Publications by authors named "Purna Kashyap"

78 Publications

Wild primate microbiomes prevent weight gain in germ-free mice.

Anim Microbiome 2020 May 7;2(1):16. Epub 2020 May 7.

Biotechnology Institute, University of Minnesota, 1479 Gortner Avenue, Saint Paul, MN, 55108, USA.

Background: The gut microbiome harbors trillions of bacteria that play a major role in dietary nutrient extraction and host metabolism. Metabolic diseases such as obesity and diabetes are associated with shifts in microbiome composition and have been on the rise in Westernized or highly industrialized countries. At the same time, Westernized diets low in dietary fiber have been shown to cause loss of gut microbial diversity. However, the link between microbiome composition, loss of dietary fiber, and obesity has not been well defined.

Results: To study the interactions between gut microbiota, dietary fiber, and weight gain, we transplanted captive and wild douc gut microbiota into germ-free mice and then exposed them to either a high- or low-fiber diet. The group receiving captive douc microbiota gained significantly more weight, regardless of diet, while mice receiving a high-fiber diet and wild douc microbiota remained lean. In the presence of a low-fiber diet, the wild douc microbiota partially prevented weight gain. Using 16S rRNA gene amplicon sequencing we identified key bacterial taxa in each group, specifically a high relative abundance of Bacteroides and Akkermansia in captive douc FMT mice and a higher relative abundance of Lactobacillus and Clostridium in the wild douc FMT mice.

Conclusions: In the context of our germ-free mouse experiment, wild douc microbiota could serve as a reservoir for microbes for cross-species transplants. Our results suggest that wild douc microbiota are tailored to diverse fiber diets and can prevent weight gain when exposed to a native diet.
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http://dx.doi.org/10.1186/s42523-020-00033-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807445PMC
May 2020

Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson's disease.

Gut Microbes 2021 Jan;13(1):1866974

Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms' including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.
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http://dx.doi.org/10.1080/19490976.2020.1866974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833732PMC
January 2021

Berberine alters gut microbial function through modulation of bile acids.

BMC Microbiol 2021 01 11;21(1):24. Epub 2021 Jan 11.

Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.

Background: Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome.

Results: Germfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P < 0.05), most notably deoxycholic acid (DCA) (P < 0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na/H antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community.

Conclusions: This work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.
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http://dx.doi.org/10.1186/s12866-020-02020-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798349PMC
January 2021

Bacterially Derived Tryptamine Increases Mucus Release by Activating a Host Receptor in a Mouse Model of Inflammatory Bowel Disease.

iScience 2020 Dec 13;23(12):101798. Epub 2020 Nov 13.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Recent studies emphasize the role of microbial metabolites in regulating gastrointestinal (GI) physiology through activation of host receptors, highlighting the potential for inter-kingdom signaling in treating GI disorders. In this study, we show that tryptamine, a tryptophan-derived bacterial metabolite, stimulates mucus release from goblet cells via activation of G-protein-coupled receptor (GPCR) 5-HT4R. Germ-free mice colonized with engineered optimized to produce tryptamine (Trp D+) exhibit decreased weight loss and increased mucus release following dextran sodium sulfate treatment when compared with mice colonized with control (Trp D-). Additional beneficial effects in preventing barrier disruption and lower disease activity index were seen only in female mice, highlighting sex-specific effects of the bacterial metabolite. This study demonstrates potential for the precise modulation of mucus release by microbially produced 5-HT4 GPCR agonist as a therapeutic strategy to treat inflammatory conditions of the GI tract.
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http://dx.doi.org/10.1016/j.isci.2020.101798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702010PMC
December 2020

Functional Gastrointestinal Disorders and the Microbiome-What Is the Best Strategy for Moving Microbiome-based Therapies for Functional Gastrointestinal Disorders into the Clinic?

Gastroenterology 2021 01 28;160(2):538-555. Epub 2020 Nov 28.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota. Electronic address:

There have been numerous human studies reporting associations between the intestinal microbiome and functional gastrointestinal disorders (FGIDs), and independently animal studies have explored microbiome-driven mechanisms underlying FGIDs. However, there is often a disconnect between human and animal studies, which hampers translation of microbiome findings to the clinic. Changes in the microbiota composition of patients with FGIDs are generally subtle, whereas changes in microbial function, reflected in the fecal metabolome, appear to be more precise indicators of disease subtype-specific mechanisms. Although we have made significant progress in characterizing the microbiome, to effectively translate microbiome science in a timely manner, we need concurrent and iterative longitudinal studies in humans and animals to determine the precise microbial functions that can be targeted to address specific pathophysiological processes in FGIDs. A systems approach integrating multiple data layers rather than evaluating individual data layers of symptoms, physiological changes, or -omics data in isolation will allow for validation of mechanistic insights from animal studies while also allowing new discovery. Patient stratification for clinical trials based on functional microbiome alterations and/or pathophysiological measurements may allow for more accurate determination of efficacy of individual microbiome-targeted interventions designed to correct an underlying abnormality. In this review, we outline current approaches and knowledge, and identify gaps, to provide a potential roadmap for accelerating translation of microbiome science toward microbiome-targeted personalized treatments for FGIDs.
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http://dx.doi.org/10.1053/j.gastro.2020.10.058DOI Listing
January 2021

Plasmid Acquisition Alters Vancomycin Susceptibility in Clostridioides difficile.

Gastroenterology 2021 Feb 14;160(3):941-945.e8. Epub 2020 Nov 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota. Electronic address:

The increasing incidence of primary and recurring Clostridioides difficile infections (CDI), which evade current treatment strategies, reflects the changing biology of C difficile. Here, we describe a putative plasmid-mediated mechanism potentially driving decreased sensitivity of C difficile to vancomycin treatment. We identified a broad host range transferable plasmid in a C difficile strain associated with lack of adequate response to vancomycin treatment. The transfer of this plasmid to a vancomycin-susceptible C difficile isolate decreased its susceptibility to vancomycin in vitro and resulted in more severe disease in a humanized mouse model. Our findings suggest plasmid acquisition in the gastrointestinal tract to be a possible mechanism underlying vancomycin treatment failure in patients with CDI, but further work is needed to characterize the mechanism by which plasmid genes determine vancomycin susceptibility in C difficile.
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http://dx.doi.org/10.1053/j.gastro.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878333PMC
February 2021

A Potential Role for Stress-Induced Microbial Alterations in IgA-Associated Irritable Bowel Syndrome with Diarrhea.

Cell Rep Med 2020 Oct;1(7)

Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.
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http://dx.doi.org/10.1016/j.xcrm.2020.100124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659537PMC
October 2020

A Diet for Healthy Weight: Why Reaching a Consensus Seems Difficult.

Nutrients 2020 Sep 30;12(10). Epub 2020 Sep 30.

Department of Gastroenterology and Hepatology and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.

Overweight and obesity are global health problems that contribute to the rising prevalence of non-communicable diseases, such as type 2 diabetes, heart disease, and certain cancers. The World Health Organization recognizes obesity as a primarily diet-induced, preventable condition, yet losing weight or keeping weight loss permanent is a universal challenge. In the U.S., formal dietary guidelines have existed since 1980. Over the same time-period, the incidence of obesity has skyrocketed. Here, we present our perspective on why current dietary guidelines are not always supported by a robust body of scientific data and emphasize the critical need for accelerated nutrition research funding. A clear understanding of the interaction of dietary patterns with system-level biological changes in a precise, response-specific manner can help inform evidence-based nutrition education, policy, and practice.
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http://dx.doi.org/10.3390/nu12102997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600493PMC
September 2020

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

J Gastrointest Surg 2020 Sep 28. Epub 2020 Sep 28.

Department of General Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.
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http://dx.doi.org/10.1007/s11605-020-04551-4DOI Listing
September 2020

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

Cell 2020 09 10;182(6):1460-1473.e17. Epub 2020 Sep 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109273PMC
September 2020

Parkinson's disease: Are gut microbes involved?

Am J Physiol Gastrointest Liver Physiol 2020 11 2;319(5):G529-G540. Epub 2020 Sep 2.

Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1152/ajpgi.00058.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087343PMC
November 2020

Microbiota on biotics: probiotics, prebiotics, and synbiotics to optimize growth and metabolism.

Am J Physiol Gastrointest Liver Physiol 2020 09 5;319(3):G382-G390. Epub 2020 Aug 5.

Section of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.

The early stages of the metagenomics era produced countless observational studies linking various human diseases to alterations in the gut microbiota. Only recently have we begun to decipher the causal roles that gut microbes play in many of these conditions. Despite an incomplete understanding of how gut microbes influence pathophysiology, clinical trials have tested empirically numerous microbiota-targeting therapies to prevent or treat disease. Unsurprisingly, these trials have yielded mixed results. Nonetheless, the consumer market for probiotics, prebiotics, and synbiotics continues to grow. This theme paper highlights recent discoveries of mechanisms underlying diet-microbial-host interactions as they pertain to growth and metabolism and discusses current and future applications of microbiota-targeting therapies in the context of child malnutrition as well as obesity and its metabolic comorbidities, including nonalcoholic fatty liver disease and cardiovascular disease. We also highlight current challenges and identify future directions to facilitate a more efficient and direct path to clinical impact.
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http://dx.doi.org/10.1152/ajpgi.00028.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509258PMC
September 2020

Spotlight: Probiotics Guidelines.

Gastroenterology 2020 08 22;159(2):707. Epub 2020 Jul 22.

Section of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Baylor College of, Medicine and Texas Children's Hospital, Houston, TX.

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http://dx.doi.org/10.1053/j.gastro.2020.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046260PMC
August 2020

Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials.

Gastroenterology 2020 08 24;159(2):467-480. Epub 2020 Jun 24.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Anesthesia, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; The Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background & Aims: We aimed to compare the effectiveness of single- vs multiple-strain probiotics in a network meta-analysis of randomized trials.

Methods: We searched MEDLINE, Embase, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, BIOSIS Previews, and Google Scholar through January 1, 2019, for studies of single-strain and multistrain probiotic formulations on the outcomes of preterm, low-birth-weight neonates. We used a frequentist approach for network meta-analysis and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence. Primary outcomes included all-cause mortality, severe necrotizing enterocolitis (NEC) (Bell stage II or more), and culture-proven sepsis.

Results: We analyzed data from 63 trials involving 15,712 preterm infants. Compared with placebo, a combination of 1 or more Lactobacillus species (spp) and 1 or more Bifidobacterium spp was the only intervention with moderate- or high-quality evidence of reduced all-cause mortality (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39-0.80). Among interventions with moderate- or high-quality evidence for efficacy compared with placebo, combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp, Bifidobacterium animalis subspecies lactis, Lactobacillus reuteri, or Lactobacillus rhamnosus significantly reduced severe NEC (OR, 0.35 [95% CI, 0.20-0.59]; OR, 0.31 [95% CI, 0.13-0.74]; OR, 0.55 [95% CI, 0.34-0.91]; and OR, 0.44 [95% CI, 0.21-0.90], respectively). There was moderate- or high-quality evidence that combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp and Saccharomyces boulardii reduced the number of days to reach full feeding (mean reduction of 3.30 days [95% CI, reduction of 5.91-0.69 days]). There was moderate- or high-quality evidence that, compared with placebo, the single-species product B animalis subsp lactis or L reuteri significantly reduced duration of hospitalization (mean reduction of 13.00 days [95% CI, reduction of 22.71-3.29 days] and mean reduction of 7.89 days [95% CI, reduction of 11.60-4.17 days], respectively).

Conclusions: In a systematic review and network meta-analysis of studies to determine the effects of single-strain and multistrain probiotic formulations on outcomes of preterm, low-birth-weight neonates, we found moderate to high evidence for the superiority of combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp vs single- and other multiple-strain probiotic treatments. The combinations of Bacillus spp and Enterococcus spp, and 1 or more Bifidobacterium spp and Streptococcus salivarius subsp thermophilus, might produce the largest reduction in NEC development. Further trials are needed.
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http://dx.doi.org/10.1053/j.gastro.2020.05.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014956PMC
August 2020

AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders.

Gastroenterology 2020 08 9;159(2):708-738.e4. Epub 2020 Jun 9.

Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.

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http://dx.doi.org/10.1053/j.gastro.2020.05.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018518PMC
August 2020

Impact of air quality on the gastrointestinal microbiome: A review.

Environ Res 2020 07 7;186:109485. Epub 2020 Apr 7.

Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA; Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Electronic address:

Background: Poor air quality is increasingly associated with several gastrointestinal diseases suggesting a possible association between air quality and the human gut microbiome. However, details on this remain largely unexplored as current available research is scarce. The aim of this comprehensive rigorous review was to summarize the existing reports on the impact of indoor or outdoor airborne pollutants on the animal and human gut microbiome and to outline the challenges and suggestions to expand this field of research.

Methods And Results: A comprehensive search of several databases (inception to August 9, 2019, humans and animals, English language only) was designed and conducted by an experienced librarian to identify studies describing the impact of air pollution on the human gut microbiome. The retrieved articles were assessed independently by two reviewers. This process yielded six original research papers on the animal GI gastrointestinal microbiome and four on the human gut microbiome. β-diversity analyses from selected animal studies demonstrated a significantly different composition of the gut microbiota between control and exposed groups but changes in α-diversity were less uniform. No consistent findings in α or β-diversity were reported among the human studies. Changes in microbiota at the phylum level disclosed substantial discrepancies across animal and human studies.

Conclusions: A different composition of the gut microbiome, particularly in animal models, is associated with exposure to air pollution. Air pollution is associated with various taxa changes, which however do not follow a clear pattern. Future research using standardized methods are critical to replicate these initial findings and advance this emerging field.
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http://dx.doi.org/10.1016/j.envres.2020.109485DOI Listing
July 2020

High-fat diet-induced alterations to gut microbiota and gut-derived lipoteichoic acid contributes to the development of enteric neuropathy.

Neurogastroenterol Motil 2020 07 13;32(7):e13838. Epub 2020 Mar 13.

University of Idaho, Moscow, ID, USA.

Background: High-fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram-positive bacteria and short-chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility.

Methods: We fed germ-free (GF) and conventionally raised (CR) mice either a high-fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations.

Key Results: High-fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF-HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram-positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons.

Conclusions & Inferences: Gut microbial alterations induced increase in Gram-positive bacterial LTA may contribute to enteric neuropathy.
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http://dx.doi.org/10.1111/nmo.13838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319907PMC
July 2020

Clostridioides difficile Whole-genome Sequencing Differentiates Relapse With the Same Strain From Reinfection With a New Strain.

Clin Infect Dis 2021 03;72(5):806-813

Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Current approaches in tracking Clostridioides difficile infection (CDI) and individualizing patient management are incompletely defined.

Methods: We recruited 468 subjects with CDI at Mayo Clinic Rochester between May and December 2016 and performed whole-genome sequencing (WGS) on C. difficile isolates from 397. WGS was also performed on isolates from a subset of the subjects at the time of a recurrence of infection. The sequence data were analyzed by determining core genome multilocus sequence type (cgMLST), with isolates grouped by allelic differences and the predicted ribotype.

Results: There were no correlations between C. difficile isolates based either on cgMLST or ribotype groupings and CDI outcome. An epidemiologic assessment of hospitalized subjects harboring C. difficile isolates with ≤2 allelic differences, based on standard infection prevention and control assessment, revealed no evidence of person-to-person transmission. Interestingly, community-acquired CDI subjects in 40% of groups with ≤2 allelic differences resided within the same zip code. Among 18 subjects clinically classified as having recurrent CDI, WGS revealed 14 with initial and subsequent isolates differing by ≤2 allelic differences, suggesting a relapse of infection with the same initial strain, and 4 with isolates differing by >50 allelic differences, suggesting reinfection. Among the 5 subjects classified as having a reinfection based on the timing of recurrence, 3 had isolates with ≤2 allelic differences between them, suggesting a relapse, and 2 had isolates differing by >50 allelic differences, suggesting reinfection.

Conclusions: Our findings point to potential transmission of C. difficile in the community. WGS better differentiates relapse from reinfection than do definitions based on the timing of recurrence.
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http://dx.doi.org/10.1093/cid/ciaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935391PMC
March 2021

A decreased abundance of clostridia characterizes the gut microbiota in eosinophilic esophagitis.

Physiol Rep 2019 10;7(20):e14261

Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Abnormalities in the gut microbiome are associated with suppressed Th2 response (Belizario et al., 2018 Mediators Inflamm. 2018:2037838) and predisposition to atopic disease such as asthma and eczema. We investigated if this applies to eosinophilic esophagitis (EoE). Stool bacterial DNA was extracted and followed by 16S rRNA amplification from 12 patients with eosinophilic esophagitis and 12 controls. Alpha- and beta-diversity were analyzed. Only two patients had asthma or atopy and one patient was on budesonide. No patients were on PPIs. Patients with EoE had lower gut microbiota alpha diversity (species richness, P = 0.09; Shannon index, P = 0.01). The microbial composition was distinct as evidenced by significantly different beta diversity (P = 0.03) when compared to healthy controls. There were also significant differences in relative abundance at multiple taxonomic levels when comparing the two communities; at the phylum level, we observed a marked decrease in Firmicutes and increase in Bacteroidetes and at the order and family level there were significant decreases in Clostridia and Clostridiales in patients with EoE (q ≤ 0.1). We conclude that there are significant differences in microbial community structure, microbial richness, and evenness and a significant decrease in taxa within the Clostridia in patients with EoE. Our data suggest that Clostridia based interventions could be tested as adjuncts to current therapeutic strategies in EoE.
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http://dx.doi.org/10.14814/phy2.14261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813259PMC
October 2019

The ' lifestyle' of bile acid 7α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice.

Gut Microbes 2020 05 9;11(3):381-404. Epub 2019 Jun 9.

Department of Animal Sciences, University of Illinois at Urbana-Champaign , Urbana, IL, USA.

The formation of secondary bile acids by gut microbes is a current topic of considerable biomedical interest. However, a detailed understanding of the biology of anaerobic bacteria in the genus that are capable of generating secondary bile acids is lacking. We therefore sought to determine the transcriptional responses of two prominent secondary bile acid producing bacteria, and to bile salts () and the cecal environment of gnotobiotic mice. The genomes of DSM 15053 and DSM 13275 were closed, and found to encode 3,647 genes (3,584 protein-coding) and 2,363 predicted genes (of which 2,239 are protein-coding), respectively, and 1,035 orthologs were shared between and . RNA-Seq analysis was performed in growth medium alone, and in the presence of cholic acid (CA) and deoxycholic acid (DCA). Growth with CA resulted in differential expression (>0.58 logFC; FDR < 0.05) of 197 genes in and 118 genes in . The bile acid-inducible operons () from each organism were highly upregulated in the presence of CA but not DCA. We then colonized germ-free mice with human gut bacterial isolates capable of metabolizing taurine-conjugated bile acids. This consortium included bile salt hydrolase-expressing ATCC 8492, ATCC 8482, DSM 20701, as well as taurine-respiring DSM 11045, and deoxycholic/lithocholic acid generating DSM 15053 and DSM 13275. Butyrate and iso-bile acid-forming ATCC 27340 was also included. The Bacteroidetes made up 84.71% of 16S rDNA cecal reads, , constituted 14.7%, and the clostridia made up <.75% of 16S rDNA cecal reads. Bile acid metabolomics of the cecum, serum, and liver indicate that the synthetic community were capable of functional bile salt deconjugation, oxidation/isomerization, and 7α-dehydroxylation of bile acids. Cecal metatranscriptome analysis revealed expression of genes involved in metabolism of taurine-conjugated bile acids. The transcriptomes of and suggest fermentation of simple sugars and utilization of amino acids glycine and proline as electron acceptors. Genes predicted to be involved in trimethylamine (TMA) formation were also expressed.
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http://dx.doi.org/10.1080/19490976.2019.1618173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524365PMC
May 2020

Model of personalized postprandial glycemic response to food developed for an Israeli cohort predicts responses in Midwestern American individuals.

Am J Clin Nutr 2019 07;110(1):63-75

Center for Individualized Medicine, Mayo Clinic, Rochester, MN.

Background: Controlled glycemic concentrations are associated with a lower risk of conditions such as cardiovascular disease and diabetes. Models commonly used to guide interventions to control the glycemic response to food have low efficacy, with recent clinical guidelines arguing for the use of personalized approaches.

Objective: We tested the efficacy of a predictive model of personalized postprandial glycemic response to foods that was developed with an Israeli cohort and that takes into consideration food components and specific features, including the microbiome, when applied to individuals from the Midwestern US.

Design: We recruited 327 individuals for this study. Participants provided information regarding lifestyle, dietary habits, and health, as well as a stool sample for characterization of their gut microbiome. Participants were connected to continuous glucose monitors for 6 d, and the glycemic response to meals logged during this time was computed. The ability of a model trained using meals logged by the Israeli cohort to correctly predict glycemic responses in the Midwestern cohort was assessed and compared with that of a model trained using meals logged by both cohorts.

Results: When trained on the Israeli cohort meals only, model performance for predicting responses of individuals in the Midwestern cohort was better (R = 0.596) than that observed for models taking into consideration the carbohydrate (R = 0.395) or calorie content of the meals alone (R = 0.336). Performance increased (R = 0.618) when the model was trained on meals from both cohorts, likely because of the observed differences in age distribution, diet, and microbiome.

Conclusions: We show that the modeling framework described in Zeevi et al. for an Israeli cohort is applicable to a Midwestern population, and outperforms commonly used approaches for the control of blood glucose responses. The adaptation of the model to the Midwestern cohort further enhances performance and is a promising means for designing effective nutritional interventions to control glycemic responses to foods. This trial was registered at clinicaltrials.gov as NCT02945514.
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http://dx.doi.org/10.1093/ajcn/nqz028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599737PMC
July 2019

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Nat Commun 2019 05 1;10(1):2012. Epub 2019 May 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.
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http://dx.doi.org/10.1038/s41467-019-09964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494866PMC
May 2019

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS.

Gut 2020 01 28;69(1):62-73. Epub 2019 Mar 28.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS.

Design: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states.

Results: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota.

Conclusion: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.
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http://dx.doi.org/10.1136/gutjnl-2018-317416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765451PMC
January 2020

Assessment of a Personalized Approach to Predicting Postprandial Glycemic Responses to Food Among Individuals Without Diabetes.

JAMA Netw Open 2019 02 1;2(2):e188102. Epub 2019 Feb 1.

Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: Emerging evidence suggests that postprandial glycemic responses (PPGRs) to food may be influenced by and predicted according to characteristics unique to each individual, including anthropometric and microbiome variables. Interindividual diversity in PPGRs to food requires a personalized approach for the maintenance of healthy glycemic levels.

Objectives: To describe and predict the glycemic responses of individuals to a diverse array of foods using a model that considers the physiology and microbiome of the individual in addition to the characteristics of the foods consumed.

Design, Setting, And Participants: This cohort study using a personalized predictive model enrolled 327 individuals without diabetes from October 11, 2016, to December 13, 2017, in Minnesota and Florida to be part of a study lasting 6 days. The study measured anthropometric variables, described the gut microbial composition, and assessed blood glucose levels every 5 minutes using a continuous glucose monitor. Participants logged their food and activity information for the duration of the study. A predictive model of individualized PPGRs to a diverse array of foods was trained and applied.

Main Outcomes And Measures: Glycemic responses to food consumed over 6 days for each participant. The predictive model of personalized PPGRs considered individual features, including the microbiome, in addition to the features of the foods consumed.

Results: Postprandial response to the same foods varied across 327 individuals (mean [SD] age, 45 [12] years; 78.0% female). A model predicting each individual's responses to food that considers several individual factors in addition to food features had better overall performance (R = 0.62) than current standard-of-care approaches using nutritional content alone (R = 0.34 for calories and R = 0.40 for carbohydrates) to control postprandial glycemic levels.

Conclusions And Relevance: Across the cohort of adults without diabetes who were examined, a personalized predictive model that considers unique features of the individual, such as clinical characteristics, physiological variables, and the microbiome, in addition to nutrient content was more predictive than current dietary approaches that focus only on the calorie or carbohydrate content of foods. Providing individuals with tools to manage their glycemic responses to food based on personalized predictions of their PPGRs may allow them to maintain their blood glucose levels within limits associated with good health.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.8102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484621PMC
February 2019

US Immigration Westernizes the Human Gut Microbiome.

Cell 2018 11;175(4):962-972.e10

Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, MN 55455, USA; Biotechnology Institute, University of Minnesota, Minneapolis, MN 55455, USA; Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Many US immigrant populations develop metabolic diseases post immigration, but the causes are not well understood. Although the microbiome plays a role in metabolic disease, there have been no studies measuring the effects of US immigration on the gut microbiome. We collected stool, dietary recalls, and anthropometrics from 514 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants and 19 Karen individuals sampled before and after immigration, as well as from 36 US-born European American individuals. Using 16S and deep shotgun metagenomic DNA sequencing, we found that migration from a non-Western country to the United States is associated with immediate loss of gut microbiome diversity and function in which US-associated strains and functions displace native strains and functions. These effects increase with duration of US residence and are compounded by obesity and across generations.
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http://dx.doi.org/10.1016/j.cell.2018.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498444PMC
November 2018

uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea.

Sci Transl Med 2018 10;10(464)

Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with , the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing infection in susceptible patients.
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http://dx.doi.org/10.1126/scitranslmed.aam7019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537101PMC
October 2018

An Increased Abundance of Clostridiaceae Characterizes Arthritis in Inflammatory Bowel Disease and Rheumatoid Arthritis: A Cross-sectional Study.

Inflamm Bowel Dis 2019 04;25(5):902-913

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: Inflammatory bowel diseases (IBDs) are a group of heterogeneous inflammatory conditions affecting the gastrointestinal tract. Although there is considerable evidence linking the gut microbiota to intestinal inflammation, there is limited knowledge on its potential role in the development of extraintestinal manifestations of IBD.

Methods: Four groups of patients were included: IBD-associated arthropathy (IBD-A); IBD without arthropathy (IBD-N); rheumatoid arthritis (RA); and non-IBD, nonarthritis controls. DNA from stool samples was isolated and sequenced using the Illumina platform. Paired-end reads were quality-controlled using SHI7 and processed with SHOGUN. Abundance and diversity analyses were performed using QIIME, and compositional biomarker identification was performed using LEfSe.

Results: One hundred eighty patients were included in the analysis. IBD-A was associated with an increased abundance of microbial tyrosine degradation pathways when compared with IBD-N (P = 0.02), whereas IBD-A and RA patients both shared an increased abundance of Clostridiaceae when compared with controls (P = 0.045). We found that history of bowel surgery was a significant source of variability (P = 0.001) among all IBD patients and was associated with decreased alpha diversity and increased abundance of Enterobacteriaceae (P = 0.004).

Conclusions: An increased abundance of gut microbial tyrosine degradation pathways was associated with IBD-A. An increased abundance of Clostridiaceae was shared by both IBD-A and RA patients and suggests a potentially common microbial link for inflammatory arthritis. The increased abundance of Enterobacteriaceae, previously reported in IBD, may be due to the effects of previous bowel surgery and highlights the importance of controlling for this variable in future studies.
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http://dx.doi.org/10.1093/ibd/izy318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458525PMC
April 2019

The Gut Microbiome in Adult and Pediatric Functional Gastrointestinal Disorders.

Clin Gastroenterol Hepatol 2019 01 25;17(2):256-274. Epub 2018 Aug 25.

Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

The importance of gut microbiota in gastrointestinal (GI) physiology was well described, but our ability to study gut microbial ecosystems in their entirety was limited by culture-based methods prior to the sequencing revolution. The advent of high-throughput sequencing opened new avenues, allowing us to study gut microbial communities as an aggregate, independent of our ability to culture individual microbes. Early studies focused on association of changes in gut microbiota with different disease states, which was necessary to identify a potential role for microbes and generate novel hypotheses. Over the past few years the field has moved beyond associations to better understand the mechanistic implications of the microbiome in the pathophysiology of complex diseases. This movement also has resulted in a shift in our focus toward therapeutic strategies, which rely on better understanding the mediators of gut microbiota-host cross-talk. It is not surprising the gut microbiome has been implicated in the pathogenesis of functional gastrointestinal disorders given its role in modulating physiological processes such as immune development, GI motility and secretion, epithelial barrier integrity, and brain-gut communication. In this review, we focus on the current state of knowledge and future directions in microbiome research as it pertains to functional gastrointestinal disorders. We summarize the factors that help shape the gut microbiome in human beings. We discuss data from animal models and human studies to highlight existing paradigms regarding the mechanisms underlying microbiota-mediated alterations in physiological processes and their relevance in human interventions. While translation of microbiome science is still in its infancy, the outlook is optimistic and we are advancing in the right direction toward precise mechanism-based microbiota therapies.
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http://dx.doi.org/10.1016/j.cgh.2018.08.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314902PMC
January 2019

Gut Microbial Carbohydrate Metabolism Hinders Weight Loss in Overweight Adults Undergoing Lifestyle Intervention With a Volumetric Diet.

Mayo Clin Proc 2018 08;93(8):1104-1110

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

The rising incidence of obesity requires the reevaluation of our current therapeutic strategies to optimize patient outcomes. The objective of this study was to determine whether compositional and functional characteristics of the gut microbiota in adults predict responses to a comprehensive lifestyle intervention program in overweight and obese adults. We recruited 26 participants from the Mayo Clinic Obesity Treatment Research Program between August 6, 2013, and September 12, 2013, to participate in a lifestyle intervention program for weight loss. Adults aged 18 to 65 years with a body mass index of 27 to 39.9 kg/m and able to provide informed consent were included in the study. Fecal stool samples were obtained at baseline and after 3 months. Loss of at least 5% of baseline weight after 3 months was defined as success. Clinical characteristics and gut microbial composition and function were compared between those who achieved at least 5% and those who achieved less than 5% weight loss. After 3 months, 9 of 26 participants lost at least 5% of their weight. The mean weight loss was 7.89 kg (95% CI, 6.46-9.32 kg) in the success group and 1.51 kg (95% CI, 0.52-2.49 kg) in the less than 5% weight loss group. An increased abundance of Phascolarctobacterium was associated with success. In contrast, an increased abundance of Dialister and of genes encoding gut microbial carbohydrate-active enzymes was associated with failure to lose 5% body weight. A gut microbiota with increased capability for carbohydrate metabolism appears to be associated with decreased weight loss in overweight and obese patients undergoing a lifestyle intervention program.
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http://dx.doi.org/10.1016/j.mayocp.2018.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107068PMC
August 2018