Arrhythmic gut microbiome signatures for risk profiling of Type-2 Diabetes

Abstract

29To combat the epidemic increase in Type-2-Diabetes (T2D), risk factors need to be 30 identified. Diet, lifestyle and the gut microbiome are among the most important factors 31 affecting metabolic health. We demonstrate in 1,976 subjects of a prospective population 32 cohort that specific gut microbiota members show diurnal oscillations in their relative 33 abundance and we identified 13 taxa with disrupted rhythmicity in T2D. Prediction 34 models based on this signature classified T2D with an area under the curve of 73%. BMI 35 as microbiota-independent risk marker further improved diagnostic classification of T2D. 36 The validity of this arrhythmic risk signature to predict T2D was confirmed in 699 KORA 37 subjects five years after initial sampling. Shotgun metagenomic analysis linked 26 38 pathways associated with xenobiotic, amino acid, fatty acid, and taurine metabolism to 39 the diurnal oscillation of gut bacteria. In summary, we determined a cohort-specific risk 40 pattern of arrhythmic taxa which significantly contributes to the classification and 41 prediction of T2D, highlighting the importance of circadian rhythmicity of the 42 microbiome in targeting metabolic human diseases. 43 44 Main 45Increasing evidence links the human gut microbiome to metabolic health (1), and altered 46 microbial profiles are associated with obesity, insulin resistance, and Type-2-Diabetes (T2D) 47 (2-9). Population-based studies highlighted a significant degree of variability in inter-individual 48 microbiome differences (10, 11), regional effects (12), and drug-associated changes in the gut 49 microbiome (13, 14), which complicates the identification of disease-related microbial risk 50 factors. Despite extensive investigations of the role of the gut microbiome in metabolic 51 diseases, especially T2D, there is still no consensus on disease-related bacterial taxa with 52 diagnostic relevance. 53The circadian clock, which synchronizes daily food intake behaviour and metabolism with the 54 day and night cycle (15), has recently been proposed to influence microbial homeostasis (16). 55Daytime-dependent fluctuations were identified in both the oral and faecal microbiota (16, 17). 56Circadian rhythms in gut microbiota composition and function are sensitive to diet and feeding 57 patterns in murine models (16, 18). Although diet-induced obesity dampens cyclic microbial 58 fluctuations in rodents (18), and epidemiological studies continue to show associations between 59 circadian clock dysfunction due to modern lifestyle and T2D (reviewed in (19)), the clinical 60 relevance of daily microbial oscillations in human diseases is unclear and requires confirmation 61 in human population studies. 62To understand whether circadian rhythms affect microbiome features related to the onset and 63 progression of metabolic diseases, we considered the daytime of stool sampling in microbiota 64 analysis of a regionally confined prospective cohort (KORA). We provide the first 65 demonstration of robust diurnal oscillations in faecal microbiota...

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome

“…We conducted the largest single country genome-wide association analysis of microbial traits followed by Mendelian Randomization (MR) analysis to elucidate the genetic link between humans and their associated microbiota. Our study comprised five independent cohorts from German biobanks located in Northern Germany (Kiel, Schleswig-Holstein; PopGen 12 , n=724; FoCus, n=957), North-Eastern Germany (Greifswald, Mecklenburg-Western Pomerania; SHIP, n=2,029; SHIP-TREND, n=3,382), 13,14 and Southern Germany (Augsburg, Bavaria; KORA, n=1,864; 15,16 see Methods for details).…”

A time-restricted feeding intervention in children and adolescents with obesity: The TRansForm study protocol

“…In agreement, alterations in circadian systems may contribute to obesity-related complications in humans, including T2D and hypertension (29)(30)(31)(32)(33)(34)(35)(36). In recent years, several studies have unveiled a functional interaction between circadian rhythms and the gut microbiome that may influence host metabolism and glucose homeostasis (37)(38)(39)(40). The gut microbiome itself has been shown to be an important player in the development of obesity and T2D (41-43).…”

Diurnal rhythmicity of fecal microbiota and metabolite profiles in the first year of life: a randomized controlled interventional trial with infant formula

“…4E). Variation in abundance of metabolites and bacteria according to the sampling daytime was previously identified in adult populations 27,28 . To evaluate whether this also occurs in infants in the first year of life, we analyzed daytime-dependent fluctuations in metabolite abundance at age 3 months.…”

“…So far, circadian clock mechanisms were believed to be restricted to photosynthetic bacteria, such as cyanobacteria, but, in single bacterial cultures circadian oscillations were found in gene expression of non-photosynthetic Bacillus subtilis 24 and swarming behavior of the gut bacterium Klebsiella aerogenes 25 , suggesting the presence of endogenous circadian clocks in specific gut bacteria. In recent years, time-of-day dependent fluctuations in the abundance of certain gut bacterial species were shown at the individual and population level 26,27 . Growing evidence provides a link between loss of rhythmicity and disease pathology 27 .…”