Gut Firmicutes Research Articles

Increased abundance of Firmicutes and depletion of Bacteroidota predicts poor outcome in chronic lymphocytic leukemia.

Evidence indicates that there are significant alterations in gut microbiota diversity and composition in patients with hematological malignancies. The present study investigated the oral and intestinal microbiome in patients with chronic lymphocytic leukemia (CLL) (n=81) and age-matched healthy volunteers (HVs; n=21) using 16S ribosomal RNA next-generation sequencing. Changes in both oral and gut microbiome structures were identified, with a high abundance of Proteobacteria and depletion of Bacteroidetes in CLL as compared to HVs. Oral and stool samples of patients with CLL revealed a significant change in the abundance of short-chain fatty acid-producing genera in comparison with HVs. Furthermore, the relative abundance of oral and intestine Bacteroidetes was significantly decreased in patients with CLL with negative prognostic features, including unmutated immunoglobulin heavy chain gene (IGHV). Notably, an increased abundance of gut Firmicutes was found to be associated with high expression of CD38. Finally, the present study suggested the log Firmicutes/Bacteroidota ratio as a novel intestinal microbiome signature associated with a shorter time to first treatment in individuals with CLL. The findings indicate that oral and gut microbial diversity in CLL might point to the inflammatory-related modulation of the clinical course of the disease.

Emergence of rare and low abundant anaerobic gut Firmicutes is associated with a significant downfall of Klebsiella in human colon cancer

Gut bacterial dysbiosis has been linked to several gastrointestinal diseases, including deadly colorectal cancer (CRC), a leading cause of mortality in cancer patients. However, perturbation in gut bacteriome during colon cancer (CC, devoid of colorectal malignancy) remains poorly explored. Here, 16S rRNA gene amplicon sequencing was carried out for fecal DNA samples targeted to hypervariable V3–V4 region by employing MiSeq platform to explore the gut bacterial community shift in CC patients. While alpha diversity indices predicted high species richness and diversity, beta diversity showed marked gut bacterial compositional dissimilarity in CC versus healthy controls (HC, n = 10 each). We observed a significant (p < 0.05, Wilcoxon Rank-Sum test) emergence of low-abundant anaerobic taxa, including Parvimonas and Peptostreptococcus, in addition to Subdoligranulum, Coprococcus, Holdemanella, Solobacterium, Bilophila, Blautia, Dorea, Moryella and several unidentified taxa, mainly affiliated to Firmicutes, in CC patients. In addition, we also traced the emergence of putative probiotic taxon Slackia, belonging to Actinomycetota, in CC patients. The emergence of anaerobic Firmicutes in CC is accompanied by a significant (p < 0.05) decline in the Klebsiella, as determined through linear discriminant analysis effect size (LEfSe) and heat tree analyses. Shifts in core microbiome and variation in network correlation were also witnessed. Taken together, this study highlighted a significant and consistent emergence of rare anaerobic Firmicutes suggesting possible anaerobiosis driving gut microbial community shift, which could be exploited in designing diagnostic and therapeutic tools targeted to CC.

Abstract 649: Comparative effects of combustible cigarette versus electronic cigarette exposures on K-ras mutant lung cancer

Abstract Combustible cigarette smoking (CCS) is causally related to ~90% of all lung cancers and induces various tumor-initiating effects, some of which (e.g., inflammation) are not reversible even after smoking cessation. More recently, use of non-combustible smoking vectors, such as electronic cigarette vapors (ECV), have rapidly increased, especially among youth. Despite this emerging public health concern, the long-term impact of ECV exposure is poorly understood. Our lab sought to assess the safety of ECV and determine their influence on immune dysfunction and lung cancer progression by comparing the effects of CCS and ECV in an airway epithelial specific K-ras mutant mouse model of lung adenocarcinoma (CC-LR). Three cohorts of 6-week-old CC-LR mice were exposed to either room air, CCS, or ECV 5 days per week for 8 weeks. For CCS exposure, mice were exposed to CCS from 3R4F research cigarettes at a rate of 3 puffs/min for 2 hours each day using the SCIREQ integrated Cigarette Smoking Robot. For ECV exposure, mice were exposed to 72 mg/ml of liquid nicotine in 50% propylene glycol/vegetable glycerin solution at a rate of 3 puffs/min for 2 hours using the SCIREQ Electronic Nicotine Delivery System. While CCS led to a significant increase in tumor burden (25%), ECV showed no significant changes compared to room air-exposed control. Bronchoalveolar lavage fluid had significantly increased total lung immune cell infiltrates in both CCS (30%) and ECV (25%), particularly in macrophage and lymphocyte populations. Immunophenotyping of CCS and ECV exposed lungs displayed pronounced pro-tumor immunosuppressive phenotypes, characterized by significantly decreased CD4+ IFNγ+ and CD8+ GZMB+ cytotoxic T cells along with a significantly elevated CD4+ FOXP3+ regulatory T cells. Furthermore, the cytotoxic cytokine IFNγ was significantly reduced in lungs of CCS- (7-fold) and ECV-exposed (2-fold) mice compared to room air-exposed controls. We also found increased levels of the immunosuppressive cytokine IL-10 in lungs of CCS- and ECV-exposed mice. Previous studies have shown IL-10 to play an important role in microbiome-associated immune modulation, hence we performed a preliminary gut and lung microbiome study to assess microbiome dissimilarity in these cohorts. Taxonomic profiling via 16S rRNA gene sequencing of matched stool and lung samples showed differences in the relative abundance of several lung Proteobacteria spp. while gut Firmicutes, particularly Turicibacter and Ileibacterium, were increased by CCS and ECV. In conclusion, while both CCS and ECV increased immune suppression, ECV did not significantly promote tumorigenesis during this timeframe of intervention. Future studies probing differences in microbiome-modulated CCS and ECV immune dysfunction can help pave way for identification of new targets that foster new interception and early treatment strategies for K-ras mutant lung cancer. Citation Format: Walter V. Velasco Torrez, Maria T. Grimaldo, Michael J. Clowers, Bo Yuan, Segundo del Aguila Soto, Iman Bouchelkia, Javier Eduardo Moreno Barragan, Umesh C. Karandikar, Joseph F. Petrosino, Florencia McAllister, Humam Kadara, Kristi Louise Hoffman, Seyed Javad Moghaddam. Comparative effects of combustible cigarette versus electronic cigarette exposures on K-ras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 649.

Gut microbiota in Chinese and Japanese patients with cardiovascular diseases: a systematic review and meta-analysis.

Cardiovascular disease (CVD) is a major threat to public health. Compare the gut microbial composition between Chinese and Japanese patients with cardiovascular diseases and healthy subjects. Observational studies with Chinese and Japanese populations. Reviews, duplicate, book chapters, and other irrelevant studies were excluded. Independent searching by two investigators (LLJ, HJL). Data from eleven studies (with 960 subjects) were included for the meta-analysis. The meta-analysis showed that the abundance of Firmicutes in patients with cardiovascular disease was [ES=0.42, 95%CI, (0.34, 0.50), P<.01], while the abundance of Firmicutes in control subjects was [ES=0.36, 95%CI, (0.23, 0.49), P<.01] (ES: effect size). When compared to control subjects, the differential expression of Firmicutes abundance in patients with CVDs was [MD = 15.21, 95%CI (8.95, 21.48), P<.01] (MD: mean difference). The ratio of Firmicutes abundance in patients with CVDs to the control subjects was [RR=1.28, 95%CI (0.98, 1.67), P=.07]. The ratio of Firmicutes in coronary heart disease (CHD) patients and controls was [RR=1.42, 95%CI (1.05, 1.94), P=.02]. Firmicutes/Bacteroidetes ratio is [OR=1.64 95%CI (1.11, 2.42), P=.01]. Our data show that patients with cardiovascular disease had higher levels of gut Firmicutes when compared to healthy controls. In addition, gut microbial dysbiosis was present in patients with cardiovascular diseases. Due to limited quality and quantity of selected studies, conclusions from the current study need to be validated by future studies. None.

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

ABSTRACT The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-cis orientation in which the sterol rings are “kinked”, as well as small quantities of A/B-trans oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the ”flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.

Lower systemic inflammation is associated with gut firmicutes dominance and reduced liver injury in a novel ambulatory model of parenteral nutrition

Background Total Parenteral Nutrition (TPN) provides lifesaving nutritional support to patients unable to maintain regular enteral nutrition (EN). Unfortunately, cholestasis is a significant side effect affecting 20–40% of paediatric patients. While the aetiology of TPN-associated injury remains ill-defined, an altered enterohepatic circulation in the absence of gut luminal nutrient content during TPN results in major gut microbial clonal shifts, resulting in metabolic endotoxemia and systemic inflammation driving liver injury and cholestasis. Hypothesis To interrogate the role of gut microbiota, using our novel ambulatory TPN piglet model, we hypothesized that clonal reduction of bacteria in Firmicutes phylum (predominant in EN) and an increase in pathogenic Gram-negative bacteria during TPN correlates with an increase in serum lipopolysaccharide and systemic inflammatory cytokines, driving liver injury. Methods Upon institutional approval, 16 animals were allocated to receive either TPN (n = 7) or EN only (n = 9). The TPN group was subdivided into a low systemic inflammation (TPN-LSI) and high systemic inflammation (TPN-HSI) based on the level of serum lipopolysaccharide. Culture-independent identification of faecal bacterial populations was determined by 16S rRNA. Results Piglets on TPN, in the TPN-HSI group, noted a loss of enterocyte protective Firmicutes bacteria and clonal proliferation of potent inflammatory and lipopolysaccharide containing pathogens: Fusobacterium, Bacteroidetes and Campylobacter compared to EN animals. Within the TPN group, the proportion of Firmicutes phylum correlated with lower portal lipopolysaccharide levels (r = −0.89). The TPN-LSI had a significantly lower level of serum bile acids compared to the TPN-HSI group (7.3 vs. 60.4 mg/dL; p = .018), increased day 14 weight (5.67 vs. 5.07 kg; p = .017) as well as a 13.7-fold decrease in serum conjugated bilirubin. Conclusion We demonstrate a novel relationship between the gut microbiota and systemic inflammation in a TPN animal model. Pertinently, the degree of gut dysbiosis correlated with the severity of systemic inflammation. This study underscores the role of gut microbiota in driving liver injury mechanisms during TPN and supports a paradigm change in therapeutic targeting of the gut microbiota to mitigate TPN-related injury. KEY MESSAGES This study identified a differential link between gut microbiota and inflammation—the higher the dysbiosis, the worse the systemic inflammatory markers. Higher levels of Firmicutes species correlated with reduced inflammation.

Host adaptation in gut Firmicutes is associated with sporulation loss and altered transmission cycle

BackgroundHuman-to-human transmission of symbiotic, anaerobic bacteria is a fundamental evolutionary adaptation essential for membership of the human gut microbiota. However, despite its importance, the genomic and biological adaptations underpinning symbiont transmission remain poorly understood. The Firmicutes are a dominant phylum within the intestinal microbiota that are capable of producing resistant endospores that maintain viability within the environment and germinate within the intestine to facilitate transmission. However, the impact of host transmission on the evolutionary and adaptive processes within the intestinal microbiota remains unknown.ResultsWe analyze 1358 genomes of Firmicutes bacteria derived from host and environment-associated habitats. Characterization of genomes as spore-forming based on the presence of sporulation-predictive genes reveals multiple losses of sporulation in many distinct lineages. Loss of sporulation in gut Firmicutes is associated with features of host-adaptation such as genome reduction and specialized metabolic capabilities. Consistent with these data, analysis of 9966 gut metagenomes from adults around the world demonstrates that bacteria now incapable of sporulation are more abundant within individuals but less prevalent in the human population compared to spore-forming bacteria.ConclusionsOur results suggest host adaptation in gut Firmicutes is an evolutionary trade-off between transmission range and colonization abundance. We reveal host transmission as an underappreciated process that shapes the evolution, assembly, and functions of gut Firmicutes.

Reshaping of the gastrointestinal microbiome alters atherosclerotic plaque inflammation resolution in mice

Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe−/− mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe−/− mice, Abx– WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx+ WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx+ mice. By 16S rRNA sequence analysis, the Abx+ mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.

Psoriasis Is Associated With Elevated Gut IL-1α and Intestinal Microbiome Alterations.

BackgroundPsoriasis is a chronic inflammatory condition that predominantly affects the skin and is associated with extracutaneous disorders, such as inflammatory bowel disease and arthritis. Changes in gut immunology and microbiota are important drivers of proinflammatory disorders and could play a role in the pathogenesis of psoriasis. Therefore, we explored whether psoriasis in a Central Asian cohort is associated with alterations in select immunological markers and/or microbiota of the gut.MethodsWe undertook a case-control study of stool samples collected from outpatients, aged 30–45 years, of a dermatology clinic in Kazakhstan presenting with plaque, guttate, or palmoplantar psoriasis (n = 20), and age-sex matched subjects without psoriasis (n = 20). Stool supernatant was subjected to multiplex ELISA to assess the concentration of 47 cytokines and immunoglobulins and to 16S rRNA gene sequencing to characterize microbial diversity in both psoriasis participants and controls.ResultsThe psoriasis group tended to have higher concentrations of most analytes in stool (29/47 = 61.7%) and gut IL-1α was significantly elevated (4.19-fold, p = 0.007) compared to controls. Levels of gut IL-1α in the psoriasis participants remained significantly unaltered up to 3 months after the first sampling (p = 0.430). Psoriasis was associated with alterations in gut Firmicutes, including elevated Faecalibacterium and decreased Oscillibacter and Roseburia abundance, but no association was observed between gut microbial diversity or Firmicutes/Bacteroidetes ratios and disease status.ConclusionsPsoriasis may be associated with gut inflammation and dysbiosis. Studies are warranted to explore the use of gut microbiome-focused therapies in the management of psoriasis in this under-studied population.

Differences in the gut Firmicutes to Bacteroidetes ratio across age groups in healthy Ukrainian population

BackgroundGut microbiota plays an important role in physiological and pathological processes of the host organism, including aging. Microbiota composition was shown to vary significantly throughout the life course. Age-related changes in the composition of microbiota were reported in several human studies. In present study, age-related dynamics of phylogenetic profile of gut microbiota was investigated in 1550 healthy participants from Ukrainian population.ResultsSignificant changes in the microbiota composition determined by qRT-PCR at the level of major microbial phyla across age groups have been observed. The relative abundance of Actinobacteria and Firmicutes phyla increased, while that of Bacteroidetes decreased from childhood to elderly age. Accordingly, the Firmicutes/Bacteroidetes (F/B) ratio was shown to significantly increase until elder age. In both sexes, odds to have F/B > 1 tended to increase with age, reaching maximum values in elder age groups [OR = 2.7 (95% CI, 1.2–6.0) and OR = 3.7 (95% CI, 1.4–9.6) for female and male 60–69-year age groups, respectively, compared to same-sex reference (0–9-year) age groups].ConclusionsIn conclusion, data from our study indicate that composition of the human intestinal microbiota at the level of major microbial phyla significantly differs across age groups. In both sexes, the F/B ratio tends to increase with age from 0–9-year to 60–69-year age groups. Further studies are needed for a better understanding of mechanisms underlying age-related dynamics of human microbiota composition.

Gu-Ben-Fang-Xiao Decoction Ameliorated Murine Asthma in Remission Stage by Modulating Microbiota-Acetate-Tregs Axis.

Dysbiosis of gut microbiota is a critical factor in the pathogenesis of asthma. Manipulating gut microbiota is a promising therapeutic intervention in asthma, and is being extensively studied. Gu-Ben-Fang-Xiao Decoction (GBFXD), derived from traditional Chinese medicine, is an effective and safe therapeutic formula for asthma in remission stage (ARS). Herein, we showed that GBFXD treatment remarkably alleviated ARS by improving respiratory function and lung histopathology. Asthmatic mice displayed a dysbiosis of gut microbiota, represented by significantly increased abundance of Bacteroidetes and decreased abundance of Firmicutes in gut, while GBFXD treatment reversed the gut dysbiosis in asthmatic mice at phylum, family, and genus levels. Moreover, our data showed that GBFXD treatment increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in asthmatic mice, such as Firmicutes, Lachnospiraceae, and Bifidobacteriaceae, which consequently led to elevated levels of SCFAs. Furthermore, GBFXD treatment significantly enhanced the regulatory T cell differentiation via SCFAs, particularly acetate, in asthmatic mice. More critically, the protective effect of GBFXD was shown to be transmissible among asthmatic mice through co-housing microbiota transplantation. Antibiotic cocktail and acetate replenishment experiments also further substantiated the importance of SCFA-producing gut microbiota in GBFXD action. We, thus, demonstrated for the first time that gut microbiota dysbiosis existed in ARS. GBFXD could ameliorate ARS through the microbiota-acetate-Tregs axis.

Effect of partial black soldier fly (Hermetia illucens L.) larvae meal replacement of fish meal in practical diets on the growth, digestive enzyme and related gene expression for rice field eel (Monopterus albus)

A ten-week feeding trial on Monopterus albus (initial weight 24.02 ± 0.02 g) was conducted to evaluate effects of four isonitrogenous and isoenergetic diets in which different proportions of fish meal (0, 2.5 %, 5% and 7.5 %) were substituted with Hermetia illucens (HI) larvae meal, corresponding to dietary inclusion levels of 0 (FM), 5.26 % (HI5.26), 10.52 % (HI10.52) and 15.78 % (HI15.78). Compared with FM, weight gain rate and condition factor of M. albus and gumminess and adhesiveness of its muscle tissue were significantly increased in HI5.26 and HI10.52 groups (P < 0.05); whereas feed conversion ratio was markedly decreased in HI5.26 (P < 0.05), and expression of hepatic FASD2 and ME2 was significantly upregulated in HI5.26 (P < 0.05). Compared with FM, cohesiveness of muscle was significantly decreased in HI groups, but hardness of muscle and expression of hepatic FAS were remarkably upregulated in HI groups (P < 0.05); ACC and ME1 mRNA levels were significantly upregulated in HI10.52 (P < 0.05); CPT2 mRNA levels were significantly upregulated in HI5.26 and HI15.78 (P < 0.05); PPARγ, G6PD and HSL mRNA levels were significantly upregulated in HI10.52 and HI15.78 (P < 0.05). Springiness and chewiness of muscle, activity of intestinal lipasewere, serum indexes (glutamic oxalacetic transaminase, catalase, malondialdehyde), several gut bacterial indices (shannon, chao1, ACE, OTUs abundance of proteobacterias) and abundance of hepatic PPARα mRNA in HI15.78 were remarkably lower than those in FM (P < 0.05), while content of crude lipid, gut firmicutes and hepatic Dgat2 mRNA were significantly lower than FM (P < 0.05). Results showed that HI improved growth performance and balance of gut bacteria of M. albus when supplemented at a rate below 15.78 %, but negative effects on lipid metabolism were observed when HI was supplemented at excessive levels.

Novel Tn916-like elements confer aminoglycoside/macrolide co-resistance in clinical isolates of Streptococcus gallolyticus ssp. gallolyticus.

Streptococcus gallolyticus ssp. gallolyticus (Sgg) is a commensal bacterium and an opportunistic pathogen. In humans it has been clinically associated with the incidence of colorectal cancer (CRC) and epidemiologically recognized as an emerging cause of infective endocarditis (IE). The standard therapy of Sgg includes the administration of a penicillin in combination with an aminoglycoside. Even though penicillin-resistant isolates have still not been reported, epidemiological studies have shown that this microbe is a reservoir of multiple acquired genes, conferring resistance to tetracyclines, aminoglycosides, macrolides and glycopeptides. However, the underlying antibiotic resistance mobilome of Sgg remains poorly understood. To investigate the mobile genetic basis of antibiotic resistance in multiresistant clinical Sgg. Isolate NTS31106099 was recovered from a patient with IE and CRC at Nantes University Hospital, France and studied by Illumina WGS and comparative genomics. Molecular epidemiology of the identified mobile element(s) was performed using antibiotic susceptibility testing (AST), PCR, PFGE and WGS. Mobility was investigated by PCR and filter mating. Two novel conjugative transposons, Tn6263 and Tn6331, confer aminoglycoside/macrolide co-resistance in clinical Sgg. They display classical family Tn916/Tn1545 modular architecture and harbour an aph(3')-III→sat4→ant(6)-Ia→erm(B) multiresistance gene cluster, related to pRE25 of Enterococcus faecium. These and/or closely related elements are highly prevalent among genetically heterogeneous clinical isolates of Sgg. Previously unknown Tn916-like mobile genetic elements conferring aminoglycoside/macrolide co-resistance make Sgg, collectively with other gut Firmicutes such as enterococci and eubacteria, a potential laterally active reservoir of these antibiotic resistance determinants among the mammalian gastrointestinal microbiota.

Changes in Gut Microbiota May Be Early Signs of Liver Toxicity Induced by Epoxiconazole in Rats

Objective: The gut microbiome is essential for human health due to its effects on disease development, drug metabolism and the immune system. It may also play a role in the interaction with environmental toxicants. However, the effect of epoxiconazole, a fungicide active ingredient from the class of azoles developed to protect crops, on the abundance and composition of the gut microbiome has never been studied. We put forward the hypothesis that changes in gut microbiota may be early signs of toxicity induced by epoxiconazole. Methods: In this study, female rats were fed with epoxiconazole-adulterated diets (0, 4 and 100 mg/kg/day) for 90 days. The gut microbiome was determined by 16S rRNA gene sequencing. Body and organ weight, and blood biochemistry were also measured after 90 days of oral epoxiconazole exposure. Results: Interestingly, the abundance of gut Firmicutes decreased, and Bacteroidetes and Proteobacteria increased. At family level, Lachnospiraceae and Enterobacteriaceae were selectively enriched following epoxiconazole exposure. Our results indicate that epoxiconazole exposure may induce changes in the gut microbiome and potential liver toxicity. Conclusion: Changes in the gut microbiome may be used as early indicators for monitoring the health risk of the host.

Alternative Spermidine Biosynthetic Route Is Critical for Growth of Campylobacter jejuni and Is the Dominant Polyamine Pathway in Human Gut Microbiota

The availability of fully sequenced bacterial genomes has revealed that many species known to synthesize the polyamine spermidine lack the spermidine biosynthetic enzymes S-adenosylmethionine decarboxylase and spermidine synthase. We found that such species possess orthologues of the sym-norspermidine biosynthetic enzymes carboxynorspermidine dehydrogenase and carboxynorspermidine decarboxylase. By deleting these genes in the food-borne pathogen Campylobacter jejuni, we found that the carboxynorspermidine decarboxylase orthologue is responsible for synthesizing spermidine and not sym-norspermidine in vivo. In polyamine auxotrophic gene deletion strains of C. jejuni, growth is highly compromised but can be restored by exogenous sym-homospermidine and to a lesser extent by sym-norspermidine. The alternative spermidine biosynthetic pathway is present in many bacterial phyla and is the dominant spermidine route in the human gut, stomach, and oral microbiomes, and it appears to have supplanted the S-adenosylmethionine decarboxylase/spermidine synthase pathway in the gut microbiota. Approximately half of the gut Firmicutes species appear to be polyamine auxotrophs, but all encode the potABCD spermidine/putrescine transporter. Orthologues encoding carboxyspermidine dehydrogenase and carboxyspermidine decarboxylase are found clustered with an array of diverse putrescine biosynthetic genes in different bacterial genomes, consistent with a role in spermidine, rather than sym-norspermidine biosynthesis. Due to the pervasiveness of ε-proteobacteria in deep sea hydrothermal vents and to the ubiquity of the alternative spermidine biosynthetic pathway in that phylum, the carboxyspermidine route is also dominant in deep sea hydrothermal vents. The carboxyspermidine pathway for polyamine biosynthesis is found in diverse human pathogens, and this alternative spermidine biosynthetic route presents an attractive target for developing novel antimicrobial compounds.

Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla

The adult human distal gut microbial community is typically dominated by 2 bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here, we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from Eubacterium rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the Firmicutes possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling, high-resolution proteomic analysis, and biochemical assays of microbial-microbial and microbial-host interactions. B. thetaiotaomicron adapts to E. rectale by up-regulating expression of a variety of polysaccharide utilization loci encoding numerous glycoside hydrolases, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is used by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of its major bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.