Transorgan short-chain fatty acid fluxes in the fasted and postprandial state in the pig.

The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, isovalerate, and valerate are end products of intestinal bacterial fermentation and important mediators in the interplay between the intestine and peripheral organs. To unravel the transorgan fluxes and mass balance comparisons of SCFAs, we measured their net fluxes across several organs in a translational pig model. In multicatheterized conscious pigs [n = 12, 25.6 (95% CI [24.2, 26.9]) kg, 8-12 wk old], SCFA fluxes across portal-drained viscera (PDV), liver, kidneys, and hindquarter (muscle compartment) were measured after an overnight fast and in the postprandial state, 4 h after administration of a fiber-free, mixed meal. PDV was the main releasing compartment of acetate, propionate, butyrate, isovalerate, and valerate during fasting and in the postprandial state (all P = 0.001). Splanchnic acetate release was high due to the absence of hepatic clearance. All other SCFAs were extensively taken up by the liver (all P < 0.05). Even though only 7% [4, 10] (propionate), 42% [23, 60] (butyrate), 26% [12, 39] (isovalerate), and 3% [0.4, 5] (valerate) of PDV release were excreted from the splanchnic area in the fasted state, splanchnic release of all SCFAs was significant (all P values ≤0.01). Splanchnic propionate, butyrate, isovalerate, and valerate release remained low but significant in the postprandial state (all P values <0.01). We identified muscle and kidneys as main peripheral SCFA metabolizing organs, taking up the majority of all splanchnically released SCFAs in the fasted state and in the postprandial state. We conclude that the PDV is the main SCFA releasing and the liver the main SCFA metabolizing organ. Splanchnically released SCFAs appear to be important energy substrates to peripheral organs not only in the fasted but also in the postprandial state.NEW & NOTEWORTHY Using a multicatheterized pig model, we identified the portal-drained viscera as the main releasing compartment of the short-chain fatty acids acetate, propionate, butyrate, isovalerate, and valerate in the fasted and postprandial states. Low hepatic acetate metabolism resulted in a high splanchnic release, whereas all other SCFAs were extensively cleared resulting in low but significant splanchnic releases. Muscle and kidneys are the main peripheral SCFA metabolizing organs during fasting and in the postprandial state.

Intestinal dysfunction in chronic disease.

PURPOSE OF REVIEW: This review will discuss recent studies showing that patients with chronic wasting diseases suffer from a variety of small intestinal impairments which might negatively impact the colonic microbiota and overall well-being. New insights will be addressed as well as novel approaches to assess intestinal function. RECENT FINDINGS: Small intestinal dysfunction can enhance the amount and alter the composition of undigested food reaching the colon. As a result of reduced protein digestion and absorption, a large amount of undigested protein might reach the colon promoting the presence of pathogenic colonic bacteria and a switch from bacterial fiber fermentation to protein fermentation. While microbial metabolites of fiber fermentation, such as short-chain fatty acids (SCFA), are mainly considered beneficial for overall health, metabolites of protein fermentation, i.e. ammonia, branched SCFAs, hydrogen sulfide, polyamines, phenols, and indoles, can exert beneficial or deleterious effects on overall health. Substantial advances have been made in the assessment of small intestinal dysfunction in chronic diseases, but studies investigating the connection to colonic microbial metabolism are needed. A promising new stable isotope approach can enable the measurement of metabolite production by the colonic microbiota. SUMMARY: Several studies have been conducted to assess intestinal function in chronic diseases. Impairments in intestinal barrier function, sugar absorption, protein digestion, and absorption, as well as small intestinal bacterial overgrowth were observed and possibly might negatively impact colonic bacterial metabolism. We suggest that improving these perturbations will improve overall patient health.

Sex related differences in muscle health and metabolism in chronic obstructive pulmonary disease.

BACKGROUND & AIMS: Sex differences in muscle function and mass, dyspnea, and clinical outcomes have been observed in patients with Chronic Obstructive Pulmonary Disease (COPD) despite a similar level of airflow obstruction. Protein and amino acid metabolism is altered in COPD, however, it remains unclear whether a difference in metabolic signature exists between males and females with COPD that may explain the observed differences in muscle health and clinical outcomes. METHODS: In 234 moderate to severe COPD patients (males/females: 113/121) and 182 healthy controls (males/females: 77/105), we assessed, besides presence of comorbidities and clinical features, muscle function by handgrip and leg dynamometry, and body composition by dual-energy x-ray absorptiometry. In the postabsorptive state, a mixture of 18 stable isotopes of amino acids was administered by pulse and arterialized blood was sampled for 2 h. Amino acid concentrations and enrichments were analyzed by LC-MS/MS to calculate whole body (net) protein breakdown (WBnetPB) and whole body production (WBP) rates (µmol/hour) of the amino acids playing a known role in muscle health. Statistics was done by ANCOVA to examine the effects of sex, COPD, and sex-by-COPD interaction with as covariates age and lean mass. Significance was set as p < 0.05. RESULTS: Lung function was comparable between males and females with COPD. Being a female and presence of COPD were independently associated with lower appendicular lean mass, muscle strength, and WBnetPB (p < 0.05). Being a male was associated with higher visceral adipose tissue, C-reactive protein (CRP) (p < 0.05), and higher prevalence of heart failure and obstructive sleep apnea. Sex-by-COPD interactions were found indicating lower fat mass (p = 0.0005) and WBPs of phenylalanine (measure of whole body protein turnover) and essential amino acids (p < 0.05), particularly in COPD females. Higher visceral adipose tissue (p = 0.025), CRP (p < 0.0001), and WBP of tau-methylhistidine (p = 0.010) (reflecting enhanced myofibrillar protein breakdown) were observed in COPD males. CONCLUSIONS: Presence of sex specific changes in protein and amino acid metabolism and cardiometabolic health in COPD need to be considered when designing treatment regimens to restore muscle health in males and females with COPD. CLINICAL TRIAL REGISTRY: www. CLINICALTRIALS: gov, NCT01787682, NCT01624792, NCT02157844, NCT02065141, NCT02770092, NCT02780219, NCT03327181, NCT03796455, NCT01173354, NCT01154400.

Short-chain fatty acid production in accessible and inaccessible body pools as assessed by novel stable tracer pulse approach is reduced by aging independent of presence of COPD.

BACKGROUND: Production rates of the short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which are beneficial metabolites of the intestinal microbiota, are difficult to measure in humans due to inaccessibility of the intestine to perform measurements, and the high first-pass metabolism of SCFAs in colonocytes and liver. We developed a stable tracer pulse approach to estimate SCFA whole-body production (WBP) in the accessible pool representing the systemic circulation and interstitial fluid. Compartmental modeling of plasma enrichment data allowed us to additionally calculate SCFA kinetics and pool sizes in the inaccessible pool likely representing the intestine with microbiota. We also studied the effects of aging and the presence of Chronic Obstructive Pulmonary Disease (COPD) on SCFA kinetics. METHODS: In this observational study, we designed a two-compartmental model to determine SCFA kinetics in 31 young (20-29 y) and 71 older (55-87 y) adults, as well as in 33 clinically stable patients with moderate to very severe COPD (mean (SD) FEV1, 46.5 (16.2)% of predicted). Participants received in the fasted state a pulse containing stable tracers of acetate, propionate, and butyrate intravenously and blood was sampled four times over a 30 min period. We measured tracer-tracee ratios by GC-MS and used parameters obtained from two-exponential curve fitting to calculate non-compartmental SCFA WBP and perform compartmental analysis. Statistics were done by ANCOVA. RESULTS: Acetate, propionate, and butyrate WBP and fluxes between the accessible and inaccessible pools were lower in older than young adults (all q < 0.0001). Moreover, older participants had lower acetate (q < 0.0001) and propionate (q = 0.019) production rates in the inaccessible pool as well as smaller sizes of the accessible and inaccessible acetate pools (both q < 0.0001) than young participants. WBP, compartmental SCFA kinetics, and pool sizes did not differ between COPD patients and older adults (all q > 0.05). Overall and independent of the group studied, calculated production rates in the inaccessible pool were on average 7 (acetate), 11 (propionate), and 16 (butyrate) times higher than non-compartmental WBP, and sizes of inaccessible pools were 24 (acetate), 31 (propionate), and 55 (butyrate) times higher than sizes of accessible pools (all p < 0.0001). CONCLUSION: Non-compartmental production measurements of SCFAs in the accessible pool (i.e. systemic circulation) substantially underestimate the SCFA production in the inaccessible pool, which likely represents the intestine with microbiota, as assessed by compartmental analysis.

Impaired intestinal function is associated with lower muscle and cognitive health and well-being in patients with congestive heart failure.

BACKGROUND: Small- and large-intestinal perturbations have been described as prevalent extracardiac systemic manifestations in congestive heart failure (CHF), but alterations in protein digestion and absorption and plasma short-chain fatty acid (SCFA) concentrations and the potential link with other systemic effects (muscle and cognitive health) have not been investigated in CHF. METHODS: We analyzed protein digestion and absorption with dual stable tracer method in 14 clinically stable, noncachectic CHF outpatients (mean left ventricular ejection fraction: 35.5% [95% CI, 30.9%-40.1%]) and 15 controls. Small-intestinal non-carrier-mediated permeability and active carrier-mediated glucose transport were quantified by sugar permeability test. Plasma SCFA (acetate, propionate, butyrate, isovalerate, valerate) concentrations were measured as intestinal microbial metabolites. Muscle function was assessed by isokinetic dynamometry, cognition by a battery of tests, and well-being by questionnaire. RESULTS: Protein digestion and absorption were impaired by 29.2% (P = .001) and active glucose transport by 38.4% (P = .010) in CHF. Non-carrier-mediated permeability was not altered. Whereas plasma propionate, butyrate, and isovalerate concentrations were lower in CHF (P < .05), acetate and valerate concentrations did not differ. Overall, intestinal dysfunction was associated with impaired leg muscle quality, emotional distress, and cognitive dysfunction (P < .05). CONCLUSIONS: We identified impaired protein digestion and absorption and altered SCFA concentrations as additional intestinal dysfunctions in CHF that are linked to reduced muscle and cognitive health and well-being. More research is needed to implement strategies to improve intestinal function in CHF and to investigate the mechanisms underlying its link with other systemic manifestations.

Intestinal function is impaired in patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND & AIMS: Gastrointestinal symptoms are prevalent extrapulmonary systemic manifestations of Chronic Obstructive Pulmonary Disease (COPD), but have been rarely studied. We dissected the perturbations in intestinal function in human patients with COPD using comprehensive metabolic and physiological approaches. METHODS: In this observational study, small intestinal membrane integrity and active carrier-mediated glucose transport were quantified by sugar permeability test in 21 clinically stable patients with moderate to severe COPD (mean FEV1, 41.2 (3.2) % of predicted) and 16 healthy control subjects. Protein digestion and absorption was analyzed using stable tracer kinetic methods. Plasma acetate, propionate, and butyrate concentrations were measured as markers of intestinal microbial metabolism. RESULTS: Compared with healthy controls, non carrier-mediated permeability was higher (0.062 (95% CI [0.046, 0.078]) vs. 0.037 (95% CI [0.029, 0.045]), P = 0.009) and active glucose transport lower in COPD (31.4 (95% CI [23.4, 39.4])% vs. 48.0 (95% CI [37.8, 58.3])%, P = 0.010). Protein digestion and absorption was lower in COPD (0.647 (95% CI [0.588, 0.705]) vs. 0.823 (95% CI [0.737, 0.909]), P = 0007), and impairment greater in patients with dyspnea (P = 0.038), exacerbations in preceding year (P = 0.052), and reduced transcutaneous oxygen saturation (P = 0.051), and was associated with reduced physical activity score (P = 0.016) and lower quality of life (P = 0.0007). Plasma acetate concentration was reduced in COPD (41.54 (95% CI [35.17, 47.91]) vs. 80.44 (95% CI [54.59, 106.30]) µmol/L, P = 0.001) suggesting perturbed intestinal microbial metabolism. CONCLUSIONS: We conclude that intestinal dysfunction is present in COPD, worsens with increasing disease severity, and is associated with reduced quality of life.

Risk Factors for Postural and Functional Balance Impairment in Patients with Chronic Obstructive Pulmonary Disease.

Reduced balance function has been observed during balance challenging conditions in the chronic obstructive pulmonary disease (COPD) population and is associated with an increased risk of falls. This study aimed to examine postural balance during quiet standing with eyes open and functional balance in a heterogeneous group of COPD and non-COPD (control) subjects, and to identify risk factors underlying balance impairment using a large panel of methods. In COPD and control subjects, who were mostly overweight and sedentary, postural and functional balance were assessed using center-of-pressure displacement in anterior-posterior (AP) and medio-lateral (ML) directions, and the Berg Balance Scale (BBS), respectively. COPD showed 23% greater AP sway velocity (p = 0.049). The presence of oxygen therapy, fat mass, reduced neurocognitive function, and the presence of (pre)diabetes explained 71% of the variation in postural balance in COPD. Transcutaneous oxygen saturation, a history of exacerbation, and gait speed explained 83% of the variation in functional balance in COPD. Neurocognitive dysfunction was the main risk factor for postural balance impairment in the control group. This suggests that specific phenotypes of COPD patients can be identified based on their type of balance impairment.