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Most archaea divide by binary fission using an FtsZ-based system similar to that of bacteria, but they lack many of the divisome components described in model bacterial organisms. Notably, among the multiple factors that tether FtsZ to the membrane during bacterial cell constriction, archaea only possess SepF-like homologs. Here, we combine structural, cellular, and evolutionary analyses to demonstrate that SepF is the FtsZ anchor in the human-associated archaeon Methanobrevibacter smithii . 3D super-resolution microscopy and quantitative analysis of immunolabeled cells show that SepF transiently co-localizes with FtsZ at the septum and possibly primes the future division plane. M. smithii SepF binds to membranes and to FtsZ, inducing filament bundling. High-resolution crystal structures of archaeal SepF alone and in complex with the FtsZ C-terminal domain (FtsZ CTD ) reveal that SepF forms a dimer with a homodimerization interface driving a binding mode that is different from that previously reported in bacteria. Phylogenetic analyses of SepF and FtsZ from bacteria and archaea indicate that the two proteins may date back to the Last Universal Common Ancestor (LUCA), and we speculate that the archaeal mode of SepF/FtsZ interaction might reflect an ancestral feature. Our results provide insights into the mechanisms of archaeal cell division and pave the way for a better understanding of the processes underlying the divide between the two prokaryotic domains. Most archaea divide by binary fission using an FtsZ-based system that is poorly understood. Here, the authors combine structural, cellular, and evolutionary analyses to show that the SepF protein acts as the FtsZ anchor in the archaeon Methanobrevibacter smithii .

Methanogens are anaerobic prokaryotes from the domain archaea that utilize hydrogen to reduce carbon dioxide, acetate, and a variety of methyl compounds into methane. Earlier believed to inhabit only the extreme environments, these organisms are now reported to be found in various environments including mesophilic habitats and the human body. The biological significance of methanogens for humans has been re-evaluated in the last few decades. Their contribution towards pathogenicity has received much less attention than their bacterial counterparts. In humans, methanogens have been studied in the gastrointestinal tract, mouth, and vagina, and considerable focus has shifted towards elucidating their possible role in the progression of disease conditions in humans. Methanoarchaea are also part of the human skin microbiome and proposed to play a role in ammonia turnover. Compared to hundreds of different bacterial species, the human body harbors only a handful of methanogen species represented by Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, Methanomassiliicoccus luminyensis, Candidatus Methanomassiliicoccus intestinalis, and Candidatus Methanomethylophilus alvus. Their presence in the human gut suggests an indirect correlation with severe diseases of the colon. In this review, we examine the current knowledge about the methanoarchaea in the human body and possible beneficial or less favorable interactions.

Genus and species level analysis is the best way to characterize alterations in the human gut microbiota that are associated with obesity, because the clustering of obese and lean microbiotas increases with the taxonomic depth of the analysis. Bifidobacterium genus members have been associated with a lean status, whereas different Lactobacillus species are associated both with a lean and an obese status. OBJECTIVES AND METHODS: We analyzed the fecal concentrations of Bacteroidetes, Firmicutes, Methanobrevibacter smithii, the genus Lactobacillus, five other Lactobacillus species previously linked with lean or obese populations, Escherichia coli and Bifidobacterium animalis in 263 individuals, including 134 obese, 38 overweight, 76 lean and 15 anorexic subjects to test for the correlation between bacterial concentration and body mass index (BMI). Of these subjects, 137 were used in our previous study. FINDINGS: Firmicutes were found in 498.5%, Bacteroidetes in 67%, M. smithii in 64%, E. coli in 51%, Lactobacillus species between 17 and 25% and B. animalis in 11% of individuals. The fecal concentration of Lactobacillus reuteri was positively correlated with BMI (coefficient ¼ 0.85; 95% confidence interval (CI) 0.12–0.58; P ¼ 0.02) in agreement with what was reported for Lactobacillus sakei. As reported, B. animalis (coefficient ¼ À 0.84; 95% CI À 1.61 to À 0.07; P ¼ 0.03) and M. smithii (coefficient ¼ À 0.43, 95% CI À 0.90 to 0.05; P ¼ 0.08) were negatively associated with the BMI. Unexpectedly, E. coli was found here for the first time to negatively correlate with the BMI (coefficient ¼ À 1.05; 95% CI À 1.60 to À 0.50; Po0.001). CONCLUSION: Our findings confirm the specificity of the obese microbiota and emphasize the correlation between the concentration of certain Lactobacillus species and obesity.

Obesity is associated with increased health risk and has been associated with alterations in bacterial gut microbiota, with mainly a reduction in Bacteroidetes, but few data exist at the genus and species level. It has been reported that the Lactobacillus and Bifidobacterium genus representatives may have a critical role in weight regulation as an anti-obesity effect in experimental models and humans, or as a growth-promoter effect in agriculture depending on the strains. To confirm reported gut alterations and test whether Lactobacillus or Bifidobacterium species found in the human gut are associated with obesity or lean status, we analyzed the stools of 68 obese and 47 controls targeting Firmicutes, Bacteroidetes, Methanobrevibacter smithii, Lactococcus lactis, Bifidobacterium animalis and seven species of Lactobacillus by quantitative PCR (qPCR) and culture on a Lactobacillus-selective medium. In qPCR, B. animalis (odds ratio (OR)=0.63; 95% confidence interval (CI) 0.39-1.01; P=0.056) and M. smithii (OR=0.76; 95% CI 0.59-0.97; P=0.03) were associated with normal weight whereas Lactobacillus reuteri (OR=1.79; 95% CI 1.03-3.10; P=0.04) was associated with obesity. The gut microbiota associated with human obesity is depleted in M. smithii. Some Bifidobacterium or Lactobacillus species were associated with normal weight (B. animalis) while others (L. reuteri) were associated with obesity. Therefore, gut microbiota composition at the species level is related to body weight and obesity, which might be of relevance for further studies and the management of obesity. These results must be considered cautiously because it is the first study to date that links specific species of Lactobacillus with obesity in humans.

The human gut is colonized by trillions of microbes that influence the health of their human host. Whereas many bacterial species have now been linked to a variety of different diseases, the involvement of Archaea, an evolutionarily distinct group of microbes, in human disease remains elusive. By analyzing 19 independent clinical studies, we demonstrate that associations between Archaea and human diseases are widespread yet highly heterogeneous, with a pronounced and consistent enrichment of Methanobrevibacter smithii in colorectal cancer (CRC) patients. Metabolic modelling and in vitro co-culture identified distinct mutualistic interactions of M. smithii with CRC-causing bacteria such as Fusobacterium nucleatum , including metabolic enhancement. Metabolomics further reveal archaeal-derived compounds with tumor-modulating properties. Together, our results provide mechanistic insights into how the human gut archaeome may participate in CRC-associated microbial networks through metabolic cooperation with bacteria. Here, the authors identify widespread disease associations of gut archaea, particularly in colorectal cancer, with further experiments revealing Methanobrevibacter smithii cooperation with cancer-associated bacteria and co-production of metabolites with tumor-modulating potential.

The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise indigestible dietary polysaccharides. The products of polysaccharide fermentation include short-chain fatty acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41-/- and Gpr41+/+ mice that were either conventionally-raised with a complete gut microbiota or were reared germ-free and then cocolonized as young adults with two prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methanobrevibacter smithii. Both conventionally-raised and gnotobiotic Gpr41-/- mice colonized with the model fermentative community are significantly leaner and weigh less than their WT (+/+) littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic studies of germ-free and cocolonized Gpr41-/- and +/+ littermates disclosed that Gpr41-deficiency is associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet. These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent upon the gut microbiota.

Studies of the bacterial communities of the gut microbiota have revealed a shift in the ratio of Firmicutes and Bacteroidetes in obese patients. Determining the variations of microbial communities in feces may be beneficial for the identification of specific profiles in patients with abnormal weights. The roles of the archaeon Methanobrevibacter smithii and Lactobacillus species have not been described in these studies. We developed an efficient and robust real-time PCR tool that includes a plasmid-based internal control and allows for quantification of the bacterial divisions Bacteroidetes, Firmicutes, and Lactobacillus as well as the methanogen M. smithii. We applied this technique to the feces of 20 obese subjects, 9 patients with anorexia nervosa, and 20 normal-weight healthy controls. Our results confirmed a reduction in the Bacteroidetes community in obese patients (p<0.01). We found a significantly higher Lactobacillus species concentration in obese patients than in lean controls (p=0.0197) or anorexic patients (p=0.0332). The M. smithii concentration was much higher in anorexic patients than in the lean population (p=0.0171). Lactobacillus species are widely used as growth promoters in the farm industry and are now linked to obesity in humans. The study of the bacterial flora in anorexic patients revealed an increase in M. smithii. This increase might represent an adaptive use of nutrients in this population.

Abstract Gut microbial dysbiosis has been shown to be an instrumental factor in severe acute malnutrition (SAM) and particularly, the absence of Methanobrevibacter smithii, a key player in energy harvest. Nevertheless, it remains unknown whether this absence reflects an immaturity or a loss of the microbiota. In order to assess that, we performed a case–control study in Mali using a propensity score weighting approach. The presence of M. smithii was tested using quantitative PCR on faeces collected from SAM children at inclusion and at discharge when possible or at day 15 for controls. M. smithii was highly significantly associated with the absence of SAM, detected in 40.9% controls but only in 4.2% cases (p < 0.0001). The predictive positive value for detection of M. smithii gradually increased with age in controls while decreasing in cases. Among children providing two samples with a negative first sample, no SAM children became positive, while this proportion was 2/4 in controls (p = 0.0015). This data suggests that gut dysbiosis in SAM is not an immaturity but rather features a loss of M. smithii . The addition of M. smithii as a probiotic may thus represent an important addition to therapeutic approaches to restore gut symbiosis.

A mechanistic link between trimethylamine N-oxide (TMAO) and atherogenesis has been reported. TMAO is generated enzymatically in the liver by the oxidation of trimethylamine (TMA), which is produced from dietary choline, carnitine and betaine by gut bacteria. It is known that certain members of methanogenic archaea (MA) could use methylated amines such as trimethylamine as growth substrates in culture. Therefore, we investigated the efficacy of gut colonization with MA on lowering plasma TMAO concentrations. Initially, we screened for the colonization potential and TMAO lowering efficacy of five MA species in C57BL/6 mice fed with high choline/TMA supplemented diet, and found out that all five species could colonize and lover plasma TMAO levels, although with different efficacies. The top performing MA, Methanobrevibacter smithii , Methanosarcina mazei , and Methanomicrococcus blatticola , were transplanted into Apoe −/− mice fed with high choline/TMA supplemented diet. Similar to C57BL/6 mice, following initial provision of the MA, there was progressive attrition of MA within fecal microbial communities post-transplantation during the initial 3 weeks of the study. In general, plasma TMAO concentrations decreased significantly in proportion to the level of MA colonization. In a subsequent experiment, use of antibiotics and repeated transplantation of Apoe −/− mice with M . smithii , led to high engraftment levels during the 9 weeks of the study, resulting in a sustained and significantly lower average plasma TMAO concentrations (18.2 ± 19.6 μM) compared to that in mock-transplanted control mice (120.8 ± 13.0 μM, p < 0.001). Compared to control Apoe −/− mice, M . smithii -colonized mice also had a 44% decrease in aortic plaque area (8,570 μm [95% CI 19587–151821] vs. 15,369 μm [95% CI [70058–237321], p = 0.34), and 52% reduction in the fat content in the atherosclerotic plaques (14,283 μm [95% CI 4,957–23,608] vs. 29,870 μm [95% CI 18,074–41,666], p = 0.10), although these differences did not reach significance. Gut colonization with M . smithii leads to a significant reduction in plasma TMAO levels, with a tendency for attenuation of atherosclerosis burden in Apoe −/− mice. The anti-atherogenic potential of MA should be further tested in adequately powered experiments.

The human gut microbiota is a complex ecosystem that affects a range of human physiology. In order to explore the dynamics of the human gut microbiota, we used a system of ordinary differential equations to model mathematically the biomass of three microorganism populations: Bacteroides thetaiotaomicron , Eubacterium rectale , and Methanobrevibacter smithii . Additionally, we modeled the concentrations of relevant nutrients necessary to sustain these populations over time. Our model highlights the interactions and the competition among these three species. These three microorganisms were specifically chosen due to the system’s end product, butyrate, which is a short chain fatty acid that aids in developing and maintaining the intestinal barrier in the human gut. The basis of our mathematical model assumes the gut is structured such that bacteria and nutrients exit the gut at a rate proportional to its volume, the rate of volumetric flow, and the biomass or concentration of the particular population or nutrient. We performed global sensitivity analyses using Sobol’ sensitivities to estimate the relative importance of model parameters on simulation results.