Sex-Specific Associations between Gut Microbiome and Non-Alcoholic Fatty Liver Disease among Urban Chinese Adults

Non-alcoholic fatty liver disease (NAFLD) has been linked to altered gut microbiome; however, evidence from large population-based studies is limited. We compared gut microbiome profiles of 188 male and 233 female NAFLD cases with 571 male and 567 female controls from two longitudinal studies of urban Chinese adults. History of NAFLD was assessed during surveys administered in 2004–2017. Microbiota were assessed using 16S rRNA sequencing of stool samples collected in 2015–2018. Associations of NAFLD with microbiome diversity and composition were evaluated by generalized linear or logistic regression models. Compared with controls, male cases had lower microbial α-diversity, higher abundance of genera Dialister and Streptococcus and Bifidobacterium species, lower abundance of genus Phascolarctobacterium, and lower prevalence of taxa including order RF39 (all p < 0.05). In contrast, female cases had higher α-diversity, higher abundance of genus Butyricimonas and a family of order Clostridiales, lower abundance of Dialister and Bifidobacterium species, and higher prevalence of RF39. Significant NAFLD–sex interactions were found for α-diversity and above taxa (all false discovery rate < 0.1). In conclusion, we observed sex-specific gut microbiome features related to history of NAFLD. Further studies are needed to validate our findings and evaluate the health effects of NAFLD-related gut microbiota.

Human Milk Oligosaccharide-Stimulated Bifidobacterium Species Contribute to Prevent Later Respiratory Tract Infections

(1) Background: Human milk oligosaccharides (HMOs) may support immune protection, partly via their action on the early-life gut microbiota. Exploratory findings of a randomized placebo-controlled trial associated 2′fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) formula feeding with reduced risk for reported bronchitis and lower respiratory tract illnesses (LRTI), as well as changes in gut microbiota composition. We sought to identify putative gut microbial mechanisms linked with these clinical observations. (2) Methods: We used stool microbiota composition, metabolites including organic acids and gut health markers in several machine-learning-based classification tools related prospectively to experiencing reported bronchitis or LRTI, as compared to no reported respiratory illness. We performed preclinical epithelial barrier function modelling to add mechanistic insight to these clinical observations. (3) Results: Among the main features discriminant for infants who did not experience any reported bronchitis (n = 80/106) or LRTI (n = 70/103) were the 2-HMO formula containing 2′FL and LNnT, higher acetate, fucosylated glycans and Bifidobacterium, as well as lower succinate, butyrate, propionate and 5-aminovalerate, along with Carnobacteriaceae members and Escherichia. Acetate correlated with several Bifidobacterium species. By univariate analysis, infants experiencing no bronchitis or LRTI, compared with those who did, showed higher acetate (p < 0.007) and B. longum subsp. infantis (p ≤ 0.03). In vitro experiments demonstrate that 2′FL, LNnT and lacto-N-tetraose (LNT) stimulated B. longum subsp. infantis (ATCC15697) metabolic activity. Metabolites in spent culture media, primarily due to acetate, supported epithelial barrier protection. (4) Conclusions: An early-life gut ecology characterized by Bifidobacterium-species-driven metabolic changes partly explains the observed clinical outcomes of reduced risk for bronchitis and LRTI in infants fed a formula with HMOs. (Trial registry number NCT01715246.)

A multiscale spatiotemporal model explains succession in the early infant gut microbiota as a switch from aerobic to anaerobic metabolism

The human intestinal microbiome starts to form immediately after birth, and can greatly influence the health of the infant. During the first days facultative anaerobic species generally dominate, followed by a dominance of strictly anaerobic species, particularly Bifidobacterium species. An early transition to Bifidobacterium is associated with health benefits. To study the mechanisms of this transition and its hypothesised relation to oxygen, we introduce a multiscale mathematical model that considers metabolism, spatial bacterial population dynamics and resource sharing. Based on publicly available metabolic network data, the model predicts that differences in oxygen availability explain some of the observed individual variation in succession to anaerobic species. The model also predicts that anaerobic Bifidobacterium species become dominant through metabolizing lactose with a suboptimal yield, but a higher anaerobic growth rate than its competitors. The current work is the first step towards a more comprehensive understanding of the formation of a steady state adult colonic microbiota.

Regulation of Alcohol and Acetaldehyde Metabolism by a Mixture of Lactobacillus and Bifidobacterium Species in Human

Excessive alcohol consumption is one of the most significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). There are two major ALDH isoforms, cytosolic and mitochondrial, encoded by ALDH1 and ALDH2 genes, respectively. The ALDH2 polymorphism is associated with flushing response to alcohol use. Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. A randomized, double-blind, placebo-controlled crossover clinical trial was designed to study the effects of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number of heterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde were significantly downregulated by probiotic supplementation in subjects with ALDH2*2/*1 genotype, but not in those with ALDH2*1/*1 genotype. However, there were no marked improvements in hangover score parameters between test and placebo groups. No clinically significant changes were observed in safety parameters. These results suggest that Duolac ProAP4 has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.

Regulation of Alcohol and Acetaldehyde Metabolism by a Mixture of Lactobacillus and Bifidobacterium Species in Human

Excessive alcohol consumption is one of the significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. This study involves supplementation of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number ofheterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde in the ALDH2 heterozygote group were significantly downregulated in the probiotic-supplemented group with no changes in hangover score symptoms than the placebo group. No clinically significant changes were observed in safety parameters. These results suggest that probiotic has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.

Gene–Phenotype Associations Involving Human-Residential Bifidobacteria (HRB) Reveal Significant Species- and Strain-Specificity in Carbohydrate Catabolism

Bifidobacteria are among the first colonizers of the human gastrointestinal tract. Different bacterial species use different mechanisms for utilization of various carbon sources in order to establish themselves in the complex microbial ecosystem of the gut. However, these mechanisms still need to be explored. Here, a large gene–phenotype correlation analysis was carried out to explore the metabolic and genetic diversity of bifidobacterial carbohydrate utilization abilities. In this study, we used 21 different carbohydrates to determine the growth phenotypes, the distribution of glycoside hydrolases (GHs), and gene clusters related to the utilization of multiple carbon sources in six human-residential Bifidobacterium species. Five carbohydrates significantly stimulated growth of almost all strains, while the remaining sugars exhibited species- and strain-specificity. Correspondingly, different Bifidobacterium species also had specific GHs involved in fermentation of plant or host glycans. Moreover, we analyzed several carbohydrate utilization gene clusters, such as 2-fucosyllactose (2′FL), sialic acid (SA), and fructooligosaccharide (FOS). In summary, by using 217 bifidobacterial strains and a wide range of growth substrates, our research revealed inter- and intra-species differences in bifidobacterial in terms of carbohydrate utilization. The findings of this study are useful for the process of developing prebiotics for optimum growth of probiotics, especially Bifidobacterium species.