Microbiota-dependent early-life programming of gastrointestinal motility.

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later-or not at all-showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility.

The Human Microbiome-A Physiologic Perspective.

The human microbiome consists of the microorganisms associated with the body, such as bacteria, fungi, archaea, protozoa, and viruses, along with their gene content and products. These microbes are abundant in the digestive, respiratory, renal/urinary, and reproductive systems. While microbes found in other organs/tissues are often associated with diseases, some reports suggest their presence even in healthy individuals. Lack of microbial colonization does not indicate a lack of microbial influence, as their metabolites can affect distant locations through circulation. In a healthy state, these microbes maintain a mutualistic relationship and help shape the host's physiological functions. Unlike the host's genetic content, microbial gene content and expression are dynamic and influenced by factors such as ethnicity, genetic background, sex, age, lifestyle/diet, and psychological/physical conditions. Therefore, defining a healthy microbiome becomes challenging as it is context dependent and can vary over time for an individual. Although differences in microbial composition have been observed in various diseases, these changes may reflect host alterations rather than causing the disease itself. As the field is evolving, there is increased emphasis on understanding when changes in the microbiome are an important component of pathogenesis rather than the consequence of a disease state. This article focuses on the microbial component in the digestive and respiratory tracts-the primary sites colonized by microorganisms-and the physiological functions of microbial metabolites in these systems. It also discusses their physiological functions in the central nervous and cardiovascular systems, which have no microorganism colonization under healthy conditions based on human studies. © 2024 American Physiological Society. Compr Physiol 14:5491-5519, 2024.

The COVID-19 pandemic as a modifier of DGBI symptom severity: A systematic review and meta-analysis.

BACKGROUND: This SRMA reviewed and assessed the changes in the severity of disorders of gut-brain interaction (DGBI) symptoms during the COVID-19 pandemic, and evaluated factors associated with symptom severity changes. METHODS: Electronic databases were searched until February 2024, for articles reporting on changes in symptom severity in DGBI patients during the COVID-19 pandemic. The proportion of DGBI patients who reported a change in their symptom severity were pooled using a random-effects model, and subgroup analyses were conducted to assess the effect of socio-cultural modifiers on symptom severity in DGBI. KEY RESULTS: Twelve studies including 3610 DGBI patients found that 31.4% (95% CI, 15.9-52.5) of DGBI patients experienced symptom deterioration, while 24.3% (95% CI, 10.2-47.5) experienced improvement. Countries with high gross domestic product (GDP) had a 43.5% (95% CI, 16.3-75.2) likelihood of symptom deterioration, compared to 9.2% (95% CI, 1.4-42.2) in lower GDP countries. Similarly, countries with low COVID fatality rates had a 60.1% (95% CI, 19.7-90.3) likelihood of symptom deterioration, compared to 18.3% (95% CI, 7.8-36.9) in higher fatality rate countries. Countries with lenient COVID policies had a 58.4% (95% CI, 14.1-92.3) likelihood of symptom deterioration, compared to 19% (95% CI, 8.2-38.1) in countries with stricter policies. Patients in high vaccine hesitancy countries had a 51.4% (95% CI, 19.5-82.2) likelihood of symptom deterioration, compared to 10.6% (95% CI, 2.7-33.4) in low vaccine hesitancy countries. CONCLUSIONS & INFERENCES: This meta-analysis reveals that a significantly higher proportion of DGBI patients experienced deterioration of symptoms during the COVID-19 pandemic. Various sociocultural, economic and environmental factors potentially modify the effects of the COVID-19 pandemic on DGBI.

A multifaceted ecological approach to explore links between environmental factors and the epidemiology of disorders of gut-brain interaction.

BACKGROUND: Disorders of gut-brain interaction (DGBI) are characterized by debilitating symptoms not explained by structural or biochemical abnormalities. While functional conditions present with complex, likely heterogeneous pathophysiology, we aimed to investigate if proxy measures of sociocultural and environmental factors are associated with the prevalence of various DGBI in populations across the world. METHODS: We performed an ecological study utilizing peer-reviewed published datasets reporting for 26 countries prevalence rates of DGBI (Rome Foundation Global Epidemiology Study, RFGES), with six independent variables: Helicobacter pylori prevalence and household size as proxy measures for orofecal infections, gross domestic product per capita (GDP), and median age as a proxy measures for socioeconomic development, density of fast food outlets (FFO) per 100,000 population as proxy measure for processed food exposure, and suicide mortality rate per 100,000 people, and world happiness scores were used as a proxy for psychological stress. The data were retrieved from publicly accessible datasets (United Nations, CIA World Factbook, World Bank, World Happiness Report, commercial/financial reports of a global FFO chain). We used linear regression to assess variables in univariate and multivariate analysis and report standardized ß coefficients with 95% confidence intervals (CI). KEY RESULTS: The regression model revealed that the overall prevalence of DGBI was inversely associated with both GDP per capita (ß = -0.57, 95% CI: -0.92, -0.22, p = 0.002) and happiness scores (ß = -0.433 95% CI: 0.821, -0.065, p = 0.023), while being positively associated with H. pylori prevalence (ß = 0.40, 95% CI: 0.008, 0.81, p = 0.046). The prevalence of functional constipation (FC) was also inversely associated with GDP per capita (ß = -0.50, 95% CI: -0.86, -0.13, p = 0.01) and happiness scores (ß = -0.497, 95% CI: -0.863, -0.132, p = 0.01), while being positively associated with H. pylori prevalence (ß = 0.53, 95% CI: 0.16, 0.91, p = 0.007). The Multivariate model analysis revealed that combining the factors of H. pylori prevalence, suicide rate, household size and happiness scores showed statistically significant association with FC (p = 0.039). Household size (ß = -0.43, 95% CI: -0.82, 0.038, p = 0.033) and suicide rates (ß = 0.55, 95% CI: 0.19, 0.90, p = 0.004) were statistically significantly associated with functional diarrhea. Irritable bowel syndrome (IBS) was associated with GDP per capita (ß = -0.40, 95% CI: -0.79, -0.014, p = 0.043) and happiness scores (ß = -0.390, 95% CI: -0.778, -0.003, p = 0.049). CONCLUSIONS & INFERENCES: Utilizing publicly available data, the prevalence of DGBI across diverse countries is linked to various socio-cultural and environmental factors. Collectively, the data suggests that the prevalence of DGBI is increased in less prosperous regions of the world.

Enhancing recovery from gut microbiome dysbiosis and alleviating DSS-induced colitis in mice with a consortium of rare short-chain fatty acid-producing bacteria.

The human gut microbiota is a complex community comprising hundreds of species, with a few present in high abundance and the vast majority in low abundance. The biological functions and effects of these low-abundant species on their hosts are not yet fully understood. In this study, we assembled a bacterial consortium (SC-4) consisting of B. paravirosa, C. comes, M. indica, and A. butyriciproducens, which are low-abundant, short-chain fatty acid (SCFA)-producing bacteria isolated from healthy human gut, and tested its effect on host health using germ-free and human microbiota-associated colitis mouse models. The selection also favored these four bacteria being reduced in abundance in either Ulcerative Colitis (UC) or Crohn's disease (CD) metagenome samples. Our findings demonstrate that SC-4 can colonize germ-free (GF) mice, increasing mucin thickness by activating MUC-1 and MUC-2 genes, thereby protecting GF mice from Dextran Sodium Sulfate (DSS)-induced colitis. Moreover, SC-4 aided in the recovery of human microbiota-associated mice from DSS-induced colitis, and intriguingly, its administration enhanced the alpha diversity of the gut microbiome, shifting the community composition closer to control levels. The results showed enhanced phenotypes across all measures when the mice were supplemented with inulin as a dietary fiber source alongside SC-4 administration. We also showed a functional redundancy existing in the gut microbiome, resulting in the low abundant SCFA producers acting as a form of insurance, which in turn accelerates recovery from the dysbiotic state upon the administration of SC-4. SC-4 colonization also upregulated iNOS gene expression, further supporting its ability to produce an increasing number of goblet cells. Collectively, our results provide evidence that low-abundant SCFA-producing species in the gut may offer a novel therapeutic approach to IBD.

The role of the gut microbiome in disorders of gut-brain interaction.

Disorders of Gut-Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large-scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite-host interactions, offering exciting possibilities for the future of treatment of DGBI.

Impact of PAP on the gut microbiome in OSA: A pilot study.

OBJECTIVE/BACKGROUND: Microbes within the gastrointestinal tract have emerged as modulators of the host's health. Obstructive sleep apnea (OSA) is characterized by intermittent partial, or complete, airway closure during sleep and is associated with increased risk of non-communicable diseases as well as dysbiosis of the gut microbiome. Thus, we investigated if improving nocturnal airway patency via positive airway pressure (PAP) therapy improves gut microbial diversity in recently diagnosed patients with moderate-to-severe OSA (apnea-hypopnea index ≥15.0 events/hr). PATIENTS/METHODS: Eight subjects (3 F, 56±9yrs, 33.5 ± 7.7 kg/m2, 45.0 ± 38.4 events/hr) provided stool samples before, and two months after, PAP therapy (mean adherence of 95 ± 6%, residual apnea-hypopnea index of 4.7 ± 4.6 events/hr). RESULTS: While the Shannon diversity index tended to increase following PAP (3.96 ± 0.52 to 4.18 ± 0.56, p = 0.08), there were no changes in the Observed (1,088 ± 237 to 1,136 ± 289, p = 0.28) nor Inverse-Simpson (22.4 ± 12.99 to 26.6 ± 18.23, p = 0.28) alpha diversity indices. There were also no changes in beta diversity assessed using the Bray-Curtis (p = 0.98), Jaccard (p = 0.99), WUniFrac (p = 0.98), GUniFrac (p = 0.98), or UniFrac (p = 0.98) methods. No changes in differential abundance taxa were found using a false discovery rate threshold of <0.20. CONCLUSIONS: Our data are the first to report that PAP therapy may not offset, or reverse, gut dysbiosis in patients with OSA. Accordingly, interventions which improve gut microbial health should be explored as potential adjunctive treatment options in patients with OSA to reduce their risk of developing non-communicable diseases.

Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Altered Bile Acid and Pouch Microbiota Composition in Patients With Chronic Pouchitis.

BACKGROUND: Patients with ulcerative colitis and total abdominal proctocolectomy with ileal pouch-anal anastomosis have a 50% risk of pouchitis and a 5% to 10% risk of chronic pouchitis. AIMS: The goal of the study was to compare pouch microbiota and stool bile acid composition in patients with chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. METHODS: Patients with ulcerative colitis and ileal pouch-anal anastomosis were recruited from March 20, 2014, to August 6, 2019, and categorized into normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis groups. Stool samples were subjected to bile acid quantification and 16S rRNA gene sequencing. Statistical comparisons of absolute bile acid abundance and pouch microbiota α-diversity, ß-diversity, and taxa abundance were performed among the patient groups. RESULTS: A total of 51 samples were analyzed. Both α-diversity (P = .01, species richness) and ß-diversity (P = .001) significantly differed among groups. Lithocholic acid was significantly lower in patients with chronic pouchitis/primary sclerosing cholangitis than in those with chronic pouchitis (P = .01) or normal pouch (P = .03). Decreased α-diversity was associated with an increased primary to secondary bile acid ratio (P = .002), which was also associated with changes in ß-diversity (P = .006). CONCLUSIONS: Pouch microbiota α- and ß-diversity differed among patients with normal pouch, chronic pouchitis, and chronic pouchitis/primary sclerosing cholangitis. Lithocholic acid level and primary to secondary bile acid ratio were highly associated with pouch microbiota richness, structure, and composition. These findings emphasize the associations between pouch microbiota and bile acid composition in dysbiosis and altered metabolism, suggesting that secondary bile acids are decreased in chronic pouchitis.

The α- and ß-diversity of the pouch microbiota significantly differed in chronic pouchitis, chronic pouchitis and primary sclerosing cholangitis, and normal pouch. Microbiota changes were associated with stool bile acid composition. Decreased diversity was associated with decreased secondary bile acids.

Microbiota-dependent early life programming of gastrointestinal motility.

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later - or not at all - showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.

Role of Diet-Microbiome Interaction in Gastrointestinal Disorders and Strategies to Modulate Them with Microbiome-Targeted Therapies.

Diet is an important determinant of health and consequently is often implicated in the development of disease, particularly gastrointestinal (GI) diseases, given the high prevalence of meal-related symptoms. The mechanisms underlying diet-driven pathophysiology are not well understood, but recent studies suggest that gut microbiota may mediate the effect of diet on GI physiology. In this review, we focus primarily on two distinct GI diseases where the role of diet has been best studied: irritable bowel syndrome and inflammatory bowel disease. We discuss how the concurrent and sequential utilization of dietary nutrients by the host and gut microbiota determines the eventual bioactive metabolite profiles in the gut and the biological effect of these metabolites on GI physiology. We highlight several concepts that can be gleaned from these findings, such as how distinct effects of an individual metabolite can influence diverse GI diseases, the effect of similar dietary interventions on multiple disease states, and the need for extensive phenotyping and data collection to help make personalized diet recommendations.

Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead.

Reliable biomarkers for common disorders of gut-brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.

Small Intestinal Bacterial Overgrowth Complicating Gastrointestinal Manifestations of Systemic Sclerosis: A Systematic Review and Meta-analysis.

Background/Aims: Systemic sclerosis (SSc) often is complicated by small intestinal bacterial overgrowth (SIBO). A systematic review and meta-analysis thus examined the prevalence of SIBO in SSc (SSc-subtypes), identify risk factors for SIBO in SSc and the effects of concomitant SIBO on gastrointestinal symptoms in SSc. Methods: We searched electronic databases until January-2022 for studies providing prevalence rates of SIBO in SSc. The prevalence rates, odds ratio (OR) and 95% confidence intervals (CI) of SIBO in SSc and controls were calculated. Results: The final dataset comprised 28 studies with 1112 SSc-patients and 335 controls. SIBO prevalence in SSc-patients was 39.9% (95% CI, 33.1-47.1; P = 0.006), with considerable heterogeneity, (I2 = 76.00%, P < 0.001). As compared to controls, there was a 10-fold increased SIBO prevalence in SSc-patients (OR, 9.6; 95% CI, 5.6-16.5; P < 0.001). The prevalence of SIBO was not different in limited cutaneous SSc as compared to diffuse cutaneous SSc (OR, 1.01; 95% CI, 0.46-2.20; P = 0.978). Diarrhea (OR, 5.9; 95% CI, 2.9-16.0; P = 0.001) and the association between SIBO in SSc and proton pump inhibitor use (OR, 2.3; 95% CI, 0.8-6.4; P = 0.105) failed statistical significance. Rifaximin was significantly more effective as compared to rotating antibiotic in eradicating SIBO in SSc-patients (77.8% [95% CI, 64.4-87.9]) vs 44.8% [95% CI, 31.7-58.4]; P < 0.05). Conclusions: There is a 10-fold increased prevalence of SIBO in SSc, with similar SIBO prevalence rates in SSc-subtypes. Antimicrobial therapy of SIBO-positive SSc-patients with diarrhea should be considered. However, the results must be interpreted with caution due to substantial unexplained heterogeneity in the prevalence studies, and the low sensitivity and specificity of the diagnostic tests suggesting that the reliability of the evidence may be low.

Adjustable Intragastric Balloon Leads to Significant Improvement in Obesity-Related Lipidome and Fecal Microbiome Profiles: A Proof-of-Concept Study.

INTRODUCTION: Intragastric balloons (IGBs) are a safe and effective treatment for obesity. However, limited knowledge exists on the underlying biological changes with IGB placement. METHODS: This single-institution study was part of an adjustable IGB randomized controlled trial. Subjects with obesity were randomized in a 2 is to 1 ratio to 32 weeks of IGB with diet/exercise counseling (n = 8) vs counseling alone (controls, n = 4). Diet/exercise counseling was continued for 24 weeks post-IGB removal to assess weight maintenance. We used mass spectrometry for nontargeted plasma lipidomics analysis and 16S rRNA sequencing to profile the fecal microbiome. RESULTS: Subjects with IGBs lost 15.5% of their body weight at 32 weeks vs 2.59% for controls (P < 0.05). Maintenance of a 10.5% weight loss occurred post-IGB explant. IGB placement, followed by weight maintenance, led to a -378.9 µM/L reduction in serum free fatty acids compared with pre-IGB (95% confidence interval: 612.9, -145.0). This reduction was mainly in saturated, mono, and omega-6 fatty acids when compared with pre-IGB. Polyunsaturated phosphatidylcholines also increased after IGB placement (difference of 27 µM/L; 95% confidence interval: 1.1, 52.8). Compared with controls, saturated and omega-6 free fatty acids (linoleic and arachidonic acids) were reduced after IGB placement. The fecal microbiota changed post-IGB placement and weight maintenance vs pre-IGB (P < 0.05). Further analysis showed a possible trend toward reduced Firmicutes and increased Bacteroidetes post-IGB and counseling, a change that was not conclusively different from counseling alone. DISCUSSION: IGB treatment is associated with an altered fecal microbiome profile and may have a better effect on obesity-related lipidome than counseling alone.

Microbially derived polyunsaturated fatty acid as a modulator of gastrointestinal motility.

Gastrointestinal (GI) motility requires coordination among several cell types in the intestinal epithelium and the neuromuscular apparatus. A disruption in GI motility was primarily attributed to disruption of this coordinated effort among different host cells, but recent studies have begun to uncover how the products of gut microbiota can alter GI motility by modulating the function of different host cells and the interactions among them. In this issue of the JCI, Chen, Qiu, et al. used a reverse translation approach, isolating a Shigella sp. - peristaltic contraction-inhibiting bacterium (PIB) - from a cohort of patients with intractable constipation. They identified an ω-3 polyunsaturated fatty acid (PUFA), docosapentaenoic acid (DPA), produced by this Shigella variant, as an important driver of constipation using a series of microbiologic, biochemical, and genetic manipulations combined with in vitro and in vivo studies. This finding advances the field, given that production of DPA is rare in the human gut and appears to have a distinct effect on GI physiology.

Potential Role of Inflammation-Promoting Biliary Microbiome in Primary Sclerosing Cholangitis and Cholangiocarcinoma.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. METHODS: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. RESULTS: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups. CONCLUSIONS: We identified a unique microbial signature in the bile of patients with increased duration of PSC or with CCA, suggesting a role for microbiota-driven inflammation in the pathogenesis and or progression to perihilar CCA. Further studies are needed to test this hypothesis.

Identification of shared and disease-specific host gene-microbiome associations across human diseases using multi-omic integration.

While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic (n = 208) and gut microbiome (n = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus, are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene-microbiome associations that may influence disease outcomes.

Dynamics of plasmid-mediated niche invasion, immunity to invasion, and pheromone-inducible conjugation in the murine gastrointestinal tract.

Microbial communities provide protection to their hosts by resisting pathogenic invasion. Microbial residents of a host often exclude subsequent colonizers, but this protection is not well understood. The Enterococcus faecalis plasmid pCF10, whose conjugative transfer functions are induced by a peptide pheromone, efficiently transfers in the intestinal tract of mice. Here we show that an invading donor strain established in the gastrointestinal tract of mice harboring resident recipients, resulting in a stable, mixed population comprised of approximately 10% donors and 90% recipients. We also show that the plasmid-encoded surface protein PrgB (Aggregation Substance), enhanced donor invasion of resident recipients, and resistance of resident donors to invasion by recipients. Imaging of the gastrointestinal mucosa of mice infected with differentially labeled recipients and donors revealed pheromone induction within microcolonies harboring both strains in close proximity, suggesting that adherent microcolonies on the mucosal surface of the intestine comprise an important niche for cell-cell signaling and plasmid transfer.

The promise of the gut microbiome as part of individualized treatment strategies.

Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.