Fiber mixture-specific effect on distal colonic fermentation and metabolic health in lean but not in prediabetic men.

Infusions of the short-chain fatty acid (SCFA) acetate in the distal colon improved metabolic parameters in men. Here, we hypothesized that combining rapidly and slowly fermentable fibers will enhance distal colonic acetate production and improve metabolic health. In vitro cultivation studies in a validated model of the colon were used to identify fiber mixtures that yielded high distal colonic acetate production. Subsequently, in two randomized crossover studies, lean and prediabetic overweight/obese men were included. In one study, participants received supplements of either long-chain inulin+resistant starch (INU+RS), INU or maltodextrin (PLA) the day prior to a clinical investigation day (CID). The second trial studied beta glucan+RS (BG+RS) versus BG and PLA. During each CID, breath hydrogen, indirect calorimetry, plasma metabolites/hormones were assessed during fasting and postprandial conditions. Additionally, fecal microbiota composition and SCFA were determined. In prediabetic men, INU+RS increased plasma acetate compared to INU or PLA (P < .05), but did not affect metabolic parameters. In lean men, INU+RS increased breath hydrogen and fasting plasma butyrate, which was accompanied by increased energy expenditure, carbohydrate oxidation and PYY and decreased postprandial glucose concentrations (all P < .05) compared to PLA. BG+RS increased plasma butyrate compared to PLA (P < .05) in prediabetic individuals, but did not affect other fermentation/metabolic markers in both phenotypes. Fiber-induced shifts in fecal microbiota were individual-specific and more pronounced with INU+RS versus BG+RS. Administration of INU+RS (not BG+RS) the day prior to investigation improved metabolic parameters in lean but not in prediabetic individuals, demonstrating that effects were phenotype- and fiber-specific. Further research should study whether longer-term supplementation periods are required to elicit beneficial metabolic health in prediabetic individuals. Trial registration numbers: Clinical trial No. NCT03711383 (Inulin study) and Clinical trial No. NCT03714646 (Beta glucan study).

Nutrition, Inflammation, and the Gut Microbiota among Outpatients with Active Tuberculosis Disease in India.

India has the highest rates of tuberculosis (TB) globally and a high prevalence of malnutrition; however, the interplay between host nutritional status, inflammation, and the gut microbiome in active tuberculosis disease (ATBD) is less well-studied. We examined differences in gut microbial composition and diversity based on undernutrition and inflammation status among outpatients with ATBD at the time of treatment initiation. During this exploratory cross-sectional study, outpatients (N = 32) with ATBD (confirmed by Xpert MTB/RIF) were enrolled in anti-TB treatment initiated at a hospital in rural southern India. The 16S rRNA sequencing was used to assess the composition of the gut microbiome. We assessed multiple markers of nutritional status, including micronutrient status concentrations (vitamin D [25(OH)D], vitamin B12, ferritin), anthropometry (body mass index, mid-upper arm circumference, and height), and C-reactive protein (CRP), as indicators of inflammation. We found that 25(OH)D was positively associated with the relative abundance of Oscillospira spp., a butyrate-producing genus linked with anti-inflammation effects, and that ferritin was positively associated with Proteobacteria taxa, which have been associated with worse inflammation in other studies. Finally, we found a greater abundance of inflammation-associated taxa from the Proteobacteria phylum and lower alpha-diversity indices among those who were underweight or who had low mid-upper arm circumference or short stature. In summary, we found differences in the gut microbiota composition and diversity among those with undernutrition compared with those with adequate nutrition status at the time of initiation of treatment among patients with ATBD in India. Clinical implications of these findings will need to be examined by larger longitudinal studies.

Gut Microbiota Profile and Its Association with Clinical Variables and Dietary Intake in Overweight/Obese and Lean Subjects: A Cross-Sectional Study.

We aimed to differentiate gut microbiota composition of overweight/obese and lean subjects and to determine its association with clinical variables and dietary intake. A cross-sectional study was performed with 96 overweight/obese subjects and 32 lean subjects. Anthropometric parameters were positively associated with Collinsella aerofaciens, Dorea formicigenerans and Dorea longicatena, which had higher abundance the overweight/obese subjects. Moreover, different genera of Lachnospiraceae were negatively associated with body fat, LDL and total cholesterol. Saturated fatty acids (SFAs) were negatively associated with the genus Intestinimonas, a biomarker of the overweight/obese group, whereas SFAs were positively associated with Roseburia, a biomarker for the lean group. In conclusion, Dorea formicigenerans, Dorea longicatena and Collinsella aerofaciens could be considered obesity biomarkers, Lachnospiraceae is associated with lipid cardiovascular risk factors. SFAs exhibited opposite association profiles with butyrate-producing bacteria depending on the BMI. Thus, the relationship between diet and microbiota opens new tools for the management of obesity.

Decreased Abundance of Akkermansia muciniphila Leads to the Impairment of Insulin Secretion and Glucose Homeostasis in Lean Type 2 Diabetes.

Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight. Several studies have linked the gut microbiome to obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear. A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D. The abundance of Akkermansia muciniphila (A. muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D. Its abundance correlates inversely with serum 3ß-chenodeoxycholic acid (ßCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations. The supplementation with A. muciniphila is sufficient to protect mice against high sucrose-induced impairment of glucose intolerance by decreasing ßCDCA and increasing insulin secretion and FGF15/19. Furthermore, ßCDCA inhibits insulin secretion and FGF15/19 expression. These findings suggest that decreased abundance of A. muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes.

The Baseline Gut Microbiota Directs Dieting-Induced Weight Loss Trajectories.

BACKGROUND & AIMS: Elucidating key factors affecting personal responses to food is the first step toward implementing personalized nutrition strategies in for example weight loss programs. Here, we aimed to identify factors of importance for individual weight loss trajectories in a natural setting where participants were provided dietary advice but otherwise asked to self-manage the daily caloric intake and data reporting. METHODS: A 6-month weight-reduction program with longitudinal collection of dietary, physical activity, body weight, and fecal microbiome data as well as single-nucleotide polymorphism genotypes in 83 participants was conducted, followed by integration of the high-dimensional data to define the most determining factors for weight loss in a dietician-guided, smartphone-assisted dieting program. RESULTS: The baseline gut microbiota was found to outperform other factors as a predieting predictor of individual weight loss trajectories. Weight loss was also linked to the magnitude of changes in abundances of certain bacterial species during dieting. Ruminococcus gnavus (MGS0160) was significantly enriched in obese individuals and decreased during weight loss. Akkermansia muciniphila (MGS0120) and Alistipes obesi (MGS0342) were significantly enriched in lean individuals, and their abundance increased during dieting. Finally, Blautia wexlerae (MGS0575) and Bacteroides dorei (MGS0187) were the strongest predictors for weight loss when present in high abundance at baseline. CONCLUSION: Altogether, the baseline gut microbiota was found to excel as a central personal factor in capturing the relationship between dietary factors and weight loss among individuals on a dieting program.

Gut Microbial Ecosystem in Parkinson Disease: New Clinicobiological Insights from Multi-Omics.

OBJECTIVE: Gut microbiome alterations in Parkinson disease (PD) have been reported repeatedly, but their functional relevance remains unclear. Fecal metabolomics, which provide a functional readout of microbial activity, have scarcely been investigated. We investigated fecal microbiome and metabolome alterations in PD, and their clinical relevance. METHODS: Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry. RESULTS: Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores. INTERPRETATION: Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.

Gut Microbiota Diversity in Lean Athletes Is Associated with Positive Energy Balance.

INTRODUCTION: In contrast to obesity, little is known about the human lean phenotype associated with gut microbiota composition. OBJECTIVE: We aimed to investigate whether the bacterial composition of lean athletes with a positive energy balance differs from the equal-calorie food group. METHODS: Twenty-four male participants were included in this cross-sectional study: lean athletes with a positive energy balance (LA, n 12) and control group athletes (CTRLs, n 12). Nutritional data, resting and total energy expenditure, and body composition were determined. DNA was extracted from stool samples and subjected to 16S rRNA gene analysis. RESULTS: We found 7 differentially abundant bacterial taxa between the LA and CTRL groups. Of those, 5 were significantly less abundant and 2 were enriched in the LA group. The following categories significantly associated with the community structure were identified: body fat parameters, BMI, energy intake and expenditure, oxygen consumption, and respiratory exchange ratio. CONCLUSIONS: Although we are far from a detailed interpretation of lean human body maintenance, the primary findings of our study suggest that gut microbial composition may be a factor influencing the regulation of weight gain in lean athletes with a positive energy balance.

Distinct differences in gut microbial composition and functional potential from lean to morbidly obese subjects.

INTRODUCTION: The gut microbiome may contribute to the development of obesity. So far, the extent of microbiome variation in people with obesity has not been determined in large cohorts and for a wide range of body mass index (BMI). Here, we aimed to investigate whether the faecal microbial metagenome can explain the variance in several clinical phenotypes associated with morbid obesity. METHODS: Caucasian subjects were recruited at our hospital. Blood pressure and anthropometric measurements were taken. Dietary intake was determined using questionnaires. Shotgun metagenomic sequencing was performed on faecal samples from 177 subjects. RESULTS: Subjects without obesity (n = 82, BMI 24.7 ± 2.9 kg m-2 ) and subjects with obesity (n = 95, BMI 38.6 ± 5.1 kg m-2 ) could be clearly distinguished based on microbial composition and microbial metabolic pathways. A total number of 52 bacterial species differed significantly in people with and without obesity. Independent of dietary intake, we found that microbial pathways involved in biosynthesis of amino acids were enriched in subjects with obesity, whereas pathways involved in the degradation of amino acids were depleted. Machine learning models showed that more than half of the variance in body fat composition followed by BMI could be explained by the gut microbiome, composition and microbial metabolic pathways, compared with 6% of variation explained in triglycerides and 9% in HDL. CONCLUSION: Based on the faecal microbiota composition, we were able to separate subjects with and without obesity. In addition, we found strong associations between gut microbial amino acid metabolism and specific microbial species in relation to clinical features of obesity.

Overweight and underweight status are linked to specific gut microbiota and intestinal tricarboxylic acid cycle intermediates.

BACKGROUND & AIMS: Intestinal short-chain fatty acids have been demonstrated to modulate host energy metabolism and are elevated in overweight and obese individuals. We hypothesized that other intestinal energy products especially tricarboxylic acid (TCA) cycle intermediates might also related to overweight status. In addition, little information is available regarding to the potential relationship between gut microbiota and underweight status. Therefore, the aim of this study was to investigate whether gut microbiota and intestinal energy metabolites differ in underweight, normal weight, and overweight individuals, and their correlations with host cardiometabolic risk factors. SUBJECTS/METHODS: Gut microbiome, intestinal energy metabolites, circulating cardiometabolic risk factors, and proinflammatory markers were determined in 29 underweight, 67 normal weight, and 67 overweight adults. RESULTS: The fecal concentrations of succinic acid, fumaric acid, malic acid, propionic acid, and adipic acid were significantly increased in the overweight individuals in parallel with a higher relative abundance of Veillonellacea after adjusting for multiple comparisons (all p < 0.05). The intestinal concentration of TCA cycle intermediate succinic acid was positively associated with body weight (r = 0.28, p = 0.04), and malic acid were in positive association with circulating total cholesterol, low-density lipoprotein cholesterol, and interleukin-1ß (all r > 0.25, p < 0.05). Compared with the normal weight individuals, the gut microbial α-diversity was lower in the overweight (p = 0.007 for Shannon index and p = 0.009 for Ace index) and underweight (p = 0.05 for Shannon index and p = 0.08 for Ace index) groups. However, no significant differences in the overall gut microbiota composition were observed among the three groups. CONCLUSIONS: Our findings revealed that low gut microbiota diversity was associated with both overweight and underweight status. Intestinal TCA cycle intermediates were associated with overweight development and might be potential markers for future studies related to gut microbiota and host cardiometabolic health.

Review of nutritional status, body composition, and effects of antineoplastic drug disposition.

The overall survival for children with cancer in high income countries is excellent. However, there are many disparities that may negatively affect survival, which are particularly problematic in low income countries, such as nutritional status at diagnosis and throughout therapy. Nutritional status as well as concomitant foods, supplements, and medications may play a role in overall exposure and response to chemotherapy. Emerging science around the microbiome may also play a role and should be further explored as a contributor to disease progression and therapeutic response. This article highlights some of these issues and proposes additional areas of research relevant to nutritional status and pharmacology that are needed in pediatric oncology.

Immunonutritional contribution of gut microbiota to fatty liver disease.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is indisputably the most widespread liver disease worldwide, leading to a significant increase in patient morbidity, mortality, and health care utilization. The gut microbiota and its genome (microbiome) have emerged as a novel modulator of the immunometabolic processes that NAFLD implies, but microbiota-targeted interventions have resulted both astounding and at the same time unsuccessful. The most relevant alteration appears to be the overgrowth of Gram-negative bacteria, characterized by an increased ratio of Firmicutes to Bacteroidetes, although current evidence indicates species- and strain-specific effects influencing energy harvest, the host's innate and adaptive immune systems, and epigenetic regulation as determinants of the immunomodulatory milieu in NAFLD. The genera Lactobacillus and Bifidobacterium deserve special attention since many of their probiotic strains are marketed for human consumption, even more so when considering that, in conjunction with prebiotics, they are potential modulators of gut microbiota composition and/or metabolic activity. Here, a better understanding of the major intestinal microbial factors with a detrimental or preventive role in NAFLD, and of the dynamic interplay between gut microbiome and host factors, appears crucial in defining the exposome for the prevention and treatment of NAFLD and associated diseases such as metabolic syndrome, type-2 diabetes, and obesity.

INTRODUCCIÓN: La esteatosis hepática no alcohólica (NAFLD, por sus siglas en inglés) es indiscutiblemente la patología hepática más extendida a escala mundial y conlleva un aumento significativo de la utilización de la atención médica de los pacientes, así como de la morbilidad y la mortalidad. La microbiota intestinal y su genoma (microbioma) se han revelado como uno de los factores moduladores de los procesos inmunometabólicos subyacentes que desencadenan la NAFLD. Las intervenciones dirigidas a modificar la composición y/o la actividad de la microbiota han resultado sorprendentes y, al mismo tiempo, infructuosas. La disbiosis más relevante en la patología es un aumento de la proporción entre Firmicutes y Bacteroidetes. La evidencia actual indica que los efectos específicos de la especie y la cepa influyen en el resultado funcional de la microbiota sobre el metabolismo de los nutrientes, la rama innata y la adaptativa del sistema inmune, y la regulación epigenética del genoma humano en relación al NAFLD. Los géneros Lactobacillus y Bifidobacterium merecen especial atención ya que muchas cepas probióticas de estos géneros se comercializan para consumo humano, e incluso más si se considera que, junto con los prebióticos, son moduladores potenciales de la composición de la microbiota intestinal y/o su actividad metabólica. En este contexto, una mejor comprensión de los principales factores microbianos con papel perjudicial o preventivo en la NAFLD, y de la interacción dinámica entre el microbioma intestinal y los factores del huésped, parece crucial para definir el exposoma de la prevención y el tratamiento de la NAFLD y sus enfermedades asociadas, como el síndrome metabólico, la diabetes de tipo 2 y la obesidad.

Effect of the Nursing Mother on the Gut Microbiome of the Offspring During Early Mouse Development.

The development of the gut microbiome is influenced by several factors. It is acquired during and after birth and involves both maternal and environmental factors as well as the genetic disposition of the offspring. However, it is unclear if the microbiome development is directly triggered by the mode of delivery and very early contact with the mother or mostly at later stages of initial development mainly by breast milk provided by the mother. To investigate to what extent the gut microbiome composition of the offspring is determined by the nursing mother, providing breast milk, compared to the birth mother during early development, a cross-fostering experiment involving two genetically different mouse lines was developed, being prone to be obese or lean, respectively. The microbiome of the colon was analyzed by high-throughput 16S rRNA gene sequencing, when the mice were 3 weeks old. The nursing mother affected both α- and ß-diversity of the offspring's gut microbiome and shaped its composition. Especially bacterial families directly transferred by breast milk, like Streptococcaceae, or families which are strongly influenced by the quality of the breast milk like Rikenellaceae, showed a strong response. The core microbiome transferred from the obese nursing mother showed a higher robustness in comparison to the microbiome transferred from the lean nursing mother. Overall, the nursing mother impacts the gut microbial composition of the offspring during early development and might play an important role for health and disease of the animals at later stages of life.

Assessment of gut microbiota populations in lean and obese Zucker rats.

Obesity has been on the rise in the US and worldwide for the last several decades. Obesity has been associated with chronic disease development, such as certain types of cancer, type 2 diabetes, cardiovascular disease, and liver diseases. Previously, we reported that obesity promotes DMBA-induced mammary tumor development using the obese Zucker rat model. The intestinal microbiota is composed of a diverse population of obligate and facultative anaerobic microorganisms, and these organisms carry out a broad range of metabolic activities. Obesity has been linked to changes in the intestinal microbiota, but the composition of the bacterial populations in lean and obese Zucker rats has not been carefully studied. Therefore, the objective of this study was to determine the effects of obesity on the gut microbiota in this model. Lean and obese female Zucker rats (n = 16) were fed an AIN-93G-like diet for 8 weeks. Rats were weighed twice weekly, and fecal samples were collected at the beginning and end of the experiment. 16S rRNA gene sequencing was used to evaluate the composition of the fecal bacterial populations. At the outset of the study, the lean rats exhibited much lower ratios of the Firmicutes to Bacteroidetes phyla than the obese rats, but after 60 days, this ratio in the lean rats exceeded that of the obese. This shift was associated with reductions in the Bacteroidaceae, S24-7 and Paraprevotellaceae families in the lean rats. Obese rats also showed increased levels of the genus Akkermansia at day 60. PCoA plots of beta diversity showed clustering of the different test groups, indicating clear differences in intestinal microbiota populations associated with both the time point of the study and the lean or obese status in the Zucker rat model for obesity.

Acute increases in serum colonic short-chain fatty acids elicited by inulin do not increase GLP-1 or PYY responses but may reduce ghrelin in lean and overweight humans.

BACKGROUND: Colonic fermentation of dietary fibre to short-chain fatty acids (SCFA) influences appetite hormone secretion in animals, but SCFA production is excessive in obese animals. This suggests there may be resistance to the effect of SCFA on appetite hormones in obesity. OBJECTIVES: To determine the effects of inulin (IN) and resistant starch (RS) on postprandial SCFA, and gut hormone (glucagon-like peptide (GLP-1), peptide-tyrosine-tyrosine (PYY) and ghrelin) responses in healthy overweight/obese (OWO) vs lean (LN) humans. SUBJECTS/METHODS: Overnight-fasted participants (13 OWO and 12 LN) consumed 300 ml water containing 75 g glucose (GLU) as control or 75 g GLU plus 24 g IN, or 28.2 g RS using a randomised, single-blind, cross-over design. Blood for appetite hormones and SCFA was collected at intervals over 6 h. A standard lunch was served 4 h after the test drink. RESULTS: Relative to GLU, IN, but not RS, significantly increased SCFA areas under the curve (AUC) from 4-6 h (AUC4-6). Neither IN nor RS affected GLP-1 or PYY-AUC4-6. Although neither IN nor RS reduced ghrelin-AUC4-6 compared with GLU, ghrelin at 6 h after IN was significantly lower than that after GLU (P<0.05). After IN, relative to GLU, the changes in SCFA-AUC4-6 were negatively related to the changes in ghrelin-AUC4-6 (P=0.017). SCFA and hormone responses did not differ significantly between LN and OWO. CONCLUSIONS: Acute increases in colonic SCFA do not affect GLP-1 or PYY responses in LN or OWO subjects, but may reduce ghrelin. The results do not support the hypothesis that SCFA acutely stimulate PYY and GLP-1 secretion; however, a longer adaptation to increased colonic fermentation or a larger sample size may yield different results.

Relation between neonatal malnutrition and gene expression: inflammasome function in infections caused by Candida Albicans.

PURPOSE: To investigate the effects of neonatal malnutrition followed by nutritional replacement on the signaling mechanisms developed by the inflammasome complex by analyzing the expression of the targeted TLR2, TLR4, NLRP3, caspase-1 and release of IL-1ß and IL-18 by alveolar macrophages infected in vitro with Candida albicans. METHODS: Male Wistar rats (n = 24), 90-120 days, were suckled by mothers whose diet during lactation contained 17 % protein in the nourish group and 8 % protein in the malnourished group. After weaning, both groups were fed a normal protein diet. Macrophages were obtained after tracheostomy, through the collection of bronchoalveolar lavage fluid. The quantification of the expression levels of targets (TLR2, TLR4, NLRP3 and caspase-1) was performed by real-time RT-PCR. Production of cytokines was performed by ELISA. RESULTS: The malnourished animals during lactation showed reduced body weight from the fifth day of life, remaining until adulthood. Further, the model applied malnutrition induced a lower expression of TLR4 and caspase-1. The quantification of the TLR2 and NLRP3, as well as the release of IL-1ß and IL-18, was not different between groups of animals nourished and malnourished. The system challenged with Candida albicans showed high expression levels of all targets in the study. CONCLUSIONS: The tests demonstrate nutritional restriction during critical periods of development, although nutritional supplementation may compromise defense patterns in adulthood in a timely manner, preserving distinct signaling mechanism, so that the individual does not become widely vulnerable to infections by opportunistic pathogens.

Oscillospira: a Central, Enigmatic Component of the Human Gut Microbiota.

Oscillospira is an enigmatic bacterial genus that has never been cultured, but is constantly detected by 16S rRNA gene surveys of the human microbiome. Here we summarize recent evidence that Oscillospira is positively associated with leanness and health, speculate about its physiology, and argue its potential importance for human health.

Nucleotide 9-mers characterize the type II diabetic gut metagenome.

Discoveries of new biomarkers for frequently occurring diseases are of special importance in today's medicine. While fully developed type II diabetes (T2D) can be detected easily, the early identification of high risk individuals is an area of interest in T2D, too. Metagenomic analysis of the human bacterial flora has shown subtle changes in diabetic patients, but no specific microbes are known to cause or promote the disease. Moderate changes were also detected in the microbial gene composition of the metagenomes of diabetic patients, but again, no specific gene was found that is present in disease-related and missing in healthy metagenome. However, these fine differences in microbial taxon- and gene composition are difficult to apply as quantitative biomarkers for diagnosing or predicting type II diabetes. In the present work we report some nucleotide 9-mers with significantly differing frequencies in diabetic and healthy intestinal flora. To our knowledge, it is the first time such short DNA fragments have been associated with T2D. The automated, quantitative analysis of the frequencies of short nucleotide sequences seems to be more feasible than accurate phylogenetic and functional analysis, and thus it might be a promising direction of diagnostic research.