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We describe the anaerobic conversion of inositol stereoisomers to propionate and acetate by the abundant intestinal genus Anaerostipes . A inositol pathway was elucidated by nuclear magnetic resonance using [ 13 C]-inositols, mass spectrometry and proteogenomic analyses in A. rhamnosivorans , identifying 3-oxoacid CoA transferase as a key enzyme involved in both 3-oxopropionyl-CoA and propionate formation. This pathway also allowed conversion of phytate-derived inositol into propionate as shown with [ 13 C]-phytate in fecal samples amended with A. rhamnosivorans . Metabolic and (meta)genomic analyses explained the adaptation of Anaerostipes spp. to inositol-containing substrates and identified a propionate-production gene cluster to be inversely associated with metabolic biomarkers in (pre)diabetes cohorts. Co-administration of myo-inositol with live A. rhamnosivorans in western-diet fed mice reduced fasting-glucose levels comparing to heat-killed A. rhamnosivorans after 6-weeks treatment. Altogether, these data suggest a potential beneficial role for intestinal Anaerostipes spp. in promoting host health. Here, the authors report an anaerobic metabolic pathway from the dominant gut butyrogen Anaerostipes , showing several strains of this genus to be capable of producing propionate from dietary myo-inositol that associates with reduced fasting-glucose levels in mice.

The human microbiome functions as a separate organ in a symbiotic relationship with the host. Disruption of this host–microbe symbiosis can lead to serious health problems. Modifications to the composition and function of the microbiome have been linked to changes in host metabolic outcomes. Industrial lifestyles with high consumption of processed foods, alcoholic beverages and antibiotic use have significantly altered the gut microbiome in unfavorable ways. Therefore, understanding the causal relationship between the human microbiome and host metabolism will provide important insights into how we can better intervene in metabolic health. In this review, I will discuss the potential use of the human microbiome as a therapeutic target to improve host metabolism.

Human intestinal bacteria produce butyrate, which has signalling properties and can be used as energy source by enterocytes thus influencing colonic health. However, the pathways and the identity of bacteria involved in this process remain unclear. Here we describe the isolation from the human intestine of Intestinimonas strain AF211, a bacterium that can convert lysine stoichiometrically into butyrate and acetate when grown in a synthetic medium. Intestinimonas AF211 also converts the Amadori product fructoselysine, which is abundantly formed in heated foods via the Maillard reaction, into butyrate. The butyrogenic pathway includes a specific CoA transferase that is overproduced during growth on lysine. Bacteria related to Intestinimonas AF211 as well as the genetic coding capacity for fructoselysine conversion are abundantly present in colonic samples from some healthy human subjects. Our results indicate that protein can serve as a source of butyrate in the human colon, and its conversion by Intestinimonas AF211 and related butyrogens may protect the host from the undesired side effects of Amadori reaction products. Bacterial production of butyrate in the gut is associated with a healthy colon. Here the authors isolate an Intestinimonas strain from the human gut that can produce butyrate from lysine and fructoselysine, a potentially harmful compound formed in heated foods.

Background Akkermansia muciniphila is a human gut microbe with a key role in the physiology of the intestinal mucus layer and reported associations with decreased body mass and increased gut barrier function and health. Despite its biomedical relevance, the genomic diversity of A. muciniphila remains understudied and that of closely related species, except for A. glycaniphila , unexplored. Results We present a large-scale population genomics analysis of the Akkermansia genus using 188 isolate genomes and 2226 genomes assembled from 18,600 metagenomes from humans and other animals. While we do not detect A. glycaniphila , the Akkermansia strains in the human gut can be grouped into five distinct candidate species, including A. muciniphila , that show remarkable whole-genome divergence despite surprisingly similar 16S rRNA gene sequences. These candidate species are likely human-specific, as they are detected in mice and non-human primates almost exclusively when kept in captivity. In humans, Akkermansia candidate species display ecological co-exclusion, diversified functional capabilities, and distinct patterns of associations with host body mass. Analysis of CRISPR-Cas loci reveals new variants and spacers targeting newly discovered putative bacteriophages. Remarkably, we observe an increased relative abundance of Akkermansia when cognate predicted bacteriophages are present, suggesting ecological interactions. A. muciniphila further exhibits subspecies-level genetic stratification with associated functional differences such as a putative exo/lipopolysaccharide operon. Conclusions We uncover a large phylogenetic and functional diversity of the Akkermansia genus in humans. This variability should be considered in the ongoing experimental and metagenomic efforts to characterize the health-associated properties of A. muciniphila and related bacteria.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent liver disorder driven by metabolic dysregulation and inflammation. Recent studies highlight the importance of the gut microbiome as a key contributor to this pathology through its ability to ferment dietary sugars into ethanol, a metabolite previously overlooked in MASLD. In this review, we discuss the role of the gut microbiome in MASLD, covering functional and compositional shifts observed in the disease; we dive into the different microbial pathways of ethanol synthesis, hepatic mechanisms of ethanol clearance, and pathological consequences. We also discuss the role of a healthy microbiome in the clearance of ethanol in the gut and how microbiome-based strategies could be beneficial in targeting endogenous production of ethanol, going from the traditional probiotic–prebiotic combination to discussing new approaches.

The gut microbiome is strongly implicated in the development of obesity and type 2 diabetes mellitus (T2DM). A recent study demonstrated that 6-week oral supplementation of Anaerostipes rhamnosivorans (ARHAM) combined with the prebiotic myo-inositol (MI) reduced fasting glucose levels in mice. In the present study, we investigated the effects of a 13-week ARHAM-MI supplementation in high-fat diet-fed mice and examined the metabolic fate of MI, including its microbial conversion into short-chain fatty acids (SCFAs), using 13C-MI and stable isotope tracers in the cecum, portal vein, and peripheral blood. The results showed that the ARHAM-MI group gained less weight than the MI-only and placebo groups. Analysis of intestinal mRNA and stable isotope tracing revealed that MI is primarily absorbed in the upper gastrointestinal tract, whereas microbial conversion to SCFAs predominantly occurs in the cecum and is enhanced by ARHAM. ARHAM-MI mice also showed increased cecal Gpr43 mRNA expression, indicating enhanced SCFA-mediated signaling. Notably, SCFAs derived from MI displayed distinct distribution patterns: 13C-butyrate was detected exclusively in the cecum, 13C-propionate was present in the cecum and portal vein, whereas 13C-acetate was the only SCFA detected in peripheral blood. Collectively, ARHAM-MI co-supplementation confers modest metabolic benefits in high-fat diet-fed mice, underscoring the need to optimize the dosage and administration frequency of ARHAM-MI to enhance its therapeutic efficacy.

Background The human gut microbiome strongly influences host metabolism by fermenting dietary components into metabolites that signal to the host. Our previous work has shown that Intestinimonas butyriciproducens is a prevalent commensal bacterium with the unique ability to convert dietary fructoselysine to butyrate, a well-known signaling molecule with proven health benefits. Dietary fructoselysine is an abundant Amadori product formed in foods during thermal treatment and is part of foods rich in dietary advanced glycation end products which have been associated with cardiometabolic disease. It is therefore of interest to investigate the causal role of this bacterium and fructoselysine metabolism in metabolic disorders. Results We assessed associations of I. butyriciproducens with metabolic risk biomarkers at both strain and functional levels using a human cohort characterized by fecal metagenomic analysis. We observed that the level of the bacterial strain as well as fructoselysine fermentation genes were negatively associated with BMI, triglycerides, HbA1c, and fasting insulin levels. We also investigated the fructoselysine degradation capacity within the Intestinimonas genus using a culture-dependent approach and found that I. butyriciproducens is a key player in the butyrogenic fructoselysine metabolism in the gut. To investigate the function of I. butyriciproducens in host metabolism, we used the diet-induced obesity mouse model to mimic the human metabolic syndrome. Oral supplementation with I. butyriciproducens counteracted body weight gain, hyperglycemia, and adiposity. In addition, within the inguinal white adipose tissue, bacterial administration reduced inflammation and promoted pathways involved in browning and insulin signaling. The observed effects may be partly attributable to the formation of the short-chain fatty acids butyrate from dietary fructoselysine, as butyrate plasma and cecal levels were significantly increased by the bacterial strain, thereby contributing to the systemic effects of the bacterial treatment. Conclusions I.  butyriciproducens ameliorates host metabolism in the context of obesity and may therefore be a good candidate for new microbiota-therapeutic approaches to prevent or treat metabolic diseases. 2sp35VedkE5U1snFjpYbsA Video Abstract

We investigated the impact of dried chicory root in a randomised, placebo-controlled trial with 55 subjects at risk for type 2 diabetes on bowel function, gut microbiota and its products, and glucose homeostasis. The treatment increased stool softness (+1.1 ± 0.3 units; p =  0.034) and frequency (+0.6 ± 0.2 defecations/day; p  < 0.001), strongly modulated gut microbiota composition (7 % variation; p =  0.001), and dramatically increased relative levels (3-4-fold) of Anaerostipes and Bifidobacterium spp., in a dose-dependent, reversible manner. A synthetic community, including selected members of these genera and a Bacteroides strain, generated a butyrogenic trophic chain from the product. Faecal acetate, propionate and butyrate increased by 25.8 % (+13.0 ± 6.3 mmol/kg; p  = 0.023) as did their fasting circulating levels by 15.7 % (+7.7 ± 3.9 μM; p =  0.057). In the treatment group the glycaemic coefficient of variation decreased from 21.3 ± 0.94 to 18.3 ± 0.84 % ( p =  0.004), whereas fasting glucose and HOMA-ir decreased in subjects with low baseline Blautia levels (−0.3 ± 0.1 mmol/L fasting glucose; p =  0.0187; −0.14 ± 0.1 HOMA-ir; p =  0.045). Dried chicory root intake rapidly and reversibly affects bowel function, benefits butyrogenic trophic chains, and promotes glycaemic control.

Dietary intake of phytate has various reported health benefits. Previous work showed that the gut microbiota can convert phytate to short-chain fatty acids (SCFAs), but the microbial species and metabolic pathway are unclear. Here we identified Mitsuokella jalaludinii as an efficient phytate degrader, which works synergistically with Anaerostipes rhamnosivorans to produce the SCFA propionate. Analysis of published human gut taxonomic profiles revealed that Mitsuokella spp., in particular M. jalaludinii , are prevalent in human gut microbiomes. NMR spectroscopy using 13 C-isotope labelling, metabolomic and transcriptomic analyses identified a complete phytate degradation pathway in M. jalaludinii , including production of the intermediate Ins(2)P/ myo -inositol. The major end product, 3-hydroxypropionate, was converted into propionate via a synergistic interaction with Anaerostipes rhamnosivorans both in vitro and in mice. Upon [ 13 C 6 ]phytate administration, various 13 C-labelled components were detected in mouse caecum in contrast with the absence of [ 13 C 6 ] InsPs or [ 13 C 6 ] myo -inositol in plasma. Caco-2 cells incubated with co-culture supernatants exhibited improved intestinal barrier integrity. These results suggest that the microbiome plays a major role in the metabolism of this phytochemical and that its fermentation to propionate by M. jalaludinii and A. rhamnosivorans may contribute to phytate-driven health benefits. Mitsuokella jalaludinii and Anaerostipes rhamnosivorans degrade dietary phytate via synergistic interactions in the gut to produce the beneficial short-chain fatty acid propionate.