene expression profiles toward increased expression of genes involved in immune responses and cell fate determination, while colonization by L. plantarum led to up-regulation of lipid metabolism. These indicate that the colonizers induce host responses that are specific per intestinal location. In conclusion, we propose that A. muciniphila modulates pathways involved in establishing homeostasis for basal metabolism and immune tolerance toward commensal microbiota.
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To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
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The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
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Objectives: The impact of combination antibiotic therapy on the composition of the intestinal microbiota remains ill-defined. We aimed to assess the effect of a 1 week antibiotic regimen on the intestinal microbiota of healthy humans for a period of up to 31 months. Patients and methods: Thirteen healthy adult men received either no treatment or oral broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for 7 days. At four timepoints (prior to treatment, on day 9, day 49 and 8-31 months later) faecal samples were collected and analysed using 16S RNA gene sequencing. Results: The short-term impact of broad-spectrum antibiotics on the gut microbiota was profound, with a loss of diversity and drastic shifts in community composition. In addition, antibiotics significantly reduced the abundance of bacterial taxa with important metabolic functions, such as the production of butyrate. The microbiota showed a remarkable return towards baseline after 8-31 months, but community composition often remained altered from its initial state. Conclusions: These findings suggest that combined treatment with vancomycin, ciprofloxacin and metronidazole has a profound and long-lasting effect on microbiota composition, the consequences of which remain largely unknown.
Article
Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (T H 1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring T H 17 and T H 2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell–mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.
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Since the renaissance of microbiome research in the past decade, much insight has accumulated in comprehending forces shaping the architecture and functionality of resident microorganisms in the human gut. Of the multiple host-endogenous and host-exogenous factors involved, diet emerges as a pivotal determinant of gut microbiota community structure and function. By introducing dietary signals into the nexus between the host and its microbiota, nutrition sustains homeostasis or contributes to disease susceptibility. Herein, we summarize major concepts related to the effect of dietary constituents on the gut microbiota, highlighting chief principles in the diet-microbiota crosstalk. We then discuss the health benefits and detrimental consequences that the interactions between dietary and microbial factors elicit in the host. Finally, we present the promises and challenges that arise when seeking to incorporate microbiome data in dietary planning and portray the anticipated revolution that the field of nutrition is facing upon adopting these novel concepts.
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Objective: To investigate the utilization of antibiotics in emergency departments (EDs) of class Ⅲ general hospitals in China. Methods: Data from a national monitoring network for rational use of drugs was used. The data included prescriptions of EDs from 114 class Ⅲ general hospitals in 30 provinces (autonomous regions, municipalities) of China. A total of 10 260 595 prescriptions from October 1, 2014 to December 31, 2016 were extracted. The Anatomical Therapeutic Chemical Classification/Defined Daily Dose (DDD) system was used for the classification of antibiotics and calculation of antibiotic use intensity. An auto-regression model was used to analyze the trend over time and seasonal variation of antibiotic use in EDs. Results: The rate of antibiotic prescriptions was 27.82% in EDs, among the antibiotics prescribed, 25.58% were for the combination therapy with 2 or more antibiotic agents, and injectable antibiotic prescriptions accounted for 60.59%. Besides, the number of DDDs per 100 patient visits was 81.84. Broad-spectrum agents were the most commonly used antibiotics, among which the second and third generation cephalosporins, quinolones and macrolides accounted for 23.83%, 21.68%, 19.17% and 7.89% of all prescribed antibiotics, respectively. The use of antibiotics, including prescription frequency and use intensity, in EDs had a slight but significant increase tendency (P<0.05), and the seasonal variation of antibiotic use in EDs was obvious, characterized by the highest frequency and intensity of antibiotic use in winter, the differences were significant (P<0.05). Conclusion: The antibiotic prescription rate in EDs of classⅢ general hospitals in China was controlled at a low level, but the proportions of broad-spectrum antibiotics and injectable antibiotics were high, and a significant increase trend in antibiotic use in EDs was found.
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This study aimed to demonstrate whether exposure to bifidobacteria during early life influences immunity and alleviates the risk of immunoglobulin E (IgE)-mediated allergies in adulthood. BALB/c neonatal mice (n=54) were administered with a lyophilised cell preparation of Bifidobacterium bifidum TMC3115 (TMC3115) for 3 weeks. Following the intervention, the mice were immunised with intraperitoneal ovalbumin (OVA). The morphology and function of the intestinal epithelium were determined using histopathological examinations. Intestinal microbiota was detected using quantitative PCR and characterised using next-generation sequencing of 16S rRNA genes from faecal DNA. Caecal short-chain fatty acids (SCFAs) were measured using gas chromatography-mass spectrometry. Serum levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and immunoglobulin E (IgE) and the percentage of splenic CD4+ T cells were examined using enzyme-linked immunosorbent assay and flow cytometry, respectively. TMC3115 did not significantly affect body weight, and cause any severe systemic inflammation or other clinical symptoms among the neonatal or adult mice, although the crypt depths and Muc2-positive cells in some intestinal segments of neonatal mice were significantly lower than control. Oral TMC3115 administration significantly increased faecal microbial diversity, relative abundance of Bacteroidetes and caecal SCFAs production in neonatal mice. Following the intervention, neonatal mice treated with TMC3115 exhibited less increase in serum IgE levels induced by OVA in adults and significantly higher TNF-α and IL-10 levels than in control. Our findings indicate that the oral administration of bifidobacteria, particularly certain strains, such as TMC3115, during early life could alleviate the risk of IgE-mediated allergies in adult host animals. Modifications of intestinal microbiota, SCFAs metabolism and anti-inflammatory cytokine IL-10 production by bifidobacteria may at least in part be a key mechanism underlying the effect of bifidobacteria on the IgE-mediated immune sensitivity of hosts to attacks by allergens at both neonatal and adult stages.
Article
This study aimed to investigate how Akkermansia muciniphila can implicate type 2 diabetes mellitus and the mechanisms underlying the effects Akkermansia muciniphila on type 2 diabetes mellitus. Normal and streptozotocin-induced diabetic Sprague-Dawley rats were orally administered with Akkermansia muciniphila and solvent. After four weeks of treatment, diabetic rats orally administered with live or pasteurized Akkermansia muciniphila exhibited significant increase in the blood concentration of high-density lipoprotein, and decrease in the hepatic glycogen, serum plasminogen activator inhibitor-1, tumor necrosis factor-α, lipopolysaccharide, malondialdehyde, and total glucagon-like peptide-1. Moreover, diabetic rats orally administered with Akkermansia muciniphila showed significantly increased species alpha diversity and gene function in gut microbes. These results indicated that Akkermansia muciniphila can improve liver function, reduce gluco/lipotoxicity, alleviate oxidative stress, suppress inflammation, and normalize intestine microbiota of the host animal, thereby ameliorating type 2 diabetes mellitus. Akkermansia muciniphila might be considered as one of the ideal new probiotics used in the management of type 2 diabetes mellitus in future.
Article
Objective: To investigate the effect of ceftriaxone on the intestinal epithelium and microbiota in mice in the early-life stage, as well as the recovery of the intestinal epithelium and reconstruction of intestinal microbiota in adult mice. Methods: A total of 36 BALB/C neonatal mice were randomly divided into control group and experimental group, with 18 mice in each group. The mice in the experimental group were given ceftriaxone 100 mg/kg every day by gavage within 21 days after birth. Those in the control group were given an equal volume of normal saline by gavage. Immunohistochemistry was used to measure the expression of Ki67, Muc2, and ZO-1 in the intestinal epithelium. qPCR and next-generation sequencing were used to analyze the overall concentration and composition of fecal bacteria. Results: After 21 days of ceftriaxone intervention, the experimental group had a significant reduction in body weight, a significant reduction in the expression of Ki67 and ZO-1 and a significant increase in the expression of Muc2 in intestinal epithelial cells, a significant reduction in the overall concentration of fecal bacteria, and a significant increase in the diversity of fecal bacteria compared with the control group (P<0.05). Firmicutes was the most common type of fecal bacteria in the experimental group, and there were large amounts of Staphylococcus and Enterococcus. The experimental group had a certain degree of recovery of the intestinal epithelium, but there were still significant differences in body weight and the structure of intestinal microbiota between the two groups at 56 days after birth (P<0.05). Conclusions: Early ceftriaxone intervention significantly affects the development of the intestinal epithelium and the construction of intestinal microbiota in the early-life stage. The injury of the intestinal microbiota in the early-life stage may continue to the adult stage and affect growth and development and physiological metabolism.
Article
This study aimed to determine how antibiotic-driven intestinal dysbiosis impairs the development and differentiation of the digestive tract and immune organs of host animals. BALB/C neonatal mice were orally administered ceftriaxone or vancomycin from postnatal day 1 to day 21 and sacrificed on day 21. The diversity and abundance of the intestinal bacteria, morphological changes and barrier function of intestinal tract, and the splenic CD4⁺CD25⁺Foxp3⁺ T cells were investigated. The gut microbiota and intestinal tissue were damaged, and the numbers of Ki67-, Muc2- and ZO-1-positive cells were significantly decreased in the antibiotic treatment groups. Furthermore, the administration of ceftriaxone, but not vancomycin, led to a significant reduction in the abundance of splenic CD4⁺CD25⁺Foxp3⁺ T cells. Each antibiotic caused intestinal dysbiosis and characteristically influenced the regeneration of intestinal epithelial cells, formation of the intestinal mucus layer and tight junctions, and differentiation of splenic Foxp3+ Treg cells of the neonatal mice before any clinical side effects were observed. The potent ability of each antibiotic to affect the makeup of intestinal commensal microbiota may be a key determinant of the spectrum of antibiotics and influence the health of the host animal, at least partly.
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Animal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.
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A balanced gut microbiota is important for health, but the mechanisms maintaining homeostasis are incompletely understood. Anaerobiosis of the healthy colon drives the composition of the gut microbiota towards a dominance of obligate anaerobes, while dysbiosis is often associated with a sustained increase in the abundance of facultative anaerobic Proteobacteria, indicative of a disruption in anaerobiosis. The colonic epithelium is hypoxic, but intestinal inflammation or antibiotic treatment increases epithelial oxygenation in the colon, thereby disrupting anaerobiosis to drive a dysbiotic expansion of facultative anaerobic Proteobacteria through aerobic respiration. These observations suggest a dysbiotic expansion of Proteobacteria is a potential diagnostic microbial signature of epithelial dysfunction, a hypothesis that could spawn novel preventative or therapeutic strategies for a broad spectrum of human diseases.
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Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells and the crosstalk may play important role in intestinal mucosal immunity. In this Review, we make a comprehensive summary about crosstalk between IECs and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets.
Article
Clinical Question In children prescribed an antibiotic, is the co-administration of a probiotic associated with lower rates of antibiotic-associated diarrhea without an increase in clinically important adverse events? Bottom Line Moderate-quality evidence suggests that probiotics are associated with lower rates of antibiotic-associated diarrhea in children (aged 1 month to 18 years) without an increase in adverse events.
Article
Importance: Early-life antibiotic exposure has been associated with increased adiposity in animal models, mediated through the gut microbiome. Infant antibiotic exposure is common and often inappropriate. Studies of the association between infant antibiotics and childhood weight gain have reported inconsistent results. Objective: To assess the association between early-life antibiotic exposure and childhood weight gain. Design and setting: Retrospective, longitudinal study of singleton births and matched longitudinal study of twin pairs conducted in a network of 30 pediatric primary care practices serving more than 200,000 children of diverse racial and socioeconomic backgrounds across Pennsylvania, New Jersey, and Delaware. Participants: Children born between November 1, 2001, and December 31, 2011, at 35 weeks' gestational age or older, with birth weight of 2000 g or more and in the fifth percentile or higher for gestational age, and who had a preventive health visit within 14 days of life and at least 2 additional visits in the first year of life. Children with complex chronic conditions and those who received long-term antibiotics or multiple systemic corticosteroid prescriptions were excluded. We included 38,522 singleton children and 92 twins (46 matched pairs) discordant in antibiotic exposure. Final date of follow-up was December 31, 2012. Exposure: Systemic antibiotic use in the first 6 months of life. Main outcomes and measures: Weight, measured at preventive health visits from age 6 months through 7 years. Results: Of 38,522 singleton children (50% female; mean birth weight, 3.4 kg), 5287 (14%) were exposed to antibiotics during the first 6 months of life (at a mean age of 4.3 months). Antibiotic exposure was not significantly associated with rate of weight change (0.7%; 95% CI, -0.1% to 1.5%; P = .07, equivalent to approximately 0.05 kg; 95% CI, -0.004 to 0.11 kg of added weight gain between age 2 years and 5 years). Among 92 twins (38% female; mean birth weight, 2.8 kg), the 46 twins who were exposed to antibiotics during the first 6 months of life received them at a mean age of 4.5 months. Antibiotic exposure was not significantly associated with a weight difference (-0.09 kg; 95% CI, -0.26 to 0.08 kg; P = .30). Conclusions and relevance: Exposure to antibiotics within the first 6 months of life compared with no exposure was not associated with a statistically significant difference in weight gain through age 7 years. There are many reasons to limit antibiotic exposure in young, healthy children, but weight gain is likely not one of them.
Article
Recent advances in sequencing techniques, applied to the study of microbial communities, have provided compelling evidence that the mammalian intestinal tract harbors a complex microbial community whose composition is a critical determinant of host health in the context of metabolism and inflammation. Given that an imbalanced gut microbiota often arises from a sustained increase in abundance of the phylum Proteobacteria, the natural human gut flora normally contains only a minor proportion of this phylum. Here, we review studies that explored the association between an abnormal expansion of Proteobacteria and a compromised ability to maintain a balanced gut microbial community. We also propose that an increased prevalence of Proteobacteria is a potential diagnostic signature of dysbiosis and risk of disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:
Article
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Article
Oral supplementation with probiotic bacteria can protect against the development of allergic and inflammatory diseases. The aim of this study was to investigate potential immunomodulatory and allergy-protective effects of processed Lactobacillus rhamnosus GG (LGG)-derived supernatants early in life in neonatal mice. In vitro, RAW264.7 mouse macrophages were stimulated with viable LGG, LGG-derived supernatants, prepared from different growth phases, and different size fractions thereof, and pro- and anti-inflammatory cytokine production was analysed. Supernatant fractions were also treated with protease, DNAse or carbohydrate-digesting enzymes to define the nature of immunomodulatory components. In vivo, neonatal Balb/c mice were orally supplemented with differentially processed LGG supernatants. Starting at 4 weeks of age, a protocol of ovalbumin-induced acute allergic airway inflammation was applied and protective effects of processed LGG supernatants were assessed. Incubation of RAW264.7 cells with LGG-derived supernatants significantly increased TNFα and IL-10 production. These effects were not restricted to a particular molecular size fraction. Treatment with protease, but not with DNAse or carbohydrate-digesting enzymes, completely abolished the immunomodulatory activities. Incubation of TLR/NOD-transfected cells with LGG-derived supernatants revealed that recognition and signalling of bioactive components is mediated by TLR2 and NOD2. In vivo supplementation of newborn mice with processed LGG-derived supernatants resulted in pronounced protective effects on the allergic inflammatory response as reflected by reduced eosinophil numbers, modified T helper cell cytokine production, significantly less lung inflammation and reduced goblet cell numbers in comparison with sham-treated controls. LGG-derived supernatants exert immunomodulatory activities, and neonatal administration of specifically processed supernatants may provide an alternative to viable probiotics in reducing allergic inflammatory responses.
Article
Unlabelled: Nonalcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis, and liver inflammation, NASH is believed to be under the influence of the gut microflora. Here, the composition of gut bacterial communities of NASH, obese, and healthy children was determined by 16S ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of patients and healthy controls. UniFrac-based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family, and genus levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae, and Escherichia were the only phylum, family and genus types exhibiting significant difference between obese and NASH microbiomes. Similar blood-ethanol concentrations were observed between healthy subjects and obese non-NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels. Conclusions: The increased abundance of alcohol-producing bacteria in NASH microbiomes, elevated blood-ethanol concentration in NASH patients, and the well-established role of alcohol metabolism in oxidative stress and, consequently, liver inflammation suggest a role for alcohol-producing microbiota in the pathogenesis of NASH. We postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease.
Article
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively
Long-term use of ceftriaxone sodium induced changes in gut microbiota and immune system. Sci Rep-Uk
  • Y J Guo
  • X F Yang
  • Y Qi