Restoration Of Microbiota Research Articles

What do we know about nutrient-based strategies targeting molecular mechanisms associated with obesity-related fatty liver disease?

Obesity is a risk factor for developing nonalcoholic fatty liver disease (NAFLD), and the associated molecular mechanisms could be targeted with nutrient-based strategies. Therefore, it is necessary to review the current mechanisms to propose further treatments. Obesity facilitates the onset of insulin resistance, lipidic abnormalities, hepatic fat accumulation, lipid peroxidation, mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and inflammation, all related to further steatosis progression and fibrosis. Microbiota alterations can also influence liver disease by the translocation of pathogenic bacteria, energy extraction from short chain fatty acids (SCFAs), intestinal suppression of the expression of fasting-induced adipose factor (FIAF), reduction of bile acids, and altered choline metabolism. There are also genetic polymorphisms in metabolic proteins that predispose to a higher risk of liver diseases, such as those found in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) or also known as lysophosphatidylinositol acyltransferase 1 (LPIAT1), transmembrane channel-like 4 genes (TMC4), fat mass and obesity-associated protein (FTO), the b Klotho (KLB) and carboxylesterase (CES1). No clear dietary guidelines target all mechanisms related to NAFLD development and progression. However, energy and carbohydrate intake restriction, regular physical exercise, supplementation of antioxidants, and restoration of gut microbiota seem to have beneficial effects on the new proposed features of NAFLD.

Roux-en-Y gastric bypass-induced perturbative changes in microbial communities and metabolic pathways in rats.

Obesity has become a global health and socioeconomic problem because of an inadequate balance between energy intake and energy expenditure. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the two most commonly used strategies for weight loss, which have been proven to benefit from gut microbiota restoration. Rats received SG, RYGB, and sham operations for 10 weeks. At the end of the experiment, the fecal microbiota was analyzed using 16s rRNA gene sequencing. In addition, the shift in the plasma metabolism of rats that underwent RYGB surgery was analyzed using untargeted metabolomics. The crosstalk between microbiome and metabolites was revealed using metabolic pathway enrichment and integrated analysis. The SG surgery induced a modest shift in the gut microbiota relative to the RYGB. RYGB significantly decreased the alpha diversity and Firmicutes/Bacteroides (F/B) ratio and increased the proportion of Escherichia, Bacteroides, and Akkermansia genera compared to sham and SG operations. The predicted function of gut microbiota revealed that the RYGB surgery uniquely enhanced the capability of linoleic acid and sphingolipid metabolism. Furthermore, the circulating serine, phosphatidylcholine (PC) 20:5/22:5, riboflavin, L-carnitine, and linoleic acid were evaluated after RYGB surgery. In addition, the metabolic pathway enrichment and integrated analysis suggest that the RYGB induced Escherichia, Bacteroides, and Akkermansia might inhibit the sphingonine and phytosphingosine metabolisms from serine and promote the PC (20:5/22:5) metabolism to produce linoleic acid. This comprehensive analysis not only revealed the difference in the gut microbiota shifts after SG and RYGB but also discovered the perturbative changes in microbial communities and metabolic pathways after RYGB surgery, which provided clues for improving the beneficial effect of RYGB in metabolic disease intervention via regulating bacterial-metabolite crosstalk.

Helicobacter Pylori Infection Induces Intestinal Dysbiosis That Could Be Related to the Onset of Atherosclerosis.

Cardiovascular diseases represent one of the first causes of death around the world, and atherosclerosis is one of the first steps in the development of them. Although these problems occur mainly in elderly, the incidence in younger people is being reported, and an undetermined portion of patients without the classic risk factors develop subclinical atherosclerosis at earlier stages of life. Recently, both the H. pylori infection and the intestinal microbiota have been linked to atherosclerosis. The mechanisms behind those associations are poorly understood, but some of the proposed explanations are (a) the effect of the chronic systemic inflammation induced by H. pylori, (b) a direct action over the endothelial cells by the cytotoxin associated gene A protein, and (c) alterations of the lipid metabolism and endothelial dysfunction induced by H. pylori infection. Regarding the microbiota, several studies show that induction of atherosclerosis is related to high levels of Trimethylamine N-oxide. In this review, we present the information published about the effects of H. pylori over the intestinal microbiota and their relationship with atherosclerosis and propose a hypothesis to explain the nature of these associations. If H. pylori contributes to atherosclerosis, then interventions for eradication and restoration of the gut microbiota at early stages could represent a way to prevent disease progression.

Rural environment reduces allergic inflammation by modulating the gut microbiota

ABSTRACT Rural environments and microbiota are linked to a reduction in the prevalence of allergies. However, the mechanism underlying the reduced allergies modulated by rural residency is unclear. Here, we assessed gut bacterial composition and metagenomics in urban and rural children in the EuroPrevall-INCO cohort. Airborne dusts, including mattress and rural henhouse dusts, were profiled for bacterial and fungal composition by amplicon sequencing. Mice were repeatedly exposed to intranasal dust extracts and evaluated for their effects on ovalbumin (OVA)-induced allergic airway inflammation, and gut microbiota restoration was validated by fecal microbiota transplant (FMT) from dust-exposed donor mice. We found that rural children had fewer allergies and unique gut microbiota with fewer Bacteroides and more Prevotella. Indoor dusts in rural environments harbored higher endotoxin level and diversity of bacteria and fungi, whereas indoor urban dusts were enriched with Aspergillus and contained elevated pathogenic bacteria. Intranasal administration of rural dusts before OVA sensitization reduced respiratory eosinophils and blood IgE level in mice and also led to a recovery of gut bacterial diversity and Ruminiclostridium in the mouse model. FMT restored the protective effect by reducing OVA-induced lung eosinophils in recipient mice. Together, these results support a cause-effect relationship between exposure to dust microbiota and allergy susceptibility in children and mice. Specifically, rural environmental exposure modulated the gut microbiota, which was essential in reducing allergy in children from Southern China. Our findings support the notion that the modulation of gut microbiota by exposure to rural indoor dust may improve allergy prevention.

Intestinal Microbiota-derived Propionic Acid Protects against Zinc Oxide Nanoparticle-induced Lung Injury.

With the rapid development of nanotechnology, the risks of accidental and/or occupational exposure to zinc oxide nanoparticles (ZnONPs) are increasing. Inhalation of ZnONPs induces metal fume fever in humans and acute lung injury (ALI) in animal models. Although the intestinal microbiota is considered an important modulator of various diseases, the role and mechanism of intestinal microbiota in the pathology of ZnONP-induced ALI are unclear. Herein, we established an intratracheal instillation of a ZnONP-induced ALI mouse model and found that the inhalation of ZnONPs caused ALI along with a perturbation of intestinal flora. Antibiotic cocktail treatment-mediated depletion of intestinal microbiota aggravated ZnONP-induced ALI, and in contrast, fecal microbiota transplantation-mediated restoration of intestinal microbiota exerted the opposite effects. A decrease in short-chain fatty acids, the intestinal microbiota-derived metabolites in the plasma-in particular, acetic acid and propionic acid-occurred after exposure to ZnONPs. It is important to note that supplementation with propionic acid, but not acetic acid, ameliorated ZnONP-induced ALI. We also showed that the source of inflammatory cytokines might partially be the infiltration of macrophages. Supplementation with propionic acid was found to act on macrophages through the receptor GPR43, because knockdown of GPR43 sharply reversed the protective effects of propionic acid during the ZnONP-induced inflammatory response and oxidative stress in both primary alveolar macrophages and RAW 264.7 macrophage cell lines. Altogether, a novel gut-lung axis mechanism is revealed in which intestinal microbiota and their derived metabolite propionic acid play protective roles against ZnONP-induced ALI and suggest that fecal microbiota transplantation and supplementation with propionic acid are potential remedy strategies.

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial

Clostridioides difficile infection is an urgent antibiotic-associated health threat with few treatment options. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C difficile. We compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C difficile infection. We did a randomised, double-blind, placebo-controlled trial (EarlyFMT) at a university hospital in Aarhus, Denmark. Eligible patients were aged 18 years or older with first or second C difficile infection (defined as ≥3 watery stools [Bristol stool chart score 6-7] per day and a positive C difficile PCR test). Patients were randomly assigned (1:1) to faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125 mg oral vancomycin four times daily for 10 days. Randomisation was done by investigators using a computer-generated randomisation list provided by independent staff. Patients and investigators were masked to the treatment group. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) 8 weeks after treatment. We followed up patients for 8 weeks or until recurrence. We planned to enrol 84 patients with a prespecified interim analysis after 42 patients. The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients. The trial is registered with ClinicalTrials.gov, NCT04885946. Between June 21, 2021, and April 1, 2022, we consecutively screened 86 patients, of whom 42 were randomly assigned to faecal microbiota transplantation (n=21) or placebo (n=21). The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because a significantly lower rate of resolution was identified in the placebo group compared with the faecal microbiota transplantation group (Haybittle-Peto boundary limit p<0·001). 19 (90%; 95% CI 70-99) of 21 patients in the faecal microbiota transplantation group and seven (33%, 95% CI 15-57) of 21 patients in the placebo group had resolution of CDAD at week 8 (p=0·0003). The absolute risk reduction was 57% (95% CI 33-81). Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the faecal microbiota transplantation group and all 21 patients in the placebo group. Diarrhoea (n=23 in the faecal microbiota transplantation group; n=14 in the placebo group) and abdominal pain (n=14 in the faecal microbiota transplantation group; n=11 in the placebo group) were the most common adverse events. Three serious adverse events possibly related to study treatment occurred (n=1 in the faecal microbiota transplantation group; n=2 in the placebo group), but no deaths or colectomies during the 8-week follow-up. In patients with first or second C difficile infection, first-line faecal microbiota transplantation is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C difficile. Innovation Fund Denmark.

Effect of crude polysaccharide from seaweed, Dictyopteris divaricata (CDDP) on gut microbiota restoration and anti-diabetic activity in streptozotocin (STZ)-induced T1DM mice

Type-1 Diabetes Mellitus (T1DM) is regarded as a multifunctional, immune-related disease which causes massive destruction of islet β-cells in pancreas resulting in hyperglycemic, hypoinsulinemia and hyperlipidimic conditions. The aim of the present study, was to investigate the hypothesis that streptozotocin (STZ)-induced T1DM in Balb/c mice when treated with crude polysaccharide from seaweed, Dictyopteris divaricata (CDDP) depicts improvement in diabetes-related symptoms. Treatment with CDDP resulted in decreased body weight loss, improved food consumption and water intake disbalances. The CDDP effectively improved fasting blood glucose, oral glucose tolerance (OGTT), serum insulin, insulin secretion, rejuvenation of β-cells mass, serum lipid profile and pro-inflammatory cytokines levels. Additionally, treatment with CDDP increased the population of beneficial bacteria such as Firmicutes, Bacteroidetes and Lactobacillus at phylum, family and genus levels by 16S rRNA sequencing. Furthermore, immunohistological examination confirmed that CDDP reduces the inflammation and restored the structural morphology of colon and upraised the levels of insulin receptor substrate-1 (IRS-1), Mucin-2 (MUC-2) and tight-junction proteins (TJs) whereby maintaining the gut structures and barrier permeability. Thus, the above presented data, highlights the safe and therapeutic effects of crude polysaccharide (CDDP) from D. divaricata in the treatment and restoration of T1DM disorders and can be used as a food supplement alternative to diabetes medicine.

Effect and Mechanism of Pharmaceutical Excipients on Berberine to Alleviate Ulcerative Colitis via Regulating Gut Microbiota.

Background: Various potential effect of drugs on alleviating diseases by regulating intestinal microbiome as well as the pharmaceutical excipients on gut microbiota has been revealed. However, the interaction between them is rarely investigated. Methods: Histological analysis, immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) analysis, RT-qPCR, and 16S rRNA analysis were utilized to explore the effect mechanism of the five excipients including hydroxypropyl methylcellulose (HPMC) F4M, Eudragit (EU) S100, chitosan (CT), pectin (PT), and rheum officinale polysaccharide (DHP) on berberine (BBR) to cure UC. Results: The combined BBR with PT and DHP group exhibited better therapeutic efficacy of UC with significantly increased colon length, and decreased hematoxylin-eosin (H&E) scores than other groups. Furthermore, the expression of tight junction ZO-1 and occludin in colon tissue were upregulated, and claudin-2 was downregulated. Ultimately, the serum content of tumor necrosis (TNF)-α, interleukin (IL)-1β, and IL-6 was decreased. Moreover, the combined BBR with PT significantly promoted the restoration of gut microbiota. The relative abundance of Firmicutes and Lactobacillus was significantly increased by the supplement of PT and DHP, and the relative abundance of Proteobacteria was downregulated. Conclusions: Our study may provide a new perspective that the selection of pharmaceutical excipients could be a crucial factor affecting the drugs’ therapeutic efficiency outcome.

Age-Related NAFLD: The Use of Probiotics as a Supportive Therapeutic Intervention.

Human aging, a natural process characterized by structural and physiological changes, leads to alterations of homeostatic mechanisms, decline of biological functions, and subsequently, the organism becomes vulnerable to external stress or damage. In fact, the elderly population is prone to develop diseases due to deterioration of physiological and biological systems. With aging, the production of reactive oxygen species (ROS) increases, and this causes lipid, protein, and DNA damage, leading to cellular dysfunction and altered cellular processes. Indeed, oxidative stress plays a key role in the pathogenesis of several chronic disorders, including hepatic diseases, such as non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common liver disorder in the Western world, is characterized by intrahepatic lipid accumulation; is highly prevalent in the aging population; and is closely associated with obesity, insulin resistance, hypertension, and dyslipidemia. Among the risk factors involved in the pathogenesis of NAFLD, the dysbiotic gut microbiota plays an essential role, leading to low-grade chronic inflammation, oxidative stress, and production of various toxic metabolites. The intestinal microbiota is a dynamic ecosystem of microbes involved in the maintenance of physiological homeostasis; the alteration of its composition and function, during aging, is implicated in different liver diseases. Therefore, gut microbiota restoration might be a complementary approach for treating NAFLD. The administration of probiotics, which can relieve oxidative stress and elicit several anti-aging properties, could be a strategy to modify the composition and restore a healthy gut microbiota. Indeed, probiotics could represent a valid supplement to prevent and/or help treating some diseases, such as NAFLD, thus improving the already available pharmacological intervention. Moreover, in aging, intervention of prebiotics and fecal microbiota transplantation, as well as probiotics, will provide novel therapeutic approaches. However, the relevant research is limited, and several scientific research works need to be done in the near future to confirm their efficacy.

Human umbilical cord mesenchymal stem cells regulate immunoglobulin a secretion and remodel the diversification of intestinal microbiota to improve colitis.

BackgroundMesenchymal stem cell (MSC) therapy has emerged as a promising novel therapeutic strategy for managing inflammatory bowel disease (IBD) mainly via dampening inflammation, regulating immune disorders, and promoting mucosal tissue repair. However, in the process, the associated changes in the gut microbiota and the underlying mechanism are not yet clear.MethodsIn the present study, dextran sulfate sodium (DSS) was used to induce colitis in mice. Mice with colitis were treated with intraperitoneal infusions of MSCs from human umbilical cord mesenchymal stem cells (HUMSCs) and evaluated for severity of inflammation including weight reduction, diarrhea, bloody stools, histopathology, and mortality. The proportion of regulatory T cells (Tregs) and immunoglobulin A-positive (IgA+) plasmacytes in gut-associated lymphoid tissue were determined. The intestinal and fecal levels of IgA were tested, and the proportion of IgA-coated bacteria was also determined. Fecal microbiome was analyzed using 16S rRNA gene sequencing analyses.ResultsTreatment with HUMSCs ameliorated the clinical abnormalities and histopathologic severity of acute colitis in mice. Furthermore, the proportion of Tregs in both Peyer’s patches and lamina propria of the small intestine was significantly increased. Meanwhile, the proportion of IgA+ plasmacytes was also substantially higher in the MSCs group than that of the DSS group, resulting in elevated intestinal and fecal levels of IgA. The proportion of IgA-coated bacteria was also upregulated in the MSCs group. In addition, the microbiome alterations in mice with colitis were partially restored to resemble those of healthy mice following treatment with HUMSCs.ConclusionsTherapeutically administered HUMSCs ameliorate DSS-induced colitis partially via regulating the Tregs–IgA response, promoting the secretion of IgA, and facilitating further the restoration of intestinal microbiota, which provides a potential therapeutic mechanism for HUMSCs in the treatment of IBD.

Evaluación de actividad física como coadyuvante terapéutico para pacientes con enfermedad inflamatoria intestinal: una revisión.

Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC). Pharmacological treatment in IBD presents a loss of efficacy and side effects, inviting to consider alternative strategies, such as the practice of physical activity (PA), as a therapeutic adjuvant. The purpose of this review was to evaluate the effectiveness of PA interventions as a tool to in-crease physical fitness, and health-related quality of life (HRQoL) and improve the symptomatology in patients with CD and UC, identifying the optimal PA component. The review was performed, by searching the electronic databases Medline (PubMed), SciELO, and Cochrane Library Plus, including randomized controlled trials from the last 10 years that related to IBD and PA, until January 31, 2022. We found four studies with a total of 133 patients. The performance of PA in patients with IBD (UC and CD) increases (p&gt;0.05) physical capacity, skeletal muscle mass, bone mineral density, and HRQoL, significantly (p&lt;0.05) increasing mood. In addition, it significantly (p&lt;0.05) decreases intestinal in-flammation and extraintestinal manifestations. A trend of reduction (p&gt;0.05) of fatigue, blood pressure, and microbiota restoration was observed. Moderate PA and performed regularly for a minimum of eight weeks, favors the improve-ment of the IBD patient at the physical, psychological, HRQoL, and symptom-atology levels.

Will fecal microbiota transplantation eventually be an effective therapeutic strategy for systemic lupus erythematosus?

Gut microbiota dysbiosis serves as a potential trigger that may contribute to metabolic and immune dysregulation that underlies the development of autoimmune diseases. Fecal microbiota transplantation (FMT) is restoration of disturbed microbiota by transplanting foreign gut microbiota from healthy individuals into the gastrointestinal tract of diseased individuals. In this issue of the Journal of Autoimmunity, Huang et al. conducted a 12-week, single-arm pilot clinical trial of oral FMT capsules in patients with active SLE. No serious adverse events (AEs) or deaths were observed and the rate of the primary endpoint (SLE Responder Index-4) was 42.12%. Alternations in bacteria, metabolites and immune parameters were linked to FMT treatment and clinical response in SLE patients. This is the first FMT trial in SLE patients and provides supportive evidence that FMT appears to be a safe, feasible and potentially effective treatment modality in SLE. We await future investigations conducting larger, randomized FMT clinical trials with a longer follow-up to confirm the long-term safety, effectiveness, and potential benefits of FMT-based intervention in SLE and to further demonstrate the underlying microbiological mechanisms.

Impacts of Gut Microbiota on the Immune System and Fecal Microbiota Transplantation as a Re-Emerging Therapy for Autoimmune Diseases.

The enormous and diverse population of microorganisms residing in the digestive tracts of humans and animals influence the development, regulation, and function of the immune system. Recently, the understanding of the association between autoimmune diseases and gut microbiota has been improved due to the innovation of high-throughput sequencing technologies with high resolutions. Several studies have reported perturbation of gut microbiota as one of the factors playing a role in the pathogenesis of many diseases, such as inflammatory bowel disease, recurrent diarrhea due to Clostridioides difficile infections. Restoration of healthy gut microbiota by transferring fecal material from a healthy donor to a sick recipient, called fecal microbiota transplantation (FMT), has resolved or improved symptoms of autoimmune diseases. This (re)emerging therapy was approved for the treatment of drug-resistant recurrent C. difficile infections in 2013 by the U.S. Food and Drug Administration. Numerous human and animal studies have demonstrated FMT has the potential as the next generation therapy to control autoimmune and other health problems. Alas, this new therapeutic method has limitations, including the risk of transferring antibiotic-resistant pathogens or transmission of genes from donors to recipients and/or exacerbating the conditions in some patients. Therefore, continued research is needed to elucidate the mechanisms by which gut microbiota is involved in the pathogenesis of autoimmune diseases and to improve the efficacy and optimize the preparation of FMT for different disease conditions, and to tailor FMT to meet the needs in both humans and animals. The prospect of FMT therapy includes shifting from the current practice of using the whole fecal materials to the more aesthetic transfer of selective microbial consortia assembled in vitro or using their metabolic products.

Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy.

Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative “drug-free” cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro, animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.

Modulation, microbiota and inflammation in the adult CF gut: A prospective study

BackgroundCystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation. MethodsFourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples. ResultsThere was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment. ConclusionThere was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

Exploring the Ecological Effects of Naturally Antibiotic-Insensitive Bifidobacteria in the Recovery of the Resilience of the Gut Microbiota during and after Antibiotic Treatment.

Amoxicillin-clavulanic acid (AMC) is the most widely used antibiotic, being frequently prescribed to infants. Particular members of the genus Bifidobacterium are among the first microbial colonizers of the infant gut, and it has been demonstrated that they exhibit various activities beneficial for their human host, including promotion/maintenance of the human gut microbiota homeostasis. It has been shown that natural resistance of bifidobacteria to AMC is limited to a small number of strains. In the current study, we investigated the mitigation effects of AMC-resistant bifidobacteria in diversity preservation of the gut microbiota during AMC treatment. To this end, an in vitro coculture experiment based on infant fecal samples and an in vivo study employing a rodent model were performed. The results confirmed the ability of AMC-resistant bifidobacterial strains to bolster gut microbiota resilience, while specific covariance analysis revealed strain-specific and variable impacts on the microbiota composition by individual bifidobacterial taxa. IMPORTANCE The first microbial colonizers of the infant gut are members of the genus Bifidobacterium, which exhibit different activities beneficial to their host. Amoxicillin-clavulanic acid (AMC) is the most frequently prescribed antibiotic during infancy, and few strains of bifidobacteria are known to show a natural resistance to this antibiotic. In the present work, we evaluated the possible positive effects of AMC-resistant bifidobacterial strains in maintaining gut microbiota diversity during AMC exposure, performing an in vitro and in vivo experiment based on an infant gut model and a rodent model, respectively. Our results suggested the ability of AMC-resistant bifidobacterial strains to support gut microbiota restoration.

79-OR: Conventionalization from Cecal Transplant Recipients Protects Against Type 1 Diabetes Development in Germ-Free NOD Mice

Early-life antibiotic exposure perturbs the microbiome, dysregulates intestinal immune gene expression, and accelerates and amplifies type 1 diabetes (T1D) development in NOD mice. We have previously shown that cecal microbiota transfer (CMT) from healthy donors rescues antibiotic-induced T1D development via restoration of intestinal microbiota and baseline immune parameters. To better understand the role of specific members of the gut microbiome in T1D development, we conventionalized germ-free (GF) recipients with cecal microbiota from three donor mouse groups that had been treated as follows: 1) [Control] received PBS only; 2) [Antibiotic] (tylosin) -disrupted microbiome; and 3) given tylosin as in 2) , followed by cecal microbiota gavage [CMT-restored microbiome]. In the now-conventionalized mice, those that received the CMT-restored microbiome had a lower rate of T1D development than those that received the antibiotic-perturbed microbiota. This showed that the disease phenotypes in one generation can be transferred into the next. Conventionalization with the CMT-restored microbiota led to the most diverse microbiomes and lowest expression of antimicrobial, immune and mucin genes. Surprisingly, gavage with the Control inoculum failed to protect the conventionalized recipients against T1D development compared with the antibiotic group, led to low diversity microbiomes, low abundance of taxa S24-7 and Oscillospira, and increased expression of antimicrobial, immune, and mucin synthesis genes. We conclude that: 1) The CMT protective effect is transferrable to the next generation, and 2) the very low density of S24-7 and Oscillospira in the GF recipients conventionalized with the Control inoculum led to decreased microbiome richness and evenness, increased gene expression, and loss of T1D protection. The effects of these two taxa on T1D development in NOD mice should be further studied. Disclosure S.Pan: None. X.Zhang: None. M.J.Blaser: None. Funding National Institutes of Health (UAI22285) ; Fondation LeDucq (TransAtlantic Program 17CVD01)

Resolution of the Council of Experts “Dysbiosis. Immediate and long-term consequences of microbiome disorders and options for their correction with probiotics”

The appearance of new high-tech microbiological research methods has significantly changed the understanding of the human microbiome. The purpose of the meeting of the Council of Experts Dysbiosis. The immediate and long-term consequences of microbiome disorders and options for their correction with probiotics was the definition of modern positions about possible methods of studying the intestinal microbiome, the possibilities of correcting dysbiosis, the use of Saccharomyces boulardii CNCM I-745 to correct microbiome disorders in various clinical situations. The criteria of the microbiological norm for the intestinal microbiome have not been definitively established. To study the microbiome, a set of methods is used that combine cultural and molecular genetic methods that complement each other. Currently, there are no clinical markers of dysbiosis, and laboratory markers of dysbiosis require modification.&#x0D; Probiotics can provide restoration of the intestinal microbiota. The effectiveness and safety of the use of Saccharomyces boulardii CNCM I-745 for this purpose has been proven. In the case of acute intestinal infection, antibiotic-associated diarrhea, and the consequences of HP infection eradication, studies have a high level of evidence.&#x0D; This article is a reprint. Primary Publication: Gorelov AV, Zakharova IN, Khavkin AI, Kafarskaya LI, Usenko DV, Belmer SV, Kornienko EA, Privorotsky VF, Krasnov VV, Kondyurina EG, Panfilova VN, Tkhakushinova NKh, Plaksina AN, Rychkova OA, Pechkurov DV, Nizhevich AA, Fayzullina RA, Yablokova EA. Resolution of the Council of Experts Dysbiosis. Immediate and long-term consequences of microbiome disorders and options for their correction with probiotics. Vopr. prakt. pediatr. (Clinical Practice in Pediatrics). 2022;17(1):213221 (in Russian). DOI: 10.20953/1817-7646-2022-1-213-221. With the permission of the copyright holder. Published with reductions.

Insights into New Therapeutic Approaches for the Treatment and Management of Polycystic Ovary Syndrome: An Updated Review.

Polycystic ovary syndrome (PCOS) is a long-term, highly prevalent, complex heterogeneous, polygenic endocrine disorder characterized by both metabolic and reproductive disorders. It affects 6-23% of reproductive-age women globally. This review aims to facilitate an understanding of novel PCOS management approaches and highlight the results from relevant interventional animal and human studies. Manual search on PubMed, Cochrane, and Scopus databases was performed for relevant articles, preclinical and clinical trials based on related keywords. According to a multitude of studies, PCOS has evolved over time, but a substantial lag remains in management approaches. New insights into the cross-talk between muscle, brain, fat, and ovaries pointed out new therapeutic targets. This review has highlighted the efficacy of a wide spectrum of novel therapeutic agents [Phosphodiesterase-4 Inhibitors, Glucagon-like peptide-1 receptor agonists, nutritional supplements (Vitamins D and K, omega-3, prebiotics, probiotics and synbiotics), fecal microbiota transplantation (FMT) and intestinal cytokine IL-22] as PCOS therapeutic options. These novel therapies combine anti-inflammatory, insulinsensitizing, and anti-obesity activities, along with the restoration of the gut microbiota and thus hold the potential to address the basic pathogenic mechanisms of PCOS. Exhaustive, multicentric and multiethnic studies are vital to generating a network of normative data to better figure out the PCOS trajectory and change prognostic outcomes. Preclinical and clinical data are warranted to corroborate the new therapeutics and direct health care resources accordingly.

Deoxycholic acid-chitosan coated liposomes combined with in situ colonic gel enhances renal fibrosis therapy of emodin

BackgroundRenal fibrosis is the final common pathological feature of various chronic kidney diseases (CKD). Despite recent advances, development of new treatments strategy is needed. Emodin (EMO), an important ingredient of Chinese medicine, rhubarb (Polygonaceae Rheum palmatum l.), has been reported to inhibit the development of renal fibrosis effectively. However, the poor oral bioavailability of EMO and the insufficient monotherapy therapy compromise its efficacy. PurposeIn order to enhance renal fibrosis therapy of emodin, an innovative combination therapy based on deoxycholic acid-chitosan coated liposomes (DCS-Lips) and in situ colonic gel (IGE) was developed. MethodsFor one, the DCS-Lips were prepared via electrostatic interaction by mixing anionic conventional Lips with cationic DCS, deoxycholic acid conjugated on the backbone of chitosan. The cellular uptake of FITC-labeled DCS-Lips in Caco-2 cell monolayer was evaluated by CLSM and flow cytometry, respectively. Permeability study was carried out using Caco-2 cell monolayer. For another, EMO-loaded in situ colonic gel (EMO-IGE) was prepared by mixing EMO nanosuspensions and plain in situ gel, which was obtained by the cold method. The EMO-IGE was assessed for morphology, gelation temperature, viscosity and in vitro drug release. Finally, the therapeutic efficacy of the combination strategy, oral DCS-Lips formulations and in situ colonic gel, was evaluated in unilateral ureteral obstruction (UUO) rat model. Additionally, 16S rDNA sequencing was performed on rats faces to investigate whether the combination strategy improves the microbial dysbiosis in UUO rats. ResultsThe prepared DCS-Lips produced small, uniformly sized nanoparticles, and significantly enhanced the cellular uptake and in vitro permeability of EMO compared to non-coated liposomes. Moreover, the EMO-IGE was characterized by short gelation time, optimal gelling temperature, and excellent viscosity. In UUO model, the combination of DCS-Lips (gavage) and IGE (enema) attenuated renal fibrosis effectively. The results of 16S rDNA sequencing illustrated that IGE could restore the gut microbial dysbiosis of UUO rats. ConclusionOverall, the combination of DCS-Lips and EMO-IGE alleviated renal fibrosis effectively, resulting from the improved oral bioavailability of EMO by DCS-Lips and the restoration of gut microbiota by EMO-IGE, thus, presenting an innovative and promising potential for renal fibrosis treatment.