Background and Aims Previous small studies have appraised the gut microbiome (GM) in steatosis, but large-scale studies are lacking. We studied the association of the GM diversity and composition,... Show moreBackground and Aims Previous small studies have appraised the gut microbiome (GM) in steatosis, but large-scale studies are lacking. We studied the association of the GM diversity and composition, plasma metabolites, predicted functional metagenomics, and steatosis.Approach and Results This is a cross-sectional analysis of the prospective population-based Rotterdam Study. We used 16S ribosomal RNA gene sequencing and determined taxonomy using the SILVA reference database. Alpha diversity and beta diversity were calculated using the Shannon diversity index and Bray-Curtis dissimilarities. Differences were tested across steatosis using permutational multivariate analysis of variance. Hepatic steatosis was diagnosed by ultrasonography. We subsequently selected genera using regularized regression. The functional metagenome was predicted based on the GM using Kyoto Encyclopedia of Genes and Genomes pathways. Serum metabolomics were assessed using high-throughput proton nuclear magnetic resonance. All analyses were adjusted for age, sex, body mass index, alcohol, diet, and proton-pump inhibitors. We included 1,355 participants, of whom 472 had steatosis. Alpha diversity was lower in steatosis (P = 1.1 center dot 10(-9)), and beta diversity varied across steatosis strata (P = 0.001). Lasso selected 37 genera of which three remained significantly associated after adjustment (Coprococcus3: beta = -65; Ruminococcus Gauvreauiigroup: beta = 62; and Ruminococcus Gnavusgroup: beta = 45, Q-value = 0.037). Predicted metagenome analyses revealed that pathways of secondary bile-acid synthesis and biotin metabolism were present, and D-alanine metabolism was absent in steatosis. Metabolic profiles showed positive associations for aromatic and branched chain amino acids and glycoprotein acetyls with steatosis and R. Gnavusgroup, whereas these metabolites were inversely associated with alpha diversity and Coprococcus3.Conclusions We confirmed, on a large-scale, the lower microbial diversity and association of Coprococcus and Ruminococcus Gnavus with steatosis. We additionally showed that steatosis and alpha diversity share opposite metabolic profiles. Show less
Dietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as... Show moreDietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as population-specific dietary patterns and NAFLD. Participants from two subsequent visits of the Rotterdam Study were included. All underwent serial abdominal ultrasonography (median follow-up: 4.4 years) and filled in a food frequency questionnaire. Secondary causes of steatosis were excluded. Dietary data from 389 items were collapsed into 28 food groups and a posteriori dietary patterns were identified using factor analysis. Additionally, we scored three a priori dietary patterns (Mediterranean Diet Score, Dutch Dietary Guidelines and WHO-score). Logistic mixed regression models were used to examine the relation between dietary patterns and NAFLD. Analyses were adjusted for demographic, lifestyle and metabolic factors. We included 963 participants of whom 343 had NAFLD. Follow-up data was available in 737 participants. Incident NAFLD was 5% and regressed NAFLD was 30%. We identified five a posteriori dietary patterns (cumulative explained variation [R-2] = 20%). The patterns were characterised as: vegetable and fish, red meat and alcohol, traditional, salty snacks and sauces, high fat dairy & refined grains pattern. Adherence to the traditional pattern (i.e. high intake of vegetable oils/stanols, margarines/butters, potatoes, whole grains and sweets/desserts) was associated with regression of NAFLD per SD increase in Z-score (0.40, 95% CI 0.15-1.00). Adherence to the three a priori patterns all showed regression of NAFLD, but only the WHO-score showed a distinct association (0.73, 95% CI 0.53-1.00). Hence, in this large elderly population, adherence to a plant-based, high-fibre and low-fat diet was related to regression of NAFLD. Show less
Dou, Y.Y.; Montfoort, N. van; Bosch, A. van den; Janssen, H.L.A.; Man, R.A. de; Buschow, S.I.; Woltman, A.M. 2019
The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional... Show moreThe plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-kappa B activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-kappa B in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-kappa B activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-kappa B activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-kappa B inhibition were comparable to control DCs, indicating that canonical NF-kappa B activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-kappa B inhibition during activation. In conclusion, canonical NF-kappa B activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses. The Journal of Immunology, 2010, 185: 7252-7261. Show less
