Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion

Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

Bacterial Gut Microbiota and Infections During Early Childhood

Gut microbiota composition during the first years of life is variable, dynamic and influenced by both prenatal and postnatal factors, such as maternal antibiotics administered during labor, delivery mode, maternal diet, breastfeeding, and/or antibiotic consumption during infancy. Furthermore, the microbiota displays bidirectional interactions with infectious agents, either through direct microbiota-microorganism interactions or indirectly through various stimuli of the host immune system. Here we review these interactions during childhood until 5 years of life, focusing on bacterial microbiota, the most common gastrointestinal and respiratory infections and two well characterized gastrointestinal diseases related to dysbiosis (necrotizing enterocolitis and Clostridioides difficile infection). To date, most peer-reviewed studies on the bacterial microbiota in childhood have been cross-sectional and have reported patterns of gut dysbiosis during infections as compared to healthy controls; prospective studies suggest that most children progressively return to a “healthy microbiota status” following infection. Animal models and/or studies focusing on specific preventive and therapeutic interventions, such as probiotic administration and fecal transplantation, support the role of the bacterial gut microbiota in modulating both enteric and respiratory infections. A more in depth understanding of the mechanisms involved in the establishment and maintenance of the early bacterial microbiota, focusing on specific components of the microbiota-immunity-infectious agent axis is necessary in order to better define potential preventive or therapeutic tools against significant infections in children.

Microbiota, Bacterial Carbonic Anhydrases, and Modulators of Their Activity: Links to Human Diseases?

The involvement of the human microbiome is crucial for different host functions such as protection, metabolism, reproduction, and especially immunity. However, both endogenous and exogenous factors can affect the balance of the microbiota, creating a state of dysbiosis, which can start various gastrointestinal or systemic diseases. The challenge of future medicine is to remodel the intestinal microbiota to bring it back to healthy equilibrium (eubiosis) and, thus, counteract its negative role in the diseases’ onset. The shaping of the microbiota is currently practiced in different ways ranging from diet (or use of prebiotics, probiotics, and synbiotics) to phage therapy and antibiotics, including microbiota fecal transplantation. Furthermore, because microbiota modulation is a capillary process, and because many microbiota bacteria (both beneficial and pathogenic) have carbonic anhydrases (specifically the four classes α, β, γ, and ι), we believe that the use of CA inhibitors and activators can open up new therapeutic strategies for many diseases associated with microbial dysbiosis, such as the various gastrointestinal disorders and the same colorectal cancer.

Gut microbiota dysbiosis contributes to the development of chronic obstructive pulmonary disease

Background Dysbiosis of the gut microbiome is involved in the pathogenesis of various diseases, but the contribution of gut microbes to the progression of chronic obstructive pulmonary disease (COPD) is still poorly understood. Methods We carried out 16S rRNA gene sequencing and short-chain fatty acid analyses in stool samples from a cohort of 73 healthy controls, 67 patients with COPD of GOLD stages I and II severity, and 32 patients with COPD of GOLD stages III and IV severity. Fecal microbiota from the three groups were then inoculated into recipient mice for a total of 14 times in 28 days to induce pulmonary changes. Furthermore, fecal microbiota from the three groups were inoculated into mice exposed to smoke from biomass fuel to induce COPD-like changes. Results We observed that the gut microbiome of COPD patients varied from that of healthy controls and was characterized by a distinct overall microbial diversity and composition, a Prevotella-dominated gut enterotype and lower levels of short-chain fatty acids. After 28 days of fecal transplantation from COPD patients, recipient mice exhibited elevated lung inflammation. Moreover, when mice were under both fecal transplantation and biomass fuel smoke exposure for a total of 20 weeks, accelerated declines in lung function, severe emphysematous changes, airway remodeling and mucus hypersecretion were observed. Conclusion These data demonstrate that altered gut microbiota in COPD patients is associated with disease progression in mice model.

Fecal Transplantation from db/db Mice Treated with Sodium Butyrate Attenuates Ischemic Stroke Injury

Ischemic stroke is a major global health burden, and T2D is a well-known comorbidity that aggravates brain injury after ischemic stroke. However, the underlying mechanism by which T2D exacerbates stroke injury has not been completely elucidated.

Progesterone supplementation in mice leads to microbiome alterations and weight gain in a sex-specific manner

BackgroundProgesterone is a steroid hormone produced by the ovaries, involved in pregnancy progression and necessary for successful gestation. We have previously shown that progesterone affects gut microbiota composition and leads to increased relative abundance of Bifidobacterium.ResultsIn non-pregnant female GF mice, levels of progesterone were significantly higher than in SPF mice of the same status. However, no significant differences were observed between GF and SPF males. Females treated with progesterone gained more weight than females treated with a placebo. In contrast to female mice, males treated with progesterone did not gain significantly more weight than males treated with a placebo. Progesterone supplementation led to microbial changes in females but not in males (16S rRNA sequencing). Accordingly, the weight gain observed in female mice treated with progesterone was fully transferable to both male and female germ-free mice via fecal transplantation.ConclusionsWe demonstrate that bacteria play a role in regulating progesterone levels in a female-specific manner. Furthermore, weight gain and metabolic changes associated with progesterone may be mediated by the gut microbiota.

Efficacy and safety of fecal transplantation versus targeted therapies in ulcerative colitis: network meta-analysis

Aim: We conducted this network meta-analysis to compare the efficacy and safety of targeted pharmacotherapies and fecal microbial transplantation (FMT). Patients & methods: Nineteen studies were included and there was only one head-to-head randomized controlled trial (adalimumab vs vedolizumab). Results: All interventions, including FMT, were superior to a placebo in inducing clinical remission (except adalimumab – odds ratio 1.66; 95% CI: 0.97–2.85), clinical response and endoscopic remission. FMT was comparable with other agents in achieving all efficacy outcomes. Infliximab was ranked highest in inducing clinical remission (surface under the cumulative ranking, 0.8). There was no difference in safety outcomes between FMT and other targeted therapies. Conclusion: FMT is as efficacious and as safe as other targeted therapies in inducing clinical remission, clinical response and endoscopic remission. Further studies to assess the long-term benefits are needed in order to reach a definitive conclusion.

Use of Fecal transplantation with a novel diet for mild to moderate active ulcerative colitis: The CRAFT UC randomized controlled trial

Background We evaluated whether integration of novel diets for donors and patients in addition to fecal transplantation (FT) could increase FT remission rate in refractory ulcerative colitis (UC). Methods This was a blinded randomized controlled trial in adults with active UC, defined by a simple clinical colitis activity index (SCCAI) of ≥5 and ≤ 11 and endoscopic Mayo score 2-3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on day 1and rectal enemas on days 2 and 14 without dietary conditioning of the donor. Group 2: FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet (UCED) for the patients. Group 3 received the UCED alone. The primary endpoint was week 8 clinical steroid free remission, defined as SCCAI <3. Results Sixty two of 96 planned patients were enrolled. Remission week 8 Group 1 was 2/17 (11.8%), Group 2 4/19 (21.1%), Group 3 6/15 (40%) (NS). Endoscopic remission was Group 1 2/17 (12%), Group 2 3/19 (16%), Group 3 4/15 (27%) (Group 1 vs.3 p=0.38). Mucosal healing (Mayo 0) was achieved only in Group 3 (3/15, 20%) vs. 0/36 FT patients (p=0.022). Exacerbation of disease occurred in 3/17 (17.6%) Group 1, 4/19 (21.1%) Group 2, and 1/15 (6.7%) Group 3 (Group 2 vs.3, p=0.35). Conclusions UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.

Intraspecies strain exclusion, antibiotic pretreatment, and donor selection control microbiota engraftment after fecal transplantation

Fecal microbiota transplantation (FMT) is both a promising therapeutic approach to treat microbiota-associated pathologies and an experimental tool to establish a causal role of microbiome dysbiosis in human pathologies. Although clearly efficacious in resolving recurrent Clostridioides difficile infection (rCDI), the therapeutic value of FMT in other pathologies is not yet established, and our mechanistic and ecological understanding of how FMT alters the microbiome in patients is incomplete. Here, we assembled the most comprehensive FMT trial microbiota dataset to date, including new and previously generated fecal metagenomes from FMT trials in rCDI, inflammatory bowel disease (IBD), metabolic syndrome (MetS), drug-resistant pathogen colonization (MDR), and resistance to immune checkpoint inhibitor anti-tumor therapy (ICI). We characterized post-FMT microbiota assembly in the recipients by establishing the origin of the detected strains, and we identified the clinical and ecological factors that determine the engraftment of donor strains. Our findings showed little coexistence of donor and recipient strains and linked the magnitude of donor strain engraftment to dysbiosis of the recipient microbiome. Dysbiosis and strain engraftment were low in pathologies other than rCDI but could be enhanced through pretreatment with antibiotics and lavage. Using generalized linear mixed-effects models, we demonstrate that both ecological (low recipient and high donor ɑ-diversity and relative species abundance) and clinical (antibiotic pretreatment, bowel lavage, multiple rounds of FMT) variables are associated with increased donor microbiota engraftment, and that donor strain engraftment events are predictable for individual patients and strains. Overall donor strain engraftment was not linked to FMT outcome in IBD patients but was higher in ICI patients that responded to immunotherapy after FMT. Our findings provide an ecological framework for post-FMT microbiota assembly that can predict donor strain engraftment and determine its importance for clinical outcomes, informing more targeted and personalized approaches to increase the therapeutic benefits of FMTs.

Separation of Donor and Recipient Microbial Diversity Allows Determination of Taxonomic and Functional Features of Gut Microbiota Restructuring following Fecal Transplantation

We assumed that the enrichment of successful gut microbes by lantibiotic/antibiotic resistance genes can be related to gut microbiota colonization resistance by third-party microbe phenomena and resistance to bacterium-derived or host-derived antimicrobial substances. According to this assumption, competition between the donor-derived and recipient-derived microbes as well as host immunity may play a key role in the FMT-related colonization and redistribution of recipient gut microbiota structure.