The Intestinal Microbiota and Short-Chain Fatty Acids in Association with Advanced Metrics of Glycemia and Adiposity Among Young Adults with Type 1 Diabetes and Overweight or Obesity

Daria Igudesman, Jamie Crandell, Karen D Corbin, Franklin Muntis, Dessi P Zaharieva, Anna Casu, Joan M Thomas, Cynthia M Bulik, Ian M Carroll, Brian W Pence, Richard E Pratley, Michael R Kosorok, David M Maahs, Elizabeth J Mayer-Davis, Daria Igudesman, Jamie Crandell, Karen D Corbin, Franklin Muntis, Dessi P Zaharieva, Anna Casu, Joan M Thomas, Cynthia M Bulik, Ian M Carroll, Brian W Pence, Richard E Pratley, Michael R Kosorok, David M Maahs, Elizabeth J Mayer-Davis

Abstract

Background: Comanagement of glycemia and adiposity is the cornerstone of cardiometabolic risk reduction in type 1 diabetes (T1D), but targets are often not met. The intestinal microbiota and microbiota-derived short-chain fatty acids (SCFAs) influence glycemia and adiposity but have not been sufficiently investigated in longstanding T1D.

Objectives: We evaluated the hypothesis that an increased abundance of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity were associated with improved glycemia but increased adiposity in young adults with longstanding T1D.

Methods: Participants provided stool samples at ≤4 time points (NCT03651622: https://ichgcp.net/clinical-trials-registry/NCT03651622). Sequencing of the 16S ribosomal RNA gene measured abundances of SCFA-producing intestinal microbes. GC-MS measured total and specific SCFAs (acetate, butyrate, propionate). DXA (body fat percentage and percentage lean mass) and anthropometrics (BMI) measured adiposity. Continuous glucose monitoring [percentage of time in range (70-180 mg/dL), above range (>180 mg/dL), and below range (54-69 mg/dL)] and glycated hemoglobin (i.e., HbA1c) assessed glycemia. Adjusted and Bonferroni-corrected generalized estimating equations modeled the associations of SCFA-producing gut microbes, fecal SCFAs, and intestinal microbial diversity with glycemia and adiposity. COVID-19 interrupted data collection, so models were repeated restricted to pre-COVID-19 visits.

Results: Data were available for ≤45 participants at 101 visits (including 40 participants at 54 visits pre-COVID-19). Abundance of Eubacterium hallii was associated inversely with BMI (all data). Pre-COVID-19, increased fecal propionate was associated with increased percentage of time above range and reduced percentage of time in target and below range; and abundances of 3 SCFA-producing taxa (Ruminococcus gnavus, Eubacterium ventriosum, and Lachnospira) were associated inversely with body fat percentage, of which two microbes were positively associated with percentage lean mass. Abundance of Anaerostipes was associated with reduced percentage of time in range (all data) and with increased body fat percentage and reduced percentage lean mass (pre-COVID-19).

Conclusions: Unexpectedly, fecal propionate was associated with detriment to glycemia, whereas most SCFA-producing intestinal microbes were associated with benefit to adiposity. Future studies should confirm these associations and determine their potential causal linkages in T1D.This study is registered at clinical.trials.gov (NCT03651622; https://ichgcp.net/clinical-trials-registry/NCT03651622).

Keywords: adiposity; body mass index; continuous glucose monitoring; dual-energy X-ray absorptiometry; glycemia; gut microbiota; hemoglobin A1c; short-chain fatty acids; type 1 diabetes.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Heatmaps with standardized β estimates from covariate-adjusted GEE models for associations of SCFA-producing microbes, fecal SCFAs, and α-diversity with glycemia and adiposity. (A) Results using all available data; (B) Results restricted to pre-COVID-19 data.P values were Bonferroni corrected and statistically significant at P  < 0.1 (denoted by asterisks). Units are micromoles per gram for SCFAs, normalized abundance for gen us-level intestinal microbes, and the number of unique taxa from the phylum to the genus level for intestinal microbial diversity. DXA was only performed prior to COVID-19. BFP, body fat percentage; GEE, generalized estimating equation; HbA1c, glycated hemoglobin; PLM, percentage lean mass; TAB, percentage of time above target glucose range (>180 mg/dL); TBR, percentage of time below target glucose range (54–69 mg/dL); TIR, percentage of time in target glucose range (70–180 mg/dL).
FIGURE 2
FIGURE 2
Scatterplots of raw pre-COVID-19 data for associations of fecal SCFAs with measures of glycemia that were statistically significant after adjustment for potential confounders and correction for multiple hypothesis testing. (A, B) Increased total fecal SCFAs and fecal propionate were associated with reduced percentage of time in target glucose range. (C, D) Increased fecal propionate was associated with reduced percentage of time above target glucose range (C) and percentage of time in clinical hypoglycemia (D).

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