Showing papers in "Gut microbes in 2023"

Bile acids as modulators of gut microbiota composition and function

Abstract: ABSTRACT Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but the factors driving dysbiosis remain incompletely understood. One factor governing the microbiota composition in the gut is bile. Bile acids shape the microbiota composition through their antimicrobial activity and by activating host signaling pathways that maintain gut homeostasis. Although bile acids are host-derived, their functions are integrally linked to bacterial metabolism, which shapes the composition of the intestinal bile acid pool. Conditions that change the size or composition of the bile acid pool can trigger alterations in the microbiota composition that exacerbate inflammation or favor infection with opportunistic pathogens. Therefore, manipulating the composition or size of the bile acid pool might be a promising strategy to remediate dysbiosis.

Gut-derived β-amyloid: Likely a centerpiece of the gut–brain axis contributing to Alzheimer’s pathogenesis

Abstract: ABSTRACT Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer’s disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.

Emerging issues in probiotic safety: 2023 perspectives

Abstract: ABSTRACT Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety.

Human milk oligosaccharides, antimicrobial drugs, and the gut microbiota of term neonates: observations from the KOALA birth cohort study

Abstract: ABSTRACT The infant gut microbiota affects childhood health. This pioneer microbiota may be vulnerable to antibiotic exposures, but could be supported by prebiotic oligosaccharides found in breast milk and some infant formulas. We sought to characterize the effects of several exposures on the neonatal gut microbiota, including human milk oligosaccharides (HMOs), galacto-oligosaccharides (GOS), and infant/maternal antimicrobial exposures. We profiled the stool microbiota of 1023 one-month-old infants from the KOALA Birth Cohort using 16S rRNA gene amplicon sequencing. We quantified 15 HMOs in breast milk from the mothers of 220 infants, using high-performance liquid chromatography-mass spectrometry. Both breastfeeding and antibiotic exposure decreased gut microbial diversity, but each was associated with contrasting shifts in microbiota composition. Other factors associated with microbiota composition included C-section, homebirth, siblings, and exposure to animals. Neither infant exposure to oral antifungals nor maternal exposure to antibiotics during pregnancy were associated with infant microbiota composition. Four distinct groups of breast milk HMO compositions were evident, corresponding to maternal Secretor status and Lewis group combinations defined by the presence/absence of certain fucosylated HMOs. However, we found the strongest evidence for microbiota associations between two non-fucosylated HMOs: 6’-sialyllactose (6’-SL) and lacto-N-hexaose (LNH), which were associated with lower and higher relative abundances of Bifidobacterium, respectively. Among 111 exclusively formula-fed infants, the GOS-supplemented formula was associated with a lower relative abundance of Clostridium perfringens. In conclusion, the gut microbiota is sensitive to some prebiotic and antibiotic exposures during early infancy and understanding their effects could inform future strategies for safeguarding a health-promoting infant gut microbiota.

The emerging roles of bacterial proteases in intestinal diseases

Abstract: ABSTRACT Proteases are an evolutionarily conserved family of enzymes that degrade peptide bonds and have been implicated in several common gastrointestinal (GI) diseases. Although luminal proteolytic activity is important for maintenance of homeostasis and health, the current review describes recent advances in our understanding of how overactivity of luminal proteases contributes to the pathophysiology of celiac disease, irritable bowel syndrome, inflammatory bowel disease and GI infections. Luminal proteases, many of which are produced by the microbiota, can modulate the immunogenicity of dietary antigens, reduce mucosal barrier function and activate pro-inflammatory and pro-nociceptive host signaling. Increased proteolytic activity has been ascribed to both increases in protease production and decreases in inhibitors of luminal proteases. With the identification of strains of bacteria that are important sources of proteases and their inhibitors, the stage is set to develop drug or microbial therapies to restore protease balance and alleviate disease.

Host metabolic benefits of prebiotic exopolysaccharides produced by Leuconostoc mesenteroides

Abstract: ABSTRACT Fermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.

The multifaceted virulence of adherent-invasive Escherichia coli

Abstract: ABSTRACT The surge in inflammatory bowel diseases, like Crohn’s disease (CD), is alarming. While the role of the gut microbiome in CD development is unresolved, the frequent isolation of adherent-invasive Escherichia coli (AIEC) strains from patient biopsies, together with their propensity to trigger gut inflammation, underpin the potential role of these bacteria as disease modifiers. In this review, we explore the spectrum of AIEC pathogenesis, including their metabolic versatility in the gut. We describe how AIEC strains hijack the host defense mechanisms to evade immune attrition and promote inflammation. Furthermore, we highlight the key traits that differentiate AIEC from commensal E. coli. Deciphering the main components of AIEC virulence is cardinal to the discovery of the next generation of antimicrobials that can selectively eradicate CD-associated bacteria.

Allogeneic hematopoietic cell transplantation, the microbiome, and graft-versus-host disease

Abstract: ABSTRACT Many patients with hematological malignancies, such as acute myeloid leukemia, receive an allogeneic hematopoietic cell transplantation (HCT) to cure their underlying condition. Allogeneic HCT recipients are exposed to various elements during the pre-, peri- and post-transplant period that can disrupt intestinal microbiota, including chemo- and radiotherapy, antibiotics, and dietary changes. The dysbiotic post-HCT microbiome is characterized by low fecal microbial diversity, loss of anaerobic commensals, and intestinal domination, particularly by Enterococcus species, and is associated with poor transplant outcomes. Graft-versus-host disease (GvHD) is a frequent complication of allogeneic HCT caused by immunologic disparity between donor and host cells and results in tissue damage and inflammation. Microbiota injury is particularly pronounced in allogeneic HCT recipients who go on to develop GvHD. At present, manipulation of the microbiome for example, via dietary interventions, antibiotic stewardship, prebiotics, probiotics, or fecal microbiota transplantation, is widely being explored to prevent or treat gastrointestinal GvHD. This review discusses current insights into the role of the microbiome in GvHD pathogenesis and summarizes interventions to prevent and treat microbiota injury.

Immune evasion and persistence in enteric bacterial pathogens

Abstract: ABSTRACT The major function of the mammalian immune system is to prevent and control infections caused by enteropathogens that collectively have altered human destiny. In fact, as the gastrointestinal tissues are the major interface of mammals with the environment, up to 70% of the human immune system is dedicated to patrolling them The defenses are multi-tiered and include the endogenous microflora that mediate colonization resistance as well as physical barriers intended to compartmentalize infections. The gastrointestinal tract and associated lymphoid tissue are also protected by sophisticated interleaved arrays of active innate and adaptive immune defenses. Remarkably, some bacterial enteropathogens have acquired an arsenal of virulence factors with which they neutralize all these formidable barriers to infection, causing disease ranging from mild self-limiting gastroenteritis to in some cases devastating human disease.

The gut-microbiota-brain axis in a Spanish population in the aftermath of the COVID-19 pandemic: microbiota composition linked to anxiety, trauma, and depression profiles

Abstract: ABSTRACT The prevalence of anxiety and depression soared following the COVID-19 pandemic. To effectively treat these conditions, a comprehensive understanding of all etiological factors is needed. This study investigated fecal microbial features associated with mental health outcomes (symptoms of anxiety, depression, or posttraumatic stress disorder (PTSD)) in a Spanish cohort in the aftermath of the COVID-19 pandemic. Microbial communities from stool samples were profiled in 198 individuals who completed validated, self-report questionnaires. 16S ribosomal RNA gene V3-4 amplicon sequencing was performed. Microbial diversity and community structure were analyzed, together with relative taxonomic abundance. In our cohort of N=198, 17.17% reported depressive symptoms, 37.37% state anxiety symptoms, 40.90% trait anxiety symptoms, and 8.08% PTSD symptoms, with high levels of comorbidity. Individuals with trait anxiety had lower Simpson’s diversity. Fusicatenibacter saccharivorans was reduced in individuals with comorbid PTSD + depression + state and trait anxiety symptoms, whilst an expansion of Proteobacteria and depletion of Synergistetes phyla were noted in individuals with depressive symptoms. The relative abundance of Anaerostipes was positively correlated with childhood trauma, and higher levels of Turicibacter sanguinis and lower levels of Lentisphaerae were found in individuals who experienced life-threatening traumas. COVID-19 infection and vaccination influenced the overall microbial composition and were associated with distinct relative taxonomic abundance profiles. These findings will help lay the foundation for future studies to identify microbial role players in symptoms of anxiety, depression, and PTSD and provide future therapeutic targets to improve mental health outcomes.

Mouse models for bacterial enteropathogen infections: insights into the role of colonization resistance

Abstract: ABSTRACT Globally, enteropathogenic bacteria are a major cause of morbidity and mortality.1-3 Campylobacter, Salmonella, Shiga-toxin-producing Escherichia coli, and Listeria are among the top five most commonly reported zoonotic pathogens in the European Union.4 However, not all individuals naturally exposed to enteropathogens go on to develop disease. This protection is attributable to colonization resistance (CR) conferred by the gut microbiota, as well as an array of physical, chemical, and immunological barriers that limit infection. Despite their importance for human health, a detailed understanding of gastrointestinal barriers to infection is lacking, and further research is required to investigate the mechanisms that underpin inter-individual differences in resistance to gastrointestinal infection. Here, we discuss the current mouse models available to study infections by non-typhoidal Salmonella strains, Citrobacter rodentium (as a model for enteropathogenic and enterohemorrhagic E. coli), Listeria monocytogenes, and Campylobacter jejuni. Clostridioides difficile is included as another important cause of enteric disease in which resistance is dependent upon CR. We outline which parameters of human infection are recapitulated in these mouse models, including the impact of CR, disease pathology, disease progression, and mucosal immune response. This will showcase common virulence strategies, highlight mechanistic differences, and help researchers from microbiology, infectiology, microbiome research, and mucosal immunology to select the optimal mouse model.

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Abstract: ABSTRACT Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.

Pol32, an accessory subunit of DNA polymerase delta, plays an essential role in genome stability and pathogenesis of Candida albicans

Abstract: ABSTRACT Candida albicans is a pathobiont that inflicts serious bloodstream fungal infections in individuals with compromised immunity and gut dysbiosis. Genomic diversity in the form of copy number alteration, ploidy variation, and loss of heterozygosity as an adaptive mechanism to adverse environments is frequently observed in C. albicans. Such genomic variations also confer a varied degree of fungal virulence and drug resistance, yet the factors propelling these are not completely understood. DNA polymerase delta (Polδ) is an essential replicative DNA polymerase in the eukaryotic cell and is yet to be characterized in C. albicans. Therefore, this study was designed to gain insights into the role of Polδ, especially its non-essential subunit Pol32, in the genome plasticity and life cycle of C. albicans. PCNA, the DNA clamp, recruits Polδ to the replication fork for processive DNA replication. Unlike in Saccharomyces cerevisiae, the PCNA interaction protein (PIP) motif of CaPol32 is critical for Polδ’s activity during DNA replication. Our comparative genetic analyses and whole-genome sequencing of POL32 proficient and deficient C. albicans cells revealed a critical role of Pol32 in DNA replication, cell cycle progression, and genome stability as SNPs, indels, and repeat variations were largely accumulated in pol32 null strain. The loss of pol32 in C. albicans conferred cell wall deformity; Hsp90 mediated azoles resistance, biofilm development, and a complete attenuation of virulence in an animal model of systemic candidiasis. Thus, although Pol32 is dispensable for cell survival, its function is essential for C. albicans pathogenesis; and we discuss its translational implications in antifungal drugs and whole-cell vaccine development.

Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis

Abstract: ABSTRACT Predicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice.

Experimental diets dictate the metabolic benefits of probiotics in obesity

Abstract: Background Growing evidence supports the use of probiotics to prevent or mitigate obesity-related dysmetabolism and non-alcoholic fatty liver disease (NAFLD). However, frequent reports of responders versus non-responders to probiotic treatment warrant a better understanding of key modifiers of host-microbe interactions. The influence of host diet on probiotic efficacy, in particular against metabolic diseases, remains elusive. Method We fed C57BL6/J mice a low fat reference diet or one of two energy-matched high fat and high sucrose diets for 12 weeks; a classical high fat diet (HFD) and a customized fast food-mimicking diet (FFMD). During the studies, mice fed either obesogenic diet were gavaged daily with one of two probiotic lactic acid bacteria (LAB) strains previously classified as Lactobaccillus, namely Limosilactobacillus reuteri (L. reuteri) or Lacticaseibacillus paracasei subsp. paracasei (L. paracasei), or vehicle. Results The tested probiotics exhibited a reproducible efficacy but dichotomous response according to the obesogenic diets used. Indeed, L. paracasei prevented weight gain, improved insulin sensitivity, and protected against NAFLD development in mice fed HFD, but not FFMD. Conversely, L. reuteri improved glucoregulatory capacity, reduced NAFLD development, and increased distal gut bile acid levels associated with changes in predicted functions of the gut microbiota exclusively in the context of FFMD-feeding. Conclusion We found that the probiotic efficacy of two LAB strains is highly dependent on experimental obesogenic diets. These findings highlight the need to carefully consider the confounding impact of diet in order to improve both the reproducibility of preclinical probiotic studies and their clinical research translatability. Graphical abstract

The diagnostic and prognostic potential of gut bacteria in inflammatory bowel disease

Abstract: ABSTRACT The gut microbiome serves as a signaling hub that integrates environmental inputs with genetic and immune signals to influence the host’s metabolism and immunity. Gut bacteria are intricately connected with human health and disease state, with specific bacteria species driving the characteristic dysbiosis found in gastrointestinal conditions such as inflammatory bowel disease (IBD); thus, gut bacteria changes could be harnessed to improve IBD diagnosis, prognosis, and treatment. The advancement in next-generation sequencing techniques such as 16S rRNA and whole-genome shotgun sequencing has allowed the exploration of the complexity of the gut microbial ecosystem with high resolution. Current microbiome data is promising and appears to perform better in some studies than the currently used fecal inflammation biomarker, calprotectin, in predicting IBD from healthy controls and irritable bowel syndrome (IBS). This study reviews current data on the differential potential of gut bacteria within IBD cohorts, and between IBD and other gastrointestinal diseases.

Segmented filamentous bacteria impede rotavirus infection via retinoic acid receptor-mediated signaling

Abstract: ABSTRACT Prevention of rotavirus (RV) infection by gut-resident segmented filamentous bacteria (SFB) is an example of the influence of gut microbiota composition on enteric viral infection. Yet, the mechanism by which SFB prevents RV infection is poorly understood. A recent report that SFB colonization of germfree mice generates retinoic acid (RA) thus activating RA receptor (RAR) signaling, which protected against Citrobacter rodentium infection, prompted us to investigate whether this pathway might contribute to SFB’s protection against RV infection. Colonization of conventional mice by SFB indeed increased intestinal RA levels and direct administration of RA partially mimicked the protection against RV infection conferred by SFB. Moreover, blockade of RAR signaling eliminated SFB’s protection against RV infection. Blockade of RAR signaling did not impact RV infection in the absence of SFB, nor did it alter the protection against RV infection conferred by bacterial flagellin, which in contrast to SFB, is dependent upon IL-22 signaling. SFB/RA-mediated prevention of RV infection was associated with an RA-dependent increase in enterocyte migration, consistent with the notion that enhanced anoikis is the ultimate means by which SFB, IL-22, and RA impede RV infection.

Microbial metabolites as modulators of the infant gut microbiome and host-microbial interactions in early life

Abstract: ABSTRACT The development of infant gut microbiome is a pivotal process affecting the ecology and function of the microbiome, as well as host health. While the establishment of the infant microbiome has been of interest for decades, the focus on gut microbial metabolism and the resulting small molecules (metabolites) has been rather limited. However, technological and computational advances are now enabling researchers to profile the plethora of metabolites in the infant gut, allowing for improved understanding of how gut microbial-derived metabolites drive microbiome community structuring and host-microbial interactions. Here, we review the current knowledge on development of the infant gut microbiota and metabolism within the first year of life, and discuss how these microbial metabolites are key for enhancing our basic understanding of interactions during the early life developmental window.

Limosilactobacillus reuteri normalizes blood–brain barrier dysfunction and neurodevelopment deficits associated with prenatal exposure to lipopolysaccharide

Abstract: ABSTRACT Maternal immune activation (MIA) derived from late gestational infection such as seen in chorioamnionitis poses a significantly increased risk for neurodevelopmental deficits in the offspring. Manipulating early microbiota through maternal probiotic supplementation has been shown to be an effective means to improve outcomes; however, the mechanisms remain unclear. In this study, we demonstrated that MIA modeled by exposing pregnant dams to lipopolysaccharide (LPS) induced an underdevelopment of the blood vessels, an increase in permeability and astrogliosis of the blood–brain barrier (BBB) at prewean age. The BBB developmental and functional deficits early in life impaired spatial learning later in life. Maternal Limosilactobacillus reuteri (L. reuteri) supplementation starting at birth rescued the BBB underdevelopment and dysfunction-associated cognitive function. Maternal L. reuteri-mediated alterations in β-diversity of the microbial community and metabolic responses in the offspring provide mechanisms and potential targets for promoting BBB integrity and long-term neurodevelopmental outcomes.

Randomized controlled trial demonstrates response to a probiotic intervention for metabolic syndrome that may correspond to diet

Abstract: ABSTRACT An individual’s immune and metabolic status is coupled to their microbiome. Probiotics offer a promising, safe route to influence host health, possibly via the microbiome. Here, we report an 18-week, randomized prospective study that explores the effects of a probiotic vs. placebo supplement on 39 adults with elevated parameters of metabolic syndrome. We performed longitudinal sampling of stool and blood to profile the human microbiome and immune system. While we did not see changes in metabolic syndrome markers in response to the probiotic across the entire cohort, there were significant improvements in triglycerides and diastolic blood pressure in a subset of probiotic arm participants. Conversely, the non-responders had increased blood glucose and insulin levels over time. The responders had a distinct microbiome profile at the end of the intervention relative to the non-responders and placebo arm. Importantly, diet was a key differentiating factor between responders and non-responders. Our results show participant-specific effects of a probiotic supplement on improving parameters of metabolic syndrome and suggest that dietary factors may enhance stability and efficacy of the supplement.

Intestinal bacteria and colorectal cancer: etiology and treatment

Abstract: ABSTRACT The etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.

Gut microbiome function and composition in infants from rural Kenya and association with human milk oligosaccharides

Abstract: ABSTRACT The gut microbiota evolves rapidly after birth, responding dynamically to environmental factors and playing a key role in short- and long-term health. Lifestyle and rurality have been shown to contribute to differences in the gut microbiome, including Bifidobacterium levels, between infants. We studied the composition, function and variability of the gut microbiomes of 6- to 11-month-old Kenyan infants (n = 105). Shotgun metagenomics showed Bifidobacterium longum to be the dominant species. A pangenomic analysis of B. longum in gut metagenomes revealed a high prevalence of B. longum subsp. infantis (B. infantis) in Kenyan infants (80%), and possible co-existence of this subspecies with B. longum subsp. longum. Stratification of the gut microbiome into community (GMC) types revealed differences in composition and functional features. GMC types with a higher prevalence of B. infantis and abundance of B. breve also had a lower pH and a lower abundance of genes encoding pathogenic features. An analysis of human milk oligosaccharides (HMOs) classified the human milk (HM) samples into four groups defined on the basis of secretor and Lewis polymorphisms revealed a higher prevalence of HM group III (Se+, Le-) (22%) than in most previously studied populations, with an enrichment in 2′-fucosyllactose. Our results show that the gut microbiome of partially breastfed Kenyan infants over the age of six months is enriched in bacteria from the Bifidobacterium community, including B. infantis, and that the high prevalence of a specific HM group may indicate a specific HMO-gut microbiome association. This study sheds light on gut microbiome variation in an understudied population with limited exposure to modern microbiome-altering factors.

Therapeutic potential of Clostridium butyricum anticancer effects in colorectal cancer

Abstract: ABSTRACT Probiotic roles of Clostridium butyricum (C.B) are involved in regulating disease and cancers, yet the mechanistic basis for these regulatory roles remains largely unknown. Here, we demonstrate that C.B reprograms the proliferation, migration, stemness, and tumor growth in CRC by regulating pivotal signal molecules including MYC. Destabilization of MYC by C.B supplementation suppresses cancer cell proliferation/metastasis, sensitizes 5-FU treatment, and boosts responsiveness of anti-PD1 therapy. MYC is a transcriptional regulator of Thymidylate synthase (TYMS), a key target of the 5-FU. Also MYC is known to impact on PD-1 expression. Mechanistically, C.B treatment of CRC cells results in MYC degradation by enhancing proteasome-mediated ubiquitination, thereby mitigating MYC-mediated 5-FU resistance and boosting anti-PD1 immunotherapeutic efficacy. Together, our findings uncover previously unappreciated links between C.B and CRC cell signaling, providing insight into the tumorigenesis modulating mechanisms of C.B in boosting chemo/immune therapies.

Intestinal mucin-type O-glycans: the major players in the host-bacteria-rotavirus interactions

Abstract: ABSTRACT Rotavirus (RV) causes severe diarrhea in young children and animals worldwide. Several glycans terminating in sialic acids (SAs) and histo-blood group antigens (HBGAs) on intestinal epithelial cell (IEC) surface have been recognized to act as attachment sites for RV. IECs are protected by the double layer of mucus of which O-glycans (including HBGAs and SAs) are a major organic component. Luminal mucins, as well as bacterial glycans, can act as decoy molecules removing RV particles from the gut. The composition of the intestinal mucus is regulated by complex O-glycan-specific interactions among the gut microbiota, RV and the host. In this review, we highlight O-glycan-mediated interactions within the intestinal lumen prior to RV attachment to IECs. A better understanding of the role of mucus is essential for the development of alternative therapeutic tools including the use of pre- and probiotics to control RV infection.

Gut microbiota: a non-target victim of pesticide-induced toxicity

Abstract: The human gut microbiota can be potentially disrupted due to exposure of various environmental contaminants, including pesticides. These contaminants enter into non-target species in multiple ways and cause potential health risks. The gut microbiota-derived metabolites have a significant role in maintaining the host's health by regulating metabolic homeostasis. An imbalance in this homeostasis can result in the development of various diseases and their pathogenesis. Pesticides have hazardous effects on the host's gut microbiota, which is evident in a few recent studies. Therefore, there is an urgent need to explore the effect of pesticide on gut microbiota-mediated metabolic changes in the host, which may provide a better understanding of pesticide-induced toxicity. The present review summarizes the pesticide-induced effects on gut microbiota, which in turn, induces changes in the release of their secondary metabolites that could lead to various host health effects.

Maternal microbe-specific modulation of the offspring microbiome and development during pregnancy and lactation

Abstract: ABSTRACT The maternal microbiome is essential for the healthy growth and development of offspring and has long-term effects later in life. Recent advances indicate that the maternal microbiome begins to regulate fetal health and development during pregnancy. Furthermore, the maternal microbiome continues to affect early microbial colonization via birth and breastfeeding. Compelling evidence indicates that the maternal microbiome is involved in the regulation of immune and brain development and affects the risk of related diseases. Modulating offspring development by maternal diet and probiotic intervention during pregnancy and breastfeeding could be a promising therapy in the future. In this review, we summarize and discuss the current understanding of maternal microbiota development, perinatal microbial metabolite transfer, mother-to-infant microbial transmission during/after birth and its association with immune and brain development as well as corresponding diseases.

Dynamic network modeling of gut microbiota during Alzheimer’s disease progression in mice

Abstract: ABSTRACT The intimate association between the gut microbiota (GM) and the central nervous system points to potential intervention strategies for neurological diseases. Nevertheless, there is currently no theoretical framework for selecting the window period and target bacteria for GM interventions owing to the complexity of the gut microecosystem. In this study, we constructed a complex network-based modeling approach to evaluate the topological features of the GM and infer the window period and bacterial candidates for GM interventions. We used Alzheimer’s disease (AD) as an example and traced the GM dynamic changes in AD and wild-type mice at one, two, three, six, and nine months of age. The results revealed alterations of the topological features of the GM from a scale-free network into a random network during AD progression, indicating severe GM disequilibrium at the late stage of AD. Through stability and vulnerability assessments of the GM networks, we identified the third month after birth as the optimal window period for GM interventions in AD mice. Further computational simulations and robustness evaluations determined that the hub bacteria were potential candidates for GM interventions. Moreover, our GM functional analysis suggested that Lachnospiraceae UCG-001 – the hub and enriched bacterium in AD mice – was the keystone bacterium for GM interventions owing to its contributions to quinolinic acid synthesis. In conclusion, this study established a complex network-based modeling approach as a practical strategy for disease interventions from the perspective of the gut microecosystem.

Vitamin D influences gut microbiota and acetate production in zebrafish (Danio rerio) to promote intestinal immunity against invading pathogens

Abstract: ABSTRACT Although evidence has shown that vitamin D (VD) influences gut homeostasis, limited knowledge is available how VD regulates intestinal immunity against bacterial infection. In the present study, cyp2r1 mutant zebrafish, lacking the capacity to metabolize VD, and zebrafish fed a diet devoid of VD, were utilized as VD-deficient animal models. Our results confirmed that the expression of antimicrobial peptides (AMPs) and IL-22 was restrained and the susceptibility to bacterial infection was increased in VD-deficient zebrafish. Furthermore, VD induced AMP expression in zebrafish intestine by activating IL-22 signaling, which was dependent on the microbiota. Further analysis uncovered that the abundance of the acetate-producer Cetobacterium in VD-deficient zebrafish was reduced compared to WT fish. Unexpectedly, VD promoted the growth and acetate production of Cetobacterium somerae under culture in vitro. Importantly, acetate treatment rescued the suppressed expression of β-defensins in VD-deficient zebrafish. Finally, neutrophils contributed to VD-induced AMP expression in zebrafish. In conclusion, our study elucidated that VD modulated gut microbiota composition and production of short-chain fatty acids (SCFAs) in zebrafish intestine, leading to enhanced immunity.

Gut microbiome at the crossroad of genetic variants and behavior disorders

Abstract: ABSTRACT Genetic variants are traditionally known to shape the susceptibility to neuropsychiatric disorders. An increasing number of studies indicate that remodeling of the gut microbiome by genetic variance serves as a versatile regulator of gut-brain crosstalk and behavior. Evidence also emerges that certain behavioral symptoms are specifically attributed to gut microbial remodeling and gut-to-brain signals, which necessitates rethinking of neuropsychiatric disease etiology and treatment from a systems perspective of reciprocal gene-microbe interactions. Here, we present an emerging picture of how gut microbes and host genetics interactively shape complex psychiatric phenotypes. We illustrate the growing understanding of how the gut microbiome is shaped by genetic changes and its connection to behavioral outcome. We also discuss working strategies and open questions in translating associative gene-microbiome-behavior findings into causal links and novel targets for neurobehavioral disorders. Dual targeting of the genetic and microbial factors may expand the space of drug discovery for neuropsychiatric diseases.

Candida albicans can foster gut dysbiosis and systemic inflammation during HIV infection

Abstract: ABSTRACT Candida albicans (C. albicans) is a ubiquitous fungal commensal component of the human microbiota, and under certain circumstances, such as during an immunocompromised state, it may initiate different types of infection. Moreover, C. albicans continuously and reciprocally interacts with the host immune system as well as with other elements of the gut microbiota, thus contributing significantly to both gut homeostasis and host immunity. People living with HIV (PLWH), including those receiving antiretroviral therapy, are characterized by a depletion of CD4 + T-cells and dysbiosis in their gut. C. albicans colonization is frequent in PLWH, causing both a high prevalence and high morbidity. Gut barrier damage and elevated levels of microbial translocation are also fairly common in this population. Herein, we take a closer look at the reciprocity among C. albicans, gut microbiota, HIV, and the host immune system, thus throwing some light on this complex interplay.