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PubMed2007

Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.

The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet. Their persistently lean phenotype is associated with increased skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream targets involved in fatty acid oxidation (acetylCoA carboxylase; carnitine-palmitoyltransferase). Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity. Although GF Fiaf-/- animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1alpha) and enzymes involved in fatty acid oxidation. Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: (i) elevated levels of Fiaf, which induces Pgc-1alpha; and (ii) increased AMPK activity. Together, these findings support the notion that the gut microbiota can influence both sides of the energy balance equation, and underscore the importance of considering our metabolome in a supraorganismal context.

AMP-Activated Protein Kinases↗

PubMed2006

Qualitative and quantitative comparison of gut bacterial colonization in enterally and parenterally fed neonatal pigs.

Total parenteral nutrition (TPN) has been associated with mucosal atrophy, impaired gut barrier function, and translocation of luminal bacteria with resultant sepsis in preterm human infants. Currently, we examined the effects of enteral (ENT) or TPN treatments on translocation events in neonatal pigs and on colonization and composition of microbiota in the neonatal gut. Newborn, colostrum-deprived pigs (<24 hours old) were fitted with intravenous catheters and were fed either ENT (n = 13) or TPN (n = 13) for 7 days. After 7 days of treatment, pigs were euthanized and samples were collected for bacterial culture from the blood, intestinal tract and organs. ENT pigs had increased numbers of bacterial genera isolated, higher concentrations of bacteria (CFU/g), and increased colonization of all segments of the intestinal tract compared to the TPN pigs. Translocation of bacteria from the intestinal tract to tissues or blood was similar (8 of 13) for both groups. The ENT group had 1/13 positive for Clostridium difficile toxin A whereas the TPN group had 5/13. We concluded that ENT favored increased bacterial concentrations comprised of more speciation in the gastrointestinal tract compared to TPN, and that TPN-treated piglets were at higher risk of colonization by toxin-expressing strains of C. difficile.

Animals↗

PubMed1995

Role of Escherichia coli P fimbriae in intestinal colonization in gnotobiotic rats.

Adherence via P fimbriae is associated with long-term persistence of Escherichia coli in the human large intestine, but a causal relationship has not been proven. In the present study, germfree rats were colonized with a mixture of two isogenic E. coli strains, one P fimbriated and the other type 1 fimbriated. Both types of fimbriae conferred adherence to rat colonic epithelial cells. With two mutant strains from a pyelonephritogenic isolate of serotype O75:K5:H-, the P-fimbriated strain 824 attained much higher numbers than its type 1-fimbriated counterpart when colonized in vivo for 2 weeks (10(10) versus 10(6) bacteria per g, respectively; P < 0.0001). The expression of P fimbriae by 824 was also retained during colonization. With transformant isogenic strains obtained from a normal fecal isolate incapable of phase variation, no benefit of P fimbriae was seen and most bacteria lost their plasmids during in vivo colonization. When the pyelonephritogenic mutant and fecal transformant strains were combined, the former colonized at high levels while the latter were suppressed. In contrast, no suppression was seen when the transformant E. coli strains colonized in combination with Lactobacillus acidophilus or Peptostreptococcus sp. The results indicate that P fimbriae, but also other bacterial traits linked to uropathogeneicity, could play an important role for persistence in the gut normal microbiota. Neither P nor type 1 fimbriae seemed to contribute to the ability to translocate to the mesenteric lymph nodes.

Animals↗

PubMed2005

Delivery of therapeutic proteins to the mucosa using genetically modified microflora.

Drug delivery through mucosal surfaces offers a panorama of opportunities. The advantages are clear and include safety, ease of administration and higher social acceptance, although the major disadvantages are drug availability and appropriate drug targeting. Most mucosa are well equipped to manage the presence of bacteria and many are actually permanently colonised with a specific microflora. Such microbiota may become attractive tools for the delivery of a specific niche of protein therapeutics. These proteins can be produced from genetically modified microbes that are common to the mucosa, and their delivery to the host tissues has been demonstrated. This concept is being developed for the delivery of proteins to the intestine, but has also been applied in delivery to the vagina, nose and mouth.

Animals↗

PubMed2005

Dietary fibres as "prebiotics": implications for colorectal cancer.

A "prebiotic" is a nondigestible food ingredient whose beneficial effects on the host result from the selective stimulation of growth and/or activity of members of the bacterial community that inhabits the human bowel (the gut microbiota). Although much of the prebiotic literature focuses on nondigestible oligosaccharides, such as oligofructose, most dietary fibres that are fermentable carbohydrates could be considered as prebiotics. Early studies suggested that colonic bacteria were risk factors for colon cancer. However, altering the composition or metabolic activity of the bowel microbiota through the use of dietary fibre might be important in reducing the prevalence of colorectal cancer. Mechanisms for beneficial effects of prebiotics might include changing the activity of exogenous carcinogens through modulating metabolic activation and/or detoxification, or stimulating the production of the short-chain fatty acid, butyrate. However, modern analytical techniques suggest that an important consequence of a modified bacterial community could be a change in the expression not only of a range of different bacterial genes in bowel contents, but also in the bowel mucosa of the host. Analogous with observations with probiotics, the stimulation of cytokines and modification of immune responses could be important in producing beneficial effects. Compared with transitory effects of probiotics, the prebiotic action of fermentable carbohydrates potentially provide the opportunity for sustainable modulation of activity of the gut microbiota. However, their mechanisms of action in humans are speculative, and research aimed at providing an integrated view of the gut microbiota and dietary fibre nutrition of humans needs to be developed.

Bacteria↗

PubMed2005

The influence of microbial metabolites on human intestinal epithelial cells and macrophages in vitro.

Microbial metabolites may influence the metabolic integrity of intestinal epithelial cells and induce mucosal immune responses. Therefore, we investigated the effects of the microbial metabolites butyrate, iso-valerate, and ammonium on Caco-2 cells and macrophages. Barrier functioning was determined by measuring transepithelial electrical resistance and basolateral recoveries of metabolites. The barrier function of Caco-2 cells remained intact after exposures. Basolateral recoveries ranged from 6.2% to 15.2%. Tumour necrosis factor-alpha and interleukin-10 were measured to determine immune reactions. The Caco-2 cells did not secrete both cytokines. Physiological concentrations of butyrate and iso-valerate stimulated the secretion of tumour necrosis factor-alpha and suppressed the secretion of interleukin-10 by macrophages that are not protected by an epithelial barrier. In contrast, ammonium concentrations as high as those produced by microbiotas of IBD patients suppressed the release of both cytokines when the barrier function is impaired.

Ammonium Chloride↗

PubMed2005

Molecular analysis of jejunal, ileal, caecal and recto-sigmoidal human colonic microbiota using 16S rRNA gene libraries and terminal restriction fragment length polymorphism.

Microbiota in gut contents of jejunum, ileum, caecum and recto-sigmoid colon obtained from three elderly individuals at autopsy were compared using 16S rRNA gene libraries and terminal restriction fragment length polymorphism (T-RFLP). Random clones of 16S rRNA gene sequences were isolated after PCR amplification with universal primer sets of total genomic DNA extracted from each sample of gut contents. An average of 90 randomly selected clones were partially sequenced (about 500 bp). T-RFLP analysis was performed using the 16S rRNA gene amplified from each sample. The lengths of the terminal restriction fragments were analysed after digestion with HhaI and MspI. The jejunal and ileal microbiota consisted of simple microbial communities of streptococci, lactobacilli, 'Gammaproteobacteria', the Enterococcus group and the Bacteroides group. Most of the species were facultative anaerobes or aerobes. The Clostridium coccoides group and the Clostridium leptum subgroup, which are the most predominant groups in human faeces, were not detected in samples from the upper gastrointestinal tract. The caecal microbiota was more complex than the jejunal and ileal microbiota. The C. coccoides group, the C. leptum subgroup and the Bacteroides group were detected in the caecum. The recto-sigmoidal colonic microbiota consisted of complex microbial communities, with numerous species that belonged to the C. coccoides group, the C. leptum subgroup, the Bacteroides group, 'Gammaproteobacteria', the Bifidobacterium group, streptococci and lactobacilli, and included more than 26 operational taxonomic units. The results showed marked individual differences in the composition of microbiota in each region.

Aged↗

PubMed2002

Fecal microbial diversity in a strict vegetarian as determined by molecular analysis and cultivation.

Fecal microbial diversity in a strictly vegetarian woman was determined by the 16S rDNA library method, terminal restriction fragment length polymorphism (T-RFLP) analysis and a culture-based method. The 16S rDNA library was generated from extracted fecal DNA, using bacteria-specific primers. Randomly selected clones were partially sequenced. T-RFLP analysis was performed using amplified 16S rDNA. The lengths of T-RF were analyzed after digestion by HhaI and MspI. The cultivated bacterial isolates were used for partial sequencing of 16S rDNA. Among 183 clones obtained, approximately 29% of the clones belonged to 13 known species. About 71% of the remaining clones were novel "phylotypes" (at least 98% similarity of clone sequence). A total of 55 species or phylotypes were identified among the 16S rDNA library, while the cultivated isolates included 22 species or phylotypes. In addition, many new phylotypes were detected from the 16S rDNA library. The 16S rDNA library and isolates commonly included the Bacteroides group, Bifidobacterium group, and Clostridium rRNA clusters IV, XIVa, XVI and XVIII. T-RFLP analysis revealed the major composition of the vegetarian gut microbiota were Clostridium rRNA subcluster XIVa and Clostridium rRNA cluster XVIII. The dominant feature of this strictly vegetarian gut microbiota was the detection of many Clostridium rRNA subcluster XIVa and C. ramosum (Clostridium rRNA cluster XVIII).

Adult↗

PubMed2003

Bacterial replacement therapy: adapting 'germ warfare' to infection prevention.

The individual bacterial members of our indigeneous microbiota are actively engaged in an on-going battle to prevent colonisation and overgrowth of their terrain by competing microbes, some of which might have pathogenic potential for the host. Humans have long attempted to intervene in these bacterial interactions. Ingestion of probiotic bacteria, particularly lactobacilli, is commonly practiced to promote well-balanced intestinal microflora. As bacterial resistance to antimicrobials has increased, so too has research into colonisation of human tissues with specific effector strains capable of out-competing known bacterial pathogens. Recent progress is particularly evident in the application of avirulent Streptococcus mutans to the control of dental caries, alpha hemolytic streptococci to reduction of otitis media recurrences and Streptococcus salivarius to streptococcal pharyngitis prevention.

Bacteria↗

PubMed2005

Genotypic diversity of Escherichia coli isolated from cecal content and mucosa of one- to six-week-old broilers.

Escherichia coli is a component of the microbiota of the avian digestive tract and is also part of some of the defined cultures used for competitive exclusion of Salmonella. Of particular interest are E. coli that are able to associate with the cecal wall because they might be part of a barrier that block pathogens from attaching and possibly from gaining entrance to intestinal tissues. In this study, repetitive element (rep)-PCR using the BOXA1R primer was used to differentiate between E. coli isolates obtained from cecal content and mucus of 1- to 6-wk-old broiler chickens. Computer-assisted analysis of the fingerprint patterns obtained from the isolates indicated the presence of 2 major groups of patterns. Collectively these 2 groups consisted of 28 clusters of patterns that differed from each other by 30% or more (dissimilarity index of > or = 0.3) and were therefore designated as operational taxonomic units. The patterns obtained from isolates from birds aged 1 to 5 wk were distributed almost equally between the 2 major groups, but approximately 90% of the patterns from isolates obtained from 6-wk-old birds belonged to only 1 of the 2 groups. The diversity of the fingerprints indicates that cecal mucus is inhabited by several types of E. coli in individual birds and in the birds housed together. Evidence for the preferential localization of specific E. coli within the cecal mucosa was not found, and therefore a range of E. coli must be able to associate tightly with the cecal mucosa.

Aging↗

PubMed2000

Ruminant gastrointestinal cell proliferation and clearance of Escherichia coli O157:H7.

Human infections with Escherichia coli O157:H7 cause hemorrhagic colitis that can progress to a life-threatening sequelae. The most common mode of disease transmission is ingestion of contaminated bovine food products, and it is well established that E. coli O157:H7 is a transient member of the bovine microbiota. However, the conditions that induce acquisition and subsequent clearance of this bacterium from the ruminant gastrointestinal tract (GIT) are not understood. Evidence that the rates of epithelial cell proliferation in the lower GIT of cattle are associated with the duration animals remained E. coli O157:H7 culture positive is presented. Cattle with slower rates of intestinal cell proliferation in the cecum and the distal colon were culture positive significantly longer than cohort cattle with faster cell proliferation rates. Cell death rates (apoptotic indices) between the short- and long-term culture-positive animals were not different. Typical grain-based finishing diets and forage-based growing diets did not effect GIT cell proliferation or the duration animals remained E. coli O157:H7 culture positive. To identify a dietary intervention that would effect GIT cell proliferation, we used sheep as a model ruminant. A fasting-refeeding regime that increased the rate of GIT cell proliferation was developed. The fasting-refeeding protocol was used in cattle to test the hypothesis that feeding interventions that increase the rate of GIT cell proliferation induce the clearance of E. coli O157:H7 from the bovine GIT.

Animal Feed↗

PubMed2005

Brussels sprouts, inulin and fermented milk alter the faecal microbiota of human microbiota-associated rats as shown by PCR-temporal temperature gradient gel electrophoresis using universal, Lactobacillus and Bifidobacterium 16S rRNA gene primers.

We investigated the effect of Brussels sprouts, inulin and a fermented milk on the faecal microbiota diversity of human microbiota-associated (HMA) rats by PCR-temporal temperature gradient gel electrophoresis (PCR-TTGE) using universal and group-specific 16S rRNA gene primers. The HMA rats were submitted to a control diet for 10 d (initial time), then switched to the experimental diets for 4 weeks (final time). Using universal primers, the mean degree of similarity between all faecal samples at initial time was 80.8 %. In the group consuming the control diet throughout the experiment, the mean degree of similarity between the PCR-TTGE profiles at initial v. final time was 76.8 %, reflecting a spontaneous temporal variation. The mean degree of similarity between control and experimental groups at final time was lower, 72.4 %, 74.4 % and 75.6 % for inulin, Brussels sprouts and fermented milk, respectively, indicating a dietary effect on the predominant populations. Using specific primers, bifidobacteria could be detected only in those rats that had consumed inulin, showing a specific increasing effect of this dietary compound. The Lactobacillus population was very heterogeneous at initial time but tended to homogenize within each dietary group. At final time, caecal contents were collected for analysis of SCFA and beta-glucuronidase activity. Inulin and Brussels sprouts increased the butyrate and acetate proportion, respectively, while the fermented milk did not modify the caecal biochemistry. This experiment shows for the first time that cruciferous vegetables are able to alter the diversity and the metabolic activities of the digestive microbiota in HMA rats.

Acetates↗

PubMed2004

Novel evidence suggesting Clostridium difficile is present in human gut microbiota more frequently than previously suspected.

Prevalence rate of Clostridium difficile in healthy human adults is believed to be very low. Our RT-PCR system using glass powder, which can eliminate PCR inhibitors, detected C. difficile toxin B mRNA in 16 of 30 fecal samples (53.3%) from healthy human adults. In contrast, we failed to detect toxin B in the same fecal samples by PCR using DNA templates extracted with phenol-chloroform. Our results suggest that PCR inhibitors in feces carried through phenol-chloroform extraction procedure might suppress the sensitivity of PCR and that C. difficile is actually present in human gut microbiota more frequently than previously suspected.

Adult↗

PubMed2025

Expansion of a bacterial operon during cancer treatment ameliorates fluoropyrimidine toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Here, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal profiling of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. Substantial shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities were revealed by 16S rRNA gene sequencing. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which was sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA+ bacteria depleted 5-FU in gut microbiota grown ex vivo and in the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ Escherichia coli, or preTA-high stool from patients with CRC. Last, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach may be generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease.

Animals↗

PubMed2006

The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients.

The bacterial community (microbiota) that inhabits the gut of humans appears to be an important source of antigens that drive the chronic immunological processes characteristic of Crohn's disease (CD) and ulcerative colitis (UC). Most of the members of the microbiota have not yet been cultured, but nucleic-acid-based methods of detection and enumeration can provide information about the community. This investigation used these methods to obtain information about the bacteria associated with mucosal surfaces in the gut of 20 CD and 15 UC patients. Biopsies were collected from inflamed and non-inflamed sites in the intestines of newly diagnosed, untreated patients. Biopsies were also collected from several intestinal sites of 14 healthy subjects. The bacterial collections associated with the biopsies were analysed by generating PCR/denaturing gradient gel electrophoresis (DGGE) profiles, the preparation of 16S rRNA gene clone libraries, and qualitative PCR to detect specific groups of bacteria. The total numbers of bacteria associated with the biopsies were determined by real-time quantitative PCR. DGGE profiles generated from the terminal ileum and various colonic regions were characteristic of each individual but differed between subjects. DGGE profiles and 16S rRNA gene libraries showed that the bacteria associated with inflamed and non-inflamed tissues did not differ. UC patients had more bacteria associated with biopsies than did CD patients (P<0.01). Statistical analysis of the composition of 16S rRNA gene libraries showed that the bacterial collections in UC and CD patients differed (P<0.05). Unclassified members of the phylum Bacteroidetes were more prevalent in CD than in UC patients. Therefore, the types and numbers of bacteria associated with biopsy samples were distinctly different for UC and CD patients. The observations made in this study should permit targeting of specific bacteriological abnormalities in investigations of the pathogenesis of inflammatory bowel diseases and provide targets for medical interventions.

Adolescent↗

PubMed2001

Differences in the gut bacterial flora of healthy and milk-hypersensitive adults, as measured by fluorescence in situ hybridization.

We enumerated the predominant gut genera from fecal samples of nine healthy and eight milk-hypersensitive adults both before and after 4 weeks Lactobacillus rhamnosus GG (LGG) supplementation. The anaerobic intestinal microflora of milk-hypersensitive adults was found to resemble that of healthy adults. LGG-consumption resulted in a significant increase in the number of bifidobacteria in healthy but not in milk-hypersensitive subjects, as well as a general increase in bacterial numbers in all other bacterial genera tested in both groups. In conclusion, the composition of the gut microbiota in milk-hypersensitive adults appears to be normal. LGG may have potential in reinforcing the endogenous flora.

Adult↗

PubMed2002

Improvement of the probiotic effect of micro-organisms by their combination with maltodextrins, fructo-oligosaccharides and polyunsaturated fatty acids.

Probiotics could represent an effective alternative to the use of synthetic substances in nutrition and medicine. The data concerning the efficacy of probiotics are often contradictory. This paper focuses on the enhancement of the efficacy of probiotics by their combination with synergistically acting components of natural origin. Maltodextrins can be obtained by enzymatic hydrolysis of starch and are suitable for consumption. Administration of Lactobacillus paracasei together with maltodextrin decreased the number of Escherichia coli colonising the jejunal mucosa of gnotobiotic piglets by 1 logarithm compared to the control group. Fructo-oligosaccharides (FOS) are naturally occurring oligosaccharides, mainly of plant origin. L. paracasei administered in combination with FOS significantly increased counts of Lactobacillus spp., Bifidobacterium spp., total anaerobes and total aerobes compared to the control group as well as the L. paracasei group. It also significantly decreased Clostridium and Enterobacterium counts in the faeces of the weanling piglets compared with the control group. Dietary lipids influence the gastrointestinal microbiota and specifically the population of lactic acid bacteria. In gnotobiotic piglets the oral administration of an oil containing polyunsaturated fatty acids (PUFA) significantly increased the number of L. paracasei adhering to jejunal mucosa compared to the control group. Our results showed that maltodextrin KMS X-70 and PUFA can be used to enhance the effect of probiotic micro-organisms in the small intestine, and similarly FOS enhance the effect of probiotic micro-organisms in the large intestine.

Animals↗

PubMed2026

Autoimmune disease-associated pathobionts: mechanisms and therapeutic potential of phage-based approaches.

The gut microbiota is a critical regulator of systemic immune homeostasis; accumulating evidence implicates specific commensal bacteria, termed "pathobionts," in autoimmune disease pathogenesis. However, the definition of pathobionts remains context-dependent, as their effects are influenced by host genetics and host-microbe interactions. In this review, we summarize representative pathobionts supported by functional evidence in selected extraintestinal autoimmune diseases and discuss how these mechanisms may inform phage-based microbiome-targeted interventions. Mechanistically, pathobionts contribute to autoimmune disease through multiple pathways, including molecular mimicry, induction of intestinal T helper 17 and T follicular helper cell responses, disruption of regulatory T cell homeostasis, intestinal barrier dysfunction, and bacterial translocation from the gut to extraintestinal sites. These processes highlight the central role of gut-associated lymphoid tissue in initiating systemic autoimmunity, and targeting disease-associated microbes represents a promising therapeutic strategy. Whole-phage therapy, which enables highly specific bacterial elimination, has shown efficacy in preclinical immune-mediated disease models, but may be affected by variable in vivo replication, bacterial receptor-mediated resistance, anti-phage immune responses, and ecological effects on the resident microbiome. Phage-derived enzymes that lyse bacterial cell walls, such as endolysins, represent a complementary therapeutic modality that specifically targets bacterial peptidoglycan through cell wall-binding and catalytic domains. Collectively, these findings support the concept that pathobiont-targeted interventions, particularly phage-based strategies, may provide microbiome-directed, immunosuppression-sparing therapeutic approaches for selected patient subsets.

Humans↗