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Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial.
Corbin, KD, Carnero, EA, Dirks, B, Igudesman, D, Yi, F, Marcus, A, Davis, TL, Pratley, RE, Rittmann, BE, Krajmalnik-Brown, R, et al
Nature communications. 2023;14(1):3161
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Composition of the human gut microbiome has been shown to be associated with chronic diseases such as obesity, however whether they have a causal effect in disease development or whether microbiota composition is a direct result of the disease is unclear. This randomised control trial of 17 individuals aimed to determine the effects of a diet designed to modulate the gut microbiome (MBD) on human energy balance compared to a typical Western style diet (WD). The MBD diet maximised fibre, resistant starch, and limited processed foods and resulted in a significant decrease in the amount of energy produced by individuals compared to the WD. It was also shown that the MBD increased the microbial composition and decreased nutrient breakdown. It was concluded that the MBD increased the amount of gut bacteria and altered the amount of energy produced by individuals on this diet. This study could be used by healthcare practitioners to understand that composition of the gut microbiome can affect the amount of energy gained from food. Diets high in fibre, starch and low in processed foods, which promote microbial diversity may help individuals to lose weight.
Abstract
The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.
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An open label, non-randomized study assessing a prebiotic fiber intervention in a small cohort of Parkinson's disease participants.
Hall, DA, Voigt, RM, Cantu-Jungles, TM, Hamaker, B, Engen, PA, Shaikh, M, Raeisi, S, Green, SJ, Naqib, A, Forsyth, CB, et al
Nature communications. 2023;14(1):926
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Risk determinants for Parkinson’s disease (PD) include both genetic and environmental factors. Whether sporadic or monogenetic in origin, environmental factors may be critical in triggering PD onset in a susceptible host or influencing disease progression. The aims of this study were to determine whether prebiotic fibres can increase short-chain fatty acids (SCFA) production in PD patient microbiota and (2) determine which prebiotics modify the microbiota and increase SCFA using a stool fermentation system. Results showed that 10 days of prebiotic intervention was both well-tolerated and safe in PD patients and decreased total gastrointestinal symptom severity score in treated PD participants. The prebiotic intervention was also associated with anti-inflammatory shifts in the intestinal microbiota, increased SCFA, reduced calprotectin (intestinal inflammation), reduced zonulin (a putative marker of intestinal barrier dysfunction/ inflammation), and a subtle, but statistically significant, reduction in neurofilament light (a marker of neurodegeneration). Authors concluded that a SCFA-promoting prebiotic fibre mixture can be used to modulate the intestinal microbiota in PD patients (i.e., the approach is feasible) and that the prebiotic mixture is well-accepted, tolerated, and safe for use in PD patients.
Abstract
A pro-inflammatory intestinal microbiome is characteristic of Parkinson's disease (PD). Prebiotic fibers change the microbiome and this study sought to understand the utility of prebiotic fibers for use in PD patients. The first experiments demonstrate that fermentation of PD patient stool with prebiotic fibers increased the production of beneficial metabolites (short chain fatty acids, SCFA) and changed the microbiota demonstrating the capacity of PD microbiota to respond favorably to prebiotics. Subsequently, an open-label, non-randomized study was conducted in newly diagnosed, non-medicated (n = 10) and treated PD participants (n = 10) wherein the impact of 10 days of prebiotic intervention was evaluated. Outcomes demonstrate that the prebiotic intervention was well tolerated (primary outcome) and safe (secondary outcome) in PD participants and was associated with beneficial biological changes in the microbiota, SCFA, inflammation, and neurofilament light chain. Exploratory analyses indicate effects on clinically relevant outcomes. This proof-of-concept study offers the scientific rationale for placebo-controlled trials using prebiotic fibers in PD patients. ClinicalTrials.gov Identifier: NCT04512599.
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Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding.
Song, SJ, Wang, J, Martino, C, Jiang, L, Thompson, WK, Shenhav, L, McDonald, D, Marotz, C, Harris, PR, Hernandez, CD, et al
Med (New York, N.Y.). 2021;2(8):951-964.e5
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Studies on model organisms show that foetal development can be modulated by microbial products from the pregnant mother’s microbiota, and early colonisation is critical for immune system development. However, natural transmission and colonisation of maternal microbes is impaired by caesarean section (CS) delivery. The aim of this study was to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. This study is a large observational study of 177 infants born to 174 mothers. Physicians assessed healthy mothers who were set to deliver vaginally or by scheduled CS. Results demonstrate that microbial differences associated with delivery mode can be reduced by exposure to a vaginal microbial source at birth. In fact, birth mode significantly differentiated infant gut and skin microbiome development, and that seeding worked to adjust the trajectory of CS-delivered infants through partial restoration of microbiome features associated with a vaginal delivery. Authors conclude that restoring natural exposures at birth may be one way to reduce the risk of CS-associated diseases such as obesity, asthma, allergies, and immune disfunctions. However, randomised clinical trials on large cohorts are needed to gain conclusive evidence for microbial restoration at birth improving health outcomes.
Abstract
BACKGROUND Early microbiota perturbations are associated with disorders that involve immunological underpinnings. Cesarean section (CS)-born babies show altered microbiota development in relation to babies born vaginally. Here we present the first statistically powered longitudinal study to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. METHODS Using 16S rRNA gene sequencing, we followed the microbial trajectories of multiple body sites in 177 babies over the first year of life; 98 were born vaginally, and 79 were born by CS, of whom 30 were swabbed with a maternal vaginal gauze right after birth. FINDINGS Compositional tensor factorization analysis confirmed that microbiota trajectories of exposed CS-born babies aligned more closely with that of vaginally born babies. Interestingly, the majority of amplicon sequence variants from maternal vaginal microbiomes on the day of birth were shared with other maternal sites, in contrast to non-pregnant women from the Human Microbiome Project (HMP) study. CONCLUSIONS The results of this observational study prompt urgent randomized clinical trials to test whether microbial restoration reduces the increased disease risk associated with CS birth and the underlying mechanisms. It also provides evidence of the pluripotential nature of maternal vaginal fluids to provide pioneer bacterial colonizers for the newborn body sites. This is the first study showing long-term naturalization of the microbiota of CS-born infants by restoring microbial exposure at birth. FUNDING C&D, Emch Fund, CIFAR, Chilean CONICYT and SOCHIPE, Norwegian Institute of Public Health, Emerald Foundation, NIH, National Institute of Justice, Janssen.
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Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults.
Liu, RT, Rowan-Nash, AD, Sheehan, AE, Walsh, RFL, Sanzari, CM, Korry, BJ, Belenky, P
Brain, behavior, and immunity. 2020;88:308-324
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Alterations to the gut microbiota may be associated with depression and anxiety disorders through a pathway known as the gut-brain axis. Inflammation may be the mediator between the two, as individuals with major depressive disorder (MDD) have reported high levels of inflammation, which the gut microbiota may have the capacity to protect against. This observational study of the gut microbiota of 90 young adults with MDD and 47 healthy controls aimed to determine the relationship between inflammatory gut microbiota and symptoms of depression. The results showed changes to several species of gut microbiota in those with MDD and that the level of change was related to MDD symptom severity. These changes were observed even in those taking psychotropic medications. Changes at the taxonomic level indicated that those with higher symptoms of depression had more pronounced differences compared with healthy controls. Although the observed differences were indicative of an inflammatory microbiome, no changes were observed in blood markers of inflammation between those individuals with MDD and healthy controls. It was concluded that the gut microbiome of individuals with MDD was different from healthy individuals in favour of an inflammatory environment. This study could be used by healthcare professionals to understand that the status of the gut microbiota may be an important measure in individuals with MDD and that a treatment plan to ensure gut health is considered may help with symptoms of depression.
Abstract
We assessed the gut microbiota of 90 American young adults, comparing 43 participants with major depressive disorder (MDD) and 47 healthy controls, and found that the MDD subjects had significantly different gut microbiota compared to the healthy controls at multiple taxonomic levels. At the phylum level, participants with MDD had lower levels of Firmicutes and higher levels of Bacteroidetes, with similar trends in the at the class (Clostridia and Bacteroidia) and order (Clostridiales and Bacteroidales) levels. At the genus level, the MDD group had lower levels of Faecalibacterium and other related members of the family Ruminococcaceae, which was also reduced relative to healthy controls. Additionally, the class Gammaproteobacteria and genus Flavonifractor were enriched in participants with MDD. Accordingly, predicted functional differences between the two groups include a reduced abundance of short-chain fatty acid production pathways in the MDD group. We also demonstrated that the magnitude of taxonomic changes was associated with the severity of depressive symptoms in many cases, and that most changes were present regardless of whether depressed participants were taking psychotropic medications. Overall, our results support a link between MDD and lower levels of anti-inflammatory, butyrate-producing bacteria, and may support a connection between the gut microbiota and the chronic, low-grade inflammation often observed in MDD patients.
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Walnuts and Vegetable Oils Containing Oleic Acid Differentially Affect the Gut Microbiota and Associations with Cardiovascular Risk Factors: Follow-up of a Randomized, Controlled, Feeding Trial in Adults at Risk for Cardiovascular Disease.
Tindall, AM, McLimans, CJ, Petersen, KS, Kris-Etherton, PM, Lamendella, R
The Journal of nutrition. 2020;150(4):806-817
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Recent evidence suggests that microbes present in the gut may have a role in the risk of heart disease development. Walnuts have in previous studies shown to be of benefit for cardiovascular health and gut microbes are thought to be the mediator of this. This secondary analysis of a randomised control trial aimed to assess diets which differentiated in walnut composition on the species diversity of gut microbes and heart disease risk in 46 individuals with obesity over an 18-week period. The results showed that a diet of walnuts and the fats they contain enriched the microbes present in the gut compared to a Western-style diet. Interestingly, a whole walnut diet showed enrichment of a species that is better able to break down and use the components of walnuts compared to a diet where only the walnut fats were present. When on a diet rich in walnuts, an increase in a species of gut bacteria related to improved heart disease risk factors was observed. It was concluded that the positive effects of walnuts on gut bacteria and heart disease risk are due to the fibre and bioactive compounds, not simply the fats they contain. This study could be used by health care professionals to recommend the inclusion of whole walnuts into the diet of individuals with obesity to enrich gut bacteria that are involved in reducing heart disease risk.
Abstract
BACKGROUND It is unclear whether the favorable effects of walnuts on the gut microbiota are attributable to the fatty acids, including α-linolenic acid (ALA), and/or the bioactive compounds and fiber. OBJECTIVE This study examined between-diet gut bacterial differences in individuals at increased cardiovascular risk following diets that replace SFAs with walnuts or vegetable oils. METHODS Forty-two adults at cardiovascular risk were included in a randomized, crossover, controlled-feeding trial that provided a 2-wk standard Western diet (SWD) run-in and three 6-wk isocaloric study diets: a diet containing whole walnuts (WD; 57-99 g/d walnuts; 2.7% ALA), a fatty acid-matched diet devoid of walnuts (walnut fatty acid-matched diet; WFMD; 2.6% ALA), and a diet replacing ALA with oleic acid without walnuts (oleic acid replaces ALA diet; ORAD; 0.4% ALA). Fecal samples were collected following the run-in and study diets to assess gut microbiota with 16S rRNA sequencing and Qiime2 for amplicon sequence variant picking. RESULTS Subjects had elevated BMI (30 ± 1 kg/m2), blood pressure (121 ± 2/77 ± 1 mmHg), and LDL cholesterol (120 ± 5 mg/dL). Following the WD, Roseburia [relative abundance (RA) = 4.2%, linear discriminant analysis (LDA) = 4], Eubacterium eligensgroup (RA = 1.4%, LDA = 4), LachnospiraceaeUCG001 (RA = 1.2%, LDA = 3.2), Lachnospiraceae UCG004 (RA = 1.0%, LDA = 3), and Leuconostocaceae (RA = 0.03%, LDA = 2.8) were most abundant relative to taxa in the SWD (P ≤ 0.05 for all). The WD was also enriched in Gordonibacter relative to the WFMD. Roseburia (3.6%, LDA = 4) and Eubacterium eligensgroup (RA = 1.5%, LDA = 3.4) were abundant following the WFMD, and Clostridialesvadin BB60group (RA = 0.3%, LDA = 2) and gutmetagenome (RA = 0.2%, LDA = 2) were most abundant following the ORAD relative to the SWD (P ≤ 0.05 for all). Lachnospiraceae were inversely correlated with blood pressure and lipid/lipoprotein measurements following the WD. CONCLUSIONS The results indicate similar enrichment of Roseburia following the WD and WFMD, which could be explained by the fatty acid composition. Gordonibacter enrichment and the inverse association between Lachnospiraceae and cardiovascular risk factors following the WD suggest that the gut microbiota may contribute to the health benefits of walnut consumption in adults at cardiovascular risk. This trial was registered at clinicaltrials.gov as NCT02210767.
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Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease.
Barengolts, E, Green, SJ, Eisenberg, Y, Akbar, A, Reddivari, B, Layden, BT, Dugas, L, Chlipala, G
PloS one. 2018;13(3):e0194171
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Obesity and type 2 diabetes (T2D) can lead to alterations of the composition of the gut microbiota. The gut microbiota, in turn, has been suggested to play a role in the development of psychological conditions, such as anxiety, depression and drug addiction. This cross-sectional study included 99 mostly overweight/obese African American men, with or without T2D, and with or without opioid addiction and other psychiatric disorders. The aim of the study was to determine, whether the gut microbiota composition was linked to T2D and the use of opioids in these patients. Furthermore, the researchers looked at the associations between leptin and oxytocin levels in the blood and the gut microbiota, and whether these hormone biomarkers could be indicative of obesity and psychosocial behaviour, such as opioid addiction. The authors found that some bacterial species in the gut were affected by T2D, diabetes medication and opioid use in the studied subjects. A relationship was also observed between leptin and oxytocin levels and the abundance of certain bacteria in the gut in subjects without T2D. The authors conclude that targeting the gut microbiota could be used for the management of T2D and associated psychiatric disorders. However, more studies are needed to provide further understanding of the connections between the gut microbiota and the brain.
Abstract
OBJECTIVE The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior. RESULTS The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04). CONCLUSIONS The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.