## 4 Discussion

Table 3: Prevalence ratios of fecal butyrate concentrations and gut microbiota diversity for obesity, central obesity, and hypertension with robust 95% confidence intervals according to tertiles of fecal butyrate and OTU richness, a measures of gut microbiota diversity. demonstrated that rates of acetate absorption and excretion are inversely correlated. Intestinal absorption of SCFAs is a function of transit time [35] and expression of SCFA transporters in the gut epithelium [2]. Inhibition of SCFA production and absorption may result in diarrhea [36], which is consistent with our own results (Table S3). The studies that have measured SCFAs in circulation, as compared to stool, have come to somewhat different conclusions with respect to the association of SCFAs with obesity and cardiometabolic health. [PERSON] et al. found that obese individuals have lower concentrations of propionate and butyrate in plasma compared to lean individuals [37]. Furthermore, in a cross-sectional study of 18 obese women, [PERSON] et al. found that serum concentrations of acetate, but not propionate or butyrate, were inversely associated with fasting and 2-h insulin levels and visceral adipose tissue [38]. Human trials and experimental murine models have shown that increasing SCFAs through a high-fiber diet or direct supplementation may have beneficial health effects. In a randomized trial of 43 type 2 diabetic patients, [PERSON] et al. found that a high-fiber diet vs. an isocaloric control diet increased fecal butyrate concentrations, while also improving fasting glucose, insulin, and HbA1c [39]. In mice, butyrate supplementation was shown to prevent insulin resistance and obesity [40], via a PPAR-dependent switch from lipogenesis to fat oxidation [41], and to reduce high-fat diet-induced intestinal barrier dysfunction and metabolic alterations, including hepatic steatosis [42]. To the best of our knowledge, we are the first to show that higher fecal SCFA excretion is associated with a measure of gut permeability. LBP is a biomarker of bacterial-derived LPS translocation from the gut to the periphery and higher serum LBP levels are thought to reflect gut permeability [43] and metabolic endotoxin [44]. In our study, serum LBP was positively correlated with adiposity and cardiometabolic risk factors. However, when further adjusted our models for LBP, associations were only modestly attenuated (Table 3), indicating this measure of gut barrier function does not fully explain the association of higher fecal SCFA excretion with excess adiposity and cardiometabolic dysfunction. Nevertheless, we provide evidence that gut microbiota dysbiosis, gut permeability, and the excretion of fecal SCFAs may be biologically related. Previous studies have found that disruption of the intestinal barrier eliminates epithelial hypoxia, increasing the amount of oxygen emanating from the colonic surface [45; 5], and favoring the expansion of facultative anaerobic pathobionts [46; 47]. In our study, individuals with high fecal SCFAs, obesity, and cardiometabolic disease risk factors showed signs of dysbiosis, including lower gut microbiota diversity and higher abundance of disease-associated microbial taxa: _Enterobacter hormaechei_[46], _Haemophilus parainfluenzae_[46; 48], _Streptococcus_[48], and _SMB53_[49]. On the other hand, participants with lower fecal SCFA excretion had a diverse microbiome, enriched in beneficial microbes including _Akkermansia muciniphila_, a taxon involved in maintaining the integrity of the mucin layer [50]; _Christensenelaceae, Methanobrevibacter_ and _Oscillospira_, taxa associated with lower BMI [51; 52; 53] and weight reduction [54]; and _Alistipes_ and _Bacteroides_, bacteria that have been purported to play a role in ameliorating obesity [55]. Thus, it is possible that differences in microbial diversity and relative abundance of key taxa, including pathobionts, may lead to gut mucosa inflammation and therefore less efficient SCFA absorption [56].