Yoghurt consumption is associated with changes in the composition of the human gut microbiome and metabolome.

BACKGROUND: Yoghurt contains live bacteria that could contribute via modulation of the gut microbiota to its reported beneficial effects such as reduced body weight gain and lower incidence of type 2 diabetes. To date, the association between yoghurt consumption and the composition of the gut microbiota is underexplored. Here we used clinical variables, metabolomics, 16S rRNA and shotgun metagenomic sequencing data collected on over 1000 predominantly female UK twins to define the link between the gut microbiota and yoghurt-associated health benefits. RESULTS: According to food frequency questionnaires (FFQ), 73% of subjects consumed yoghurt. Consumers presented a healthier diet pattern (healthy eating index: beta = 2.17 ± 0.34; P = 2.72x10-10) and improved metabolic health characterised by reduced visceral fat (beta = -28.18 ± 11.71 g; P = 0.01). According to 16S rRNA gene analyses and whole shotgun metagenomic sequencing approach consistent taxonomic variations were observed with yoghurt consumption. More specifically, we identified higher abundance of species used as yoghurt starters Streptococcus thermophilus (beta = 0.41 ± 0.051; P = 6.14x10-12) and sometimes added Bifidobacterium animalis subsp. lactis (beta = 0.30 ± 0.052; P = 1.49x10-8) in the gut of yoghurt consumers. Replication in 1103 volunteers from the LifeLines-DEEP cohort confirmed the increase of S. thermophilus among yoghurt consumers. Using food records collected the day prior to faecal sampling we showed than an increase in these two yoghurt bacteria could be transient. Metabolomics analysis revealed that B. animalis subsp. lactis was associated with 13 faecal metabolites including a 3-hydroxyoctanoic acid, known to be involved in the regulation of gut inflammation. CONCLUSIONS: Yoghurt consumption is associated with reduced visceral fat mass and changes in gut microbiome including transient increase of yoghurt-contained species (i.e. S. thermophilus and B. lactis).

Identification of an Intestinal Microbiota Signature Associated With Severity of Irritable Bowel Syndrome.

BACKGROUND & AIMS: We have limited knowledge about the association between the composition of the intestinal microbiota and clinical features of irritable bowel syndrome (IBS). We collected information on the fecal and mucosa-associated microbiota of patients with IBS and evaluated whether these were associated with symptoms. METHODS: We collected fecal and mucosal samples from adult patients who met the Rome III criteria for IBS at a secondary/tertiary care outpatient clinics in Sweden, as well as from healthy subjects. The exploratory set comprised 149 subjects (110 with IBS and 39 healthy subjects); 232 fecal samples and 59 mucosal biopsy samples were collected and analyzed by 16S ribosomal RNA targeted pyrosequencing. The validation set comprised 46 subjects (29 with IBS and 17 healthy subjects); 46 fecal samples, but no mucosal samples, were collected and analyzed. For each subject, we measured exhaled H2 and CH4, oro-anal transit time, and the severity of psychological and gastrointestinal symptoms. Fecal methanogens were measured by quantitative polymerase chain reaction. Numerical ecology analyses and a machine learning procedure were used to analyze the data. RESULTS: Fecal microbiota showed covariation with mucosal adherent microbiota. By using classic approaches, we found no differences in fecal microbiota abundance or composition between patients with IBS vs healthy patients. A machine learning procedure, a computational statistical technique, allowed us to reduce the 16S ribosomal RNA data complexity into a microbial signature for severe IBS, consisting of 90 bacterial operational taxonomic units. We confirmed the robustness of the intestinal microbial signature for severe IBS in the validation set. The signature was able to discriminate between patients with severe symptoms, patients with mild/moderate symptoms, and healthy subjects. By using this intestinal microbiota signature, we found IBS symptom severity to be associated negatively with microbial richness, exhaled CH4, presence of methanogens, and enterotypes enriched with Clostridiales or Prevotella species. This microbiota signature could not be explained by differences in diet or use of medications. CONCLUSIONS: In analyzing fecal and mucosal microbiota from patients with IBS and healthy individuals, we identified an intestinal microbiota profile that is associated with the severity of IBS symptoms. TRIAL REGISTRATION NUMBER: NCT01252550.

Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons.

Beneficial microbes that target molecules and pathways, such as oxidative stress, which can negatively affect both host and microbiota, may hold promise as an inflammatory bowel disease therapy. Prior work showed that a five-strain fermented milk product (FMP) improved colitis in T-bet(-/-) Rag2(-/-) mice. By varying the number of strains used in the FMP, we found that Lactococcus lactis I-1631 was sufficient to ameliorate colitis. Using comparative genomic analyses, we identified genes unique to L. lactis I-1631 involved in oxygen respiration. Respiration of oxygen results in reactive oxygen species (ROS) generation. Also, ROS are produced at high levels during intestinal inflammation and cause tissue damage. L. lactis I-1631 possesses genes encoding enzymes that detoxify ROS, such as superoxide dismutase (SodA). Thus, we hypothesized that lactococcal SodA played a role in attenuating colitis. Inactivation of the sodA gene abolished L. lactis I-1631's beneficial effect in the T-bet(-/-) Rag2(-/-) model. Similar effects were obtained in two additional colonic inflammation models, Il10(-/-) mice and dextran sulfate sodium-treated mice. Efforts to understand how a lipophobic superoxide anion (O2 (-)) can be detoxified by cytoplasmic lactoccocal SodA led to the finding that host antimicrobial-mediated lysis is a prerequisite for SodA release and SodA's extracytoplasmic O2 (-) scavenging. L. lactis I-1631 may represent a promising vehicle to deliver antioxidant, colitis-attenuating SodA to the inflamed intestinal mucosa, and host antimicrobials may play a critical role in mediating SodA's bioaccessibility.

Homeostasis of the gut barrier and potential biomarkers.

The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts.

Brain Structure and Response to Emotional Stimuli as Related to Gut Microbial Profiles in Healthy Women.

OBJECTIVE: Brain-gut-microbiota interactions may play an important role in human health and behavior. Although rodent models have demonstrated effects of the gut microbiota on emotional, nociceptive, and social behaviors, there is little translational human evidence to date. In this study, we identify brain and behavioral characteristics of healthy women clustered by gut microbiota profiles. METHODS: Forty women supplied fecal samples for 16S rRNA profiling. Microbial clusters were identified using Partitioning Around Medoids. Functional magnetic resonance imaging was acquired. Microbiota-based group differences were analyzed in response to affective images. Structural and diffusion tensor imaging provided gray matter metrics (volume, cortical thickness, mean curvature, surface area) as well as fiber density between regions. A sparse Partial Least Square-Discrimination Analysis was applied to discriminate microbiota clusters using white and gray matter metrics. RESULTS: Two bacterial genus-based clusters were identified, one with greater Bacteroides abundance (n = 33) and one with greater Prevotella abundance (n = 7). The Prevotella group showed less hippocampal activity viewing negative valences images. White and gray matter imaging discriminated the two clusters, with accuracy of 66.7% and 87.2%, respectively. The Prevotella cluster was associated with differences in emotional, attentional, and sensory processing regions. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus. CONCLUSIONS: These results support the concept of brain-gut-microbiota interactions in healthy humans. Further examination of the interaction between gut microbes, brain, and affect in humans is needed to inform preclinical reports that microbial modulation may affect mood and behavior.

Akkermansia muciniphila and its role in regulating host functions.

Akkermansia muciniphila is an intestinal bacterium that was isolated a decade ago from a human fecal sample. Its specialization in mucin degradation makes it a key organism at the mucosal interface between the lumen and host cells. Although it was isolated quite recently, it has rapidly raised significant interest as A. muciniphila is the only cultivated intestinal representative of the Verrucomicrobia, one of the few phyla in the human gut that can be easily detected in phylogenetic and metagenome analyses. There has also been a growing interest in A. muciniphila, due to its association with health in animals and humans. Notably, reduced levels of A. muciniphila have been observed in patients with inflammatory bowel diseases (mainly ulcerative colitis) and metabolic disorders, which suggests it may have potential anti-inflammatory properties. The aims of this review are to summarize the existing data on the intestinal distribution of A. muciniphila in health and disease, to provide insight into its ecology and its role in founding microbial networks at the mucosal interface, as well as to discuss recent research on its role in regulating host functions that are disturbed in various diseases, with a specific focus on metabolic disorders in both animals and humans.

Effect of a long-term high-protein diet on survival, obesity development, and gut microbiota in mice.

Female C57BL/6J mice were fed a regular low-fat diet or high-fat diets combined with either high or low protein-to-sucrose ratios during their entire lifespan to examine the long-term effects on obesity development, gut microbiota, and survival. Intake of a high-fat diet with a low protein/sucrose ratio precipitated obesity and reduced survival relative to mice fed a low-fat diet. By contrast, intake of a high-fat diet with a high protein/sucrose ratio attenuated lifelong weight gain and adipose tissue expansion, and survival was not significantly altered relative to low-fat-fed mice. Our findings support the notion that reduced survival in response to high-fat/high-sucrose feeding is linked to obesity development. Digital gene expression analyses, further validated by qPCR, demonstrated that the protein/sucrose ratio modulated global gene expression over time in liver and adipose tissue, affecting pathways related to metabolism and inflammation. Analysis of fecal bacterial DNA using the Mouse Intestinal Tract Chip revealed significant changes in the composition of the gut microbiota in relation to host age and dietary fat content, but not the protein/sucrose ratio. Accordingly, dietary fat rather than the protein/sucrose ratio or adiposity is a major driver shaping the gut microbiota, whereas the effect of a high-fat diet on survival is dependent on the protein/sucrose ratio.

Lactulose Challenge Determines Visceral Sensitivity and Severity of Symptoms in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) can be assigned to groups with different gastrointestinal (GI) symptoms based on results from a combined nutrient and lactulose challenge. We aimed to identify factors that predict outcomes to this challenge and to determine whether this can be used in noninvasive assessment of visceral sensitivity in patients with IBS. METHODS: We performed a prospective study of 100 patients with IBS diagnosed according to Rome III criteria (all subtypes) and seen at a secondary or tertiary care center. After an overnight fast, subjects were given a liquid breakfast (400 mL; Nutridrink) that contained 25 g lactulose. Before the challenge, we assessed visceral sensitivity (via rectal barostat), oro-anal transit time, and fecal microbiota composition (via 16S ribosomal RNA pyrosequencing); we determined IBS severity using questionnaires. The intensity of 8 GI symptoms, the level of digestive comfort, and the amount of exhaled H2 and CH4 in breath were measured before and during a 4-hour period after the liquid breakfast. RESULTS: Based on the intensity of 8 GI symptoms and level of digestive comfort during the challenge, patients were assigned to groups with high-intensity GI symptoms (HGS; n = 39) or low-intensity GI symptoms (LGS; n = 61); patients with HGS had more severe IBS (P < .0001), higher somatization (P < .01), and lower quality of life (P < .05-.01) than patients with LGS. Patients with HGS also had significantly higher rectal sensitivity to random phasic distensions (P < .05-.001, compared with patients with LGS). There were no significant differences between groups in fecal microbiota composition, exhaled gas in breath, or oro-anal transit time. CONCLUSIONS: We found, in a prospective study, that results from a lactulose challenge test could be used to determine visceral sensitivity and severity of IBS. The intensity of patient symptoms did not correlate with the composition of the fecal microbiota. The lactulose challenge test may help better characterize patients with IBS and evaluate the efficacy of new treatments. ClinicalTrial.gov no: NCT01252550.

Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.

Fermented dairy products modulate Citrobacter rodentium-induced colonic hyperplasia.

We evaluated the protective effects of fermented dairy products (FDPs) in an infection model, using the mouse pathogen Citrobacter rodentium (CR). Treatment of mice with FDP formulas A, B, and C or a control product did not affect CR colonization, organ specificity, or attaching and effacing lesion formation. Fermented dairy product A (FDP-A), but neither the supernatant from FDP-A nor ß-irradiated (IR) FDP-A, caused a significant reduction in colonic crypt hyperplasia and CR-associated pathology. Profiling the gut microbiota revealed that IR-FDP-A promoted higher levels of phylotypes belonging to Alcaligenaceae and a decrease in Lachnospiraceae (Ruminococcus) during CR infection. Conversely, FDP-A prevented a decrease in Ruminococcus and increased Turicibacteraceae (Turicibacter). Importantly, loss of Ruminococcus and Turicibacter has been associated with susceptibility to dextran sodium sulfate-induced colitis. Our results demonstrate that viable bacteria in FDP-A reduced CR-induced colonic crypt hyperplasia and prevented the loss of key bacterial genera that may contribute to disease pathology.

The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation.

OBJECTIVE: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. DESIGN: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used. RESULTS: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. CONCLUSION: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.

Comparative prebiotic potential of galacto- and fructo-oligosaccharides, native inulin, and acacia gum in Kenyan infant gut microbiota during iron supplementation.

Iron fortification to prevent anemia in African infants increases colonic iron levels, favoring the growth of enteropathogens. The use of prebiotics may be an effective strategy to reduce these detrimental effects. Using the African infant PolyFermS gut model, we compared the effect of the prebiotics short-chain galacto- with long-chain fructo-oligosaccharides (scGOS/lcFOS) and native inulin, and the emerging prebiotic acacia gum, a branched-polysaccharide-protein complex consisting of arabinose and galactose, during iron supplementation on four Kenyan infant gut microbiota. Iron supplementation did not alter the microbiota but promoted Clostridioides difficile in one microbiota. The prebiotic effect of scGOS/lcFOS and inulin was confirmed during iron supplementation in all investigated Kenyan infant gut microbiota, leading to higher abundance of bifidobacteria, increased production of acetate, propionate, and butyrate, and a significant shift in microbiota composition compared to non-supplemented microbiota. The abundance of the pathogens Clostridium difficile and Clostridium perfringens was also inhibited upon addition of the prebiotic fibers. Acacia gum had no effect on any of the microbiota. In conclusion, scGOS/lcFOS and inulin, but not acacia gum, showed a donor-independent strong prebiotic potential in Kenyan infant gut microbiota. This study demonstrates the relevance of comparing fibers in vitro prior to clinical studies.

Associations between gut microbiota and sarcopenia or its defining parameters in older adults: A systematic review.

Altered gut microbiota (GM) potentially contribute to development or worsening of sarcopenia through a gut-muscle axis. This systematic review aims to compare GM between persons with sarcopenia or low sarcopenia-defining parameters (muscle mass, strength, and physical performance) to those with preserved muscle status, as well as to clarify possible associations between sarcopenia (-defining parameters) and relative abundance (RA) of GM-taxa or GM-(α- or ß) diversity indices, in order to clarify whether there is robust evidence of the existence of a GM signature for sarcopenia. This systematic review was conducted according to the PRISMA-reporting guideline and pre-registered on PROSPERO (CRD42021259597). PubMed, Web of Science, Embase, ClinicalTrials.gov, and Cochrane library were searched until 20 July 2023. Included studies reported on GM and sarcopenia or its defining parameters. Observational studies were included with populations of mean age ≥50 years. Thirty-two studies totalling 10 781 persons (58.56% ♀) were included. Thirteen studies defined sarcopenia as a construct. Nineteen studies reported at least one sarcopenia-defining parameter (muscle mass, strength or physical performance). Studies found different GM-taxa at multiple levels to be significantly associated with sarcopenia (n = 4/6), muscle mass (n = 13/14), strength (n = 7/9), and physical performance (n = 3/3); however, directions of associations were heterogeneous and also conflicting for specific GM-taxa. Regarding ß-diversity, studies found GM of persons with sarcopenia, low muscle mass, or low strength to cluster differently compared with persons with preserved muscle status. α-diversity was low in persons with sarcopenia or low muscle mass as compared with those with preserved muscle status, indicating low richness and diversity. In line with this, α-diversity was significantly and positively associated with muscle mass (n = 3/4) and muscle strength (n = 2/3). All reported results were significant (P < 0.05). Persons with sarcopenia and low muscle parameters have less rich and diverse GM and can be separated from persons with preserved muscle mass and function based on GM-composition. Sarcopenia and low muscle parameters are also associated with different GM-taxa at multiple levels, but results were heterogeneous and no causal conclusions could be made due to the cross-sectional design of the studies. This emphasizes the need for uniformly designed cross-sectional and longitudinal trials with appropriate GM confounder control in large samples of persons with sarcopenia and clearly defined core outcome sets in order to further explore changes in GM-taxa and to determine a sarcopenia-specific GM-signature.

Prebiotics increase iron absorption and reduce the adverse effects of iron on the gut microbiome and inflammation: a randomized controlled trial using iron stable isotopes in Kenyan infants.

BACKGROUND: Iron fortificants tend to be poorly absorbed and may adversely affect the gut, especially in African children. OBJECTIVE: We assessed the effects of prebiotic galacto-oligosaccharides/fructo-oligosaccharides (GOS/FOS) on iron absorption and gut health when added to iron-fortified infant cereal. METHODS: We randomly assigned Kenyan infants (n = 191) to receive daily for 3 wk a cereal containing iron and 7.5 g GOS/FOS (7.5 g+iron group), 3 g (3-g+iron group) GOS/FOS, or no prebiotics (iron group). A subset of infants in the 2 prebiotic+iron groups (n = 66) consumed 4 stable iron isotope-labeled test meals without and with prebiotics, both before and after the intervention. Primary outcome was fractional iron absorption (FIA) from the cereal with or without prebiotics regardless of dose, before and after 3 wk of consumption. Secondary outcomes included fecal gut microbiota, iron and inflammation status, and effects of prebiotic dose. RESULTS: Median (25th-75th percentiles) FIAs from meals before intervention were as follows: 16.3% (8.0%-27.6%) without prebiotics compared with 20.5% (10.4%-33.4%) with prebiotics (Cohen d = 0.53; P < 0.001). FIA from the meal consumed without prebiotics after intervention was 22.9% (8.5%-32.4%), 41% higher than from the meal without prebiotics before intervention (Cohen d = 0.36; P = 0.002). FIA from the meal consumed with prebiotics after intervention was 26.0% (12.2%-36.1%), 60% higher than from the meal without prebiotics before intervention (Cohen d = 0.45; P = 0.007). After 3 wk, compared with the iron group, the following results were observed: 1) Lactobacillus sp. abundances were higher in both prebiotic+iron groups (P < 0.05); 2) Enterobacteriaceae sp. abundances (P = 0.022) and the sum of pathogens (P < 0.001) were lower in the 7.5-g+iron group; 3) the abundance of bacterial toxin-encoding genes was lower in the 3-g+iron group (false discovery rate < 0.05); 4) fecal pH (P < 0.001) and calprotectin (P = 0.033) were lower in the 7.5-g+iron group. CONCLUSIONS: Adding prebiotics to iron-fortified infant cereal increases iron absorption and reduces the adverse effects of iron on the gut microbiome and inflammation in Kenyan infants. This trial was registered at clinicaltrials.gov as NCT03894358.

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats.

Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (+51%; P < 0.01) and decreased the fractional turnover of cholate (-32%; P < 0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P < 0.01). PEG decreased the cytolytic activity of fecal water [54 (46-62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P < 0.01]. PEG treatment increased the contribution of Verrucomicrobia (P < 0.01) and decreased that of Firmicutes (P < 0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.

Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.

Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 µmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776).

Epithelial-microbial crosstalk in polymeric Ig receptor deficient mice.

Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of the first line of natural or adaptive antibody-mediated immune defense of the intestinal mucosa. We found that colonic epithelial cells from pIgR KO mice differentially expressed (more than twofold change) more than 200 genes compared with cells from WT mice, and upregulated the expression of antimicrobial peptides in a commensal-dependent manner. Detailed profiling of microbial communities based on 16S rRNA genes revealed differences in the commensal microbiota between pIgR KO and WT mice. Furthermore, we found that pIgR KO mice showed increased susceptibility to dextran sulfate sodium-induced colitis, and that this was driven by their conventional intestinal microbiota. Thus, in the absence of pIgR, the stability of the commensal microbiota is disturbed, gut homeostasis is compromised, and the outcome of colitis is significantly worsened.

Exploring Bifidobacterium species community and functional variations with human gut microbiome structure and health beyond infancy.

Aim: The human gut Bifidobacterium community has been studied in detail in infants and following dietary interventions in adults. However, the variability of the distribution of Bifidobacterium species and intra-species functions have been little studied, particularly beyond infancy. Here, we explore the ecology of Bifidobacterium communities in a large public dataset of human gut metagenomes, mostly corresponding to adults. Methods: We selected 9.515 unique gut metagenomes from curatedMetagenomicData. Samples were partitioned by applying Dirichlet's multinomial mixture to Bifidobacterium species. A functional analysis was performed on > 2.000 human-associated Bifidobacterium metagenome-assembled genomes (MAGs) paired with participant gut microbiome and health features. Results: We identified several Bifidobacterium-based partitions in the human gut microbiome differing in terms of the presence and abundance of Bifidobacterium species. The partitions enriched in both B. longum and B. adolescentis were associated with gut microbiome diversity and a higher abundance of butyrate producers and were more prevalent in healthy individuals. B. bifidum MAGs harboring a set of genes potentially related to phages were more prevalent in partitions associated with a lower gut microbiome diversity and were genetically more closely related. Conclusion: This study expands our knowledge of the ecology and variability of the Bifidobacterium community, particularly in adults, and its specific association with the gut microbiota and health. Its findings may guide the rational selection of Bifidobacterium strains for gut microbiome complementation according to the individual's endogenous Bifidobacterium community. Our results also suggest that gut microbiome stratification for particular genera may be relevant for studies of variations of species and associations with the gut microbiome and health.

Global branches and local states of the human gut microbiome define associations with environmental and intrinsic factors.

The gut microbiome is important for human health, yet modulation requires more insight into inter-individual variation. Here, we explored latent structures of the human gut microbiome across the human lifespan, applying partitioning, pseudotime, and ordination approaches to >35,000 samples. Specifically, three major gut microbiome branches were identified, within which multiple partitions were observed in adulthood, with differential abundances of species along branches. Different compositions and metabolic functions characterized the branches' tips, reflecting ecological differences. An unsupervised network analysis from longitudinal data from 745 individuals showed that partitions exhibited connected gut microbiome states rather than over-partitioning. Stability in the Bacteroides-enriched branch was associated with specific ratios of Faecalibacterium:Bacteroides. We also showed that associations with factors (intrinsic and extrinsic) could be generic, branch- or partition-specific. Our ecological framework for cross-sectional and longitudinal data allows a better understanding of overall variation in the human gut microbiome and disentangles factors associated with specific configurations.