Commensal Gut Research Articles

Genetic manipulations of nonmodel gut microbes.

Hundreds of microbiota gene expressions are significantly different between healthy and diseased humans. The "bottleneck" preventing a mechanistic dissection of how they affect host biology/disease is that many genes are encoded by nonmodel gut commensals and not genetically manipulatable. Approaches to efficiently identify their gene transfer methodologies and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. This paper will introduce a step-by-step protocol to identify gene transfer conditions and build the gene manipulation tools for nonmodel gut microbes, focusing on Gram-negative Bacteroidia and Gram-positive Clostridia organisms. This protocol enables us to identify gene transfer methods and develop gene manipulation tools without prior knowledge of their genome sequences, by targeting bacterial 16s ribosomal RNAs or expanding their compatible replication origins combined with clustered regularly interspaced short palindromic repeats machinery. Such an efficient and generalizable approach will facilitate functional studies that causally connect gut microbiota genes to host diseases.

Discovery of antimicrobial peptides in the global microbiome with machine learning

Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both invitro and invivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery.

Response, resistance, and recovery of gut bacteria to human-targeted drug exposure

Survival strategies of human-associated microbes to drug exposure have been mainly studied in the context of bona fide pathogens exposed to antibiotics. Less well understood are the survival strategies of non-pathogenic microbes and host-associated commensal communities to the variety of drugs and xenobiotics to which humans are exposed. The lifestyle of microbial commensals within complex communities offers a variety of ways to adapt to different drug-induced stresses. Here, we review the responses and survival strategies employed by gut commensals when exposed to drugs-antibiotics and non-antibiotics-at the individual and community level. We also discuss the factors influencing the recovery and establishment of a new community structure following drug exposure. These survival strategies are key to the stability and resilience of the gut microbiome, ultimately influencing the overall health and well-being of the host.

Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .

Phase I/II trial of healthy donor fecal microbiota transplant (hdFMT) in PD-1 relapsed/refractory (R/R) non-small cell lung cancer (NSCLC).

TPS8648 Background: A significant portion of patients (pts) with advanced NSCLC either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy administered alone or in combination with platinum chemotherapy. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1. In mice, gut microbiota modulate therapeutic activity of anti-PD-1 ICI, and administration of gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key bacterial species are associated with favorable response, although limited concordance among the identified species has been reported across studies. We and others have previously demonstrated that microbiome modulation reversed anti-PD-1 resistance in anti-PD-1 R/R melanoma, and augmented benefit of anti-PD-1 monotherapy in ICI-naïve melanoma. We hypothesize that intestinal dysbiosis mediates anti-PD-1 resistance in anti-PD-1 R/R NSCLC, and that hdFMT may resensitize NSCLC to PD-1 blockade. Methods: This is an investigator-initiated, phase II trial of hdFMT with pembrolizumab (P) in pts with R/R NSCLC progressed on prior anti-PD-1 based therapy alone or in combination with platinum chemotherapy. Pts must have measurable disease per RECIST v1.1, no untreated CNS metastases, and no contraindications to FMT administration. hdFMT is derived from non-obese, healthy, adults aged ≥18 to <70, with no chronic diseases, and no recent antibiotic exposure. Donors are screened broadly for transmissible agents including SARS-CoV-2 using bookend screening. hdFMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts receive P 200mg every 3 weeks (Q3W). hdFMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo tumor biopsies at baseline and at W8, with optional post-progression biopsy. Primary endpoint: overall response rate (ORR) assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 5% will be tested versus a 1-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design (type I error 0.04, power 0.9, when true response rate is 0.25). PFS and OS will be estimated via Kaplan-Meier method. Enrollment has commenced. Clinical trial information: NCT05669846 .

Utilization of pectin with various degress of esterification by Bacteroides xylanisolvens

The intricate relationship between the human intestinal microbiota and polysaccharides has a profound and direct impact on health outcomes. Our previous research has shown that pectin possesses beneficial properties that can combat colitis and metabolic disorders, which may be facilitated by the dominant gut commensals such as the Bacteroides genus. This study aims to delve deeper into how pectin with varying esterification degrees is utilized by ten distinct Bacteroides strains. Among the tested strains, Bacteroides xylanisolvens Bt-17 demonstrated a remarkable capacity for efficiently utilizing pectin L102, as indicated by its growth rate, sugar consumption, pH changes, and production of short-chain fatty acids. The fermentation of pectin L102 by B. xylanisolvens Bt-17 potentially led to the production of novel substrates, which in turn promoted the growth of Bacteroides stercoris Bt-8. Furthermore, we observed significant regulatory changes in multiple genes encoding glycoside hydrolases and glycosyltransferases in B. xylanisolvens Bt-17 during the degradation of pectin L102. These insights deepen our understanding of the interplay between pectin polysaccharides and the gut microbiota, and they may offer evidence for a gut microbiota-targeted mechanism underlying pectin's functional benefits.

Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Framework for exploring the sensory repertoire of the human gut microbiota.

Bacteria sense changes in their environment and transduce signals to adjust their cellular functions accordingly. For this purpose, bacteria employ various sensors feeding into multiple signal transduction pathways. Signal recognition by bacterial sensors is studied mainly in a few model organisms, but advances in genome sequencing and analysis offer new ways of exploring the sensory repertoire of many understudied organisms. The human gut is a natural target of this line of study: it is a nutrient-rich and dynamic environment and is home to thousands of bacterial species whose activities impact human health. Many gut commensals are also poorly studied compared to model organisms and are mainly known through their genome sequences. To begin exploring the signals human gut commensals sense and respond to, we have designed a framework that enables the identification of sensory domains, prediction of signals that they recognize, and experimental verification of these predictions. We validate this framework's functionality by systematically identifying amino acid sensors in selected bacterial genomes and metagenomes, characterizing their amino acid binding properties, and demonstrating their signal transduction potential.IMPORTANCESignal transduction is a central process governing how bacteria sense and respond to their environment. The human gut is a complex environment with many living organisms and fluctuating streams of nutrients. One gut inhabitant, Escherichia coli, is a model organism for studying signal transduction. However, E. coli is not representative of most gut microbes, and signaling pathways in the thousands of other organisms comprising the human gut microbiota remain poorly understood. This work provides a foundation for how to explore signals recognized by these organisms.

The Impact of Enterococcus spp. in the Immunocompromised Host: A Comprehensive Review.

The immunocompromised host is usually vulnerable to infectious diseases due to broad-spectrum treatments and immunological dysregulation. The Enterococcus genus consists of normal gut commensals, which acquire a leading role in infective processes among individuals with compromised immune systems. These microorganisms may express a potential virulence and resistance spectrum, enabling their function as severe pathogens. The Enterococcus spp. infections in immunocompromised hosts appear to be difficult to resolve due to the immunological response impairment and the possibility of facing antimicrobial-resistant strains. As regards the related risk factors, several data demonstrated that prior antibiotic exposure, medical device insertion, prolonged hospitalization and surgical interventions may lead to Enterococcus overgrowth, antibiotic resistance and spread among critical healthcare settings. Herein, we present a comprehensive review of Enterococcus spp. in the immunocompromised host, summarizing the available knowledge about virulence factors, antimicrobial-resistance mechanisms and host-pathogen interaction. The review ultimately yearns for more substantial support to further investigations about enterococcal infections and immunocompromised host response.

Differences in the effects and action modes of gut commensals against dextran sulfate sodium-induced intestinal inflammation

Inflammatory bowel disease (IBD) is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions. Gut commensals have shown different functions in IBD prevention and treatment. To gain a mechanistic understanding of how different commensals affect intestinal inflammation, we compared the protective effects of six probiotics (belonging to the genera <em>Akkermansia</em>, <em>Bifidobacterium</em>, <em>Clostridium</em>, and <em>Enterococcus</em>) on dextran sulfate sodium (DSS)-induced colitis in mice with or without gut microbiota. Anti-inflammatory properties (ratio of IL-10 and IL-12) of these strains were also evaluated in an in vitro mesenteric lymph nodes (MLN) co-culture system. Results showed that four probiotics (belonging to the species <em>B. breve</em>, <em>B. bifidum</em>, and <em>E. faecalis</em>) can alleviate colitis in normal mice. The probiotic strains differed in regulating the intestinal microbiota, cytokines (IL-10, IL-1β and IFN-γ), and tight junction function (Zonulin-1 and Occludin). By constrast, <em>A. muciniphila</em> AH39 and <em>C. butyricum</em> FHuNHHMY49T1 were not protective. Interestingly, <em>B. breve</em> JSNJJNM2 with high anti-inflammatory potential in the MLN model could relieve colitis symptoms in Abx-treated mice. Meanwhile, <em>E. faecalis</em> FJSWX25M1 induced low levels of cytokines in vitro and showed no beneficial effects. Therefore, we provided insight into the clinical application of probiotics in IBD treatment.

A methyl esterase from Bifidobacterium longum subsp. longum reshapes the prebiotic properties of apple pectin by triggering differential modulatory capacity in faecal cultures.

Pectin structures have received increasing attention as emergent prebiotics due to their capacity to promote beneficial intestinal bacteria. Yet the collective activity of gut bacterial communities to cooperatively metabolize structural variants of this substrate remains largely unknown. Herein, the characterization of a pectin methylesterase, BpeM, from Bifidobacterium longum subsp. longum, is reported. The purified enzyme was able to remove methyl groups from highly methoxylated apple pectin, and the mathematical modelling of its activity enabled to tightly control the reaction conditions to achieve predefined final degrees of methyl-esterification in the resultant pectin. Demethylated pectin, generated by BpeM, exhibited differential fermentation patterns by gut microbial communities in invitro mixed faecal cultures, promoting a stronger increase of bacterial genera associated with beneficial effects including Lactobacillus, Bifidobacterium and Collinsella. Our findings demonstrate that controlled pectin demethylation by the action of a B. longum esterase selectively modifies its prebiotic fermentation pattern, producing substrates that promote targeted bacterial groups more efficiently. This opens new possibilities to exploit biotechnological applications of enzymes from gut commensals to programme prebiotic properties.

Candidalysin: An unlikely aide for fungal gut commensalism

Fungi colonize the mammalian gastrointestinal (GI) tract and can adopt both commensal and opportunistic lifestyles. In a recent issue of Nature, Liang etal. unraveled the complex interplay between Candida morphotypes and the gut bacterial microbiota and described a key role for candidalysin in gut colonization.1.

Aerobic Microbiological Spectrum and Antibiotic Resistance in Children Operated for Anorectal Abscesses.

(1) Background: Anorectal abscesses are a relatively rare pathology in childhood. Most often, male children under 1 year of age are affected. The importance of microbiological examination for the diagnosis and treatment of such patients remains debatable among surgeons, resulting in scarce data being available in the literature. We aimed to identify the aerobic microbiological spectrum and antibiotic resistance of isolates in children undergoing operation to treat anorectal abscesses. (2) Methods: We performed a case series of 102 children diagnosed and operated for anorectal abscesses over a period of 10 years (2010-2019). Purulent wound exudate was used for microbiological evaluation, which was subsequently cultured on 5% sheep-blood agar and eosin-methylene blue agar. For microbiological identification, conventional biochemical tests and semi-automated (API 20, bioMerieux, Marcy-l'Étoile, France) tests were used, as well as automated systems (Vitek-2 Compact, bioMerieux, France). Antimicrobial susceptibility testing was performed by the disk diffusion method of Bauer-Kirby and by determining the minimal inhibitory concentrations for glycopeptides. The results were interpreted according to the EUCAST standard for the corresponding year. (3) Results: Microbiological testing in children operated for anorectal abscesses mainly identified the gut commensals that normally reside in the rectal mucosa. Monocultures were found in just over half of the cases. Escherichia coli, Klebsiella pneumoniae complex, and Proteus mirabilis were the most frequently isolated. In addition, Staphylococcus aureus was found in 7% of patients. In Gram-negative bacteria, antibiotic resistance was most often observed in penicillins, cephalosporins, sulfonamides, and fluoroquinolones. (4) Conclusions: The increasing rates of antimicrobial resistance impose the need for the local monitoring of circulating commensal bacteria associated with anorectal abscesses in children to guide antibiotic therapy when indicated.

Innate Immunity and MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.

Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice

Sepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

Intergenerational protective anti-gut commensal immunoglobulin G originates in early life

Maternal immunoglobulins of the class G (IgGs) protect offspring from enteric infection, but when, where, and how these antibodies are physiologically generated and confer protection remains enigmatic. We found that circulating IgGs in adult mice preferentially bind early-life gut commensal bacteria over their own adult gut commensal bacteria. IgG-secreting plasma cells specific for early-life gut bacteria appear in the intestine soon after weaning, where they remain into adulthood. Manipulating exposure to gut bacteria or plasma cell development before, but not after, weaning reduced IgG-secreting plasma cells targeting early-life gut bacteria throughout life. Further, the development of this anti-gut commensal IgG response coincides with the early-life interval in which goblet cell-associated antigen passages (GAPs) are present in the colon. Offspring of dams "perturbed" by B cell ablation or reduced bacterial exposure in early life were more susceptible to enteric pathogen challenge. In contrast to current concepts, protective maternal IgGs targeted translocating gut commensals in the offspring, not the enteric pathogen. These early-life events affecting anti-commensal IgG production have intergenerational effects for protection of the offspring.

Public health risk assessment and speciation of air-borne microorganisms in an office building

This study focuses on speciation of air borne microbes in an office building and health impacts of these microbes in terms of Quantitative Microbial Risk Assessment (QMRA), Hazard Quotient (HQ) and Hazard Index (HI). This is important in the wake of Sustainability Development Goal 3 (Public Health and well-being) specially when there is a lack of standards in terms of microbial air quality in office buildings where people spend 8–10 h indoors. Air borne bacterial and fungal species in different floors of the office building with varying occupancy and work profile were identified. The load of bacterial count on an average for the entire building was found to be 1917 CFU/m3. Overall, Gram-positive bacteria were predominant (>53%). Based on V3–V4 sequencing Staphylococcus scuiri (causing UTIs) was the most abundant (93.7%) and other bacterial species found were Lactobacillus hamsteri, Prevotella copri, Bacteroides plebeius Faecalibacterium prausnitzii, Bacillus coagulans (gut commensals), Shigella boydii (causes bacillary dysentery), and Propionibacterium acnes (acne producing). Fungal load was 4000 CFU/m3. Based on ITS sequencing Aspergillus (45.6%) was the dominant fungus and other fungi found were Cunninghamella, Lichtheimia, Fusarium, and Circinella Grammothele, Chondrostereum, and Pseudolagarobasidium, Candida sp., Chondrostereum, Sarocladium. The QMRA of gram-negative air borne bacteria showed a high disease burden, well over the WHO benchmark values even though Hazard Quotient (HQ) and Hazard Index (HI) was found to be negligible. These findings can contribute to the development of guidelines for seemingly safe workplaces that may harbour disease-causing microbes and calls for an immediate attention from policy makers as it is a major cause of concern for public health.

Cereal weevils' antimicrobial peptides: at the crosstalk between development, endosymbiosis and immune response.

Interactions between animals and microbes are ubiquitous in nature and strongly impact animal physiology. These interactions are shaped by the host immune system, which responds to infections and contributes to tailor the associations with beneficial microorganisms. In many insects, beneficial symbiotic associations not only include gut commensals, but also intracellular bacteria, or endosymbionts. Endosymbionts are housed within specialized host cells, the bacteriocytes, and are transmitted vertically across host generations. Host-endosymbiont co-evolution shapes the endosymbiont genome and host immune system, which not only fights against microbial intruders, but also ensures the preservation of endosymbionts and the control of their load and location. The cereal weevil Sitophilus spp. is a remarkable model in which to study the evolutionary adaptation of the immune system to endosymbiosis owing to its binary association with a unique, relatively recently acquired nutritional endosymbiont, Sodalis pierantonius. This Gram-negative bacterium has not experienced the genome size shrinkage observed in long-term endosymbioses and has retained immunogenicity. We focus here on the sixteen antimicrobial peptides (AMPs) identified in the Sitophilus oryzae genome and their expression patterns in different tissues, along host development or upon immune challenges, to address their potential functions in the defensive response and endosymbiosis homeostasis along the insect life cycle. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.

Hypoxic Functional Regulation Pathways in the GI Tract: Focus on the HIF-1α and Microbiota's Crosstalk.

Hypoxia is an essential gastrointestinal (GI) tract phenomenon that influences both physiologic and pathologic states. Hypoxia-inducible factors (HIFs), the primary drivers of cell adaptation to low-oxygen environments, have been identified as critical regulators of gut homeostasis: directly, through the induction of different proteins linked to intestinal barrier stabilization (ie, adherent proteins, tight junctions, mucins, integrins, intestinal trefoil factor, and adenosine); and indirectly, through the regulation of several immune cell types and the modulation of autophagy and inflammatory processes. Furthermore, hypoxia and HIF-related sensing pathways influence the delicate relationship existing between bacteria and mammalian host cells. In turn, gut commensals establish and maintain the physiologic hypoxia of the GI tract and HIF-α expression. Based on this premise, the goals of this review are to (1) highlight hypoxic molecular pathways in the GI tract, both in physiologic and pathophysiologic settings, such as inflammatory bowel disease; and (2) discuss a potential strategy for ameliorating gut-related disorders, by targeting HIF signaling, which can alleviate inflammatory processes, restore autophagy correct mechanisms, and benefit the host-microbiota equilibrium.

Resource competition predicts assembly of gut bacterial communities in vitro.

Microbial community dynamics arise through interspecies interactions, including resource competition, cross-feeding and pH modulation. The individual contributions of these mechanisms to community structure are challenging to untangle. Here we develop a framework to estimate multispecies niche overlaps by combining metabolomics data of individual species, growth measurements in spent media and mathematical models. We applied our framework to an in vitro model system comprising 15 human gut commensals in complex media and showed that a simple model of resource competition accounted for most pairwise interactions. Next, we built a coarse-grained consumer-resource model by grouping metabolomic features depleted by the same set of species and showed that this model predicted the composition of 2-member to 15-member communities with reasonable accuracy. Furthermore, we found that incorporation of cross-feeding and pH-mediated interactions improved model predictions of species coexistence. Our theoretical model and experimental framework can be applied to characterize interspecies interactions in bacterial communities in vitro.