Integria Healthcare Symposium 2021Restoring the Seat of Health 1
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut Health
Dr Elizabeth SteelsPhD, GradDip(Nutr), GradCert(Ed), BSc(Hon)
Adjunct Senior Research Fellow, School of Pharmacy, UQ
Evidence Sciences Pty. Ltd.
Integria Healthcare Symposium 2021Restoring the Seat of Health 2
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Topics for Today
• Constipation and the functional axis of constipation
• Impact of dietary fibre and polyphenols
• Clinical study
Functional Constipation
Integria Healthcare Symposium 2021Restoring the Seat of Health 3
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Functional Constipation (FC)
• Is a primary disorder without underlying cause (excludes those with acondition that affects bowel motions)
• <3 stool motions per week on average
• Mostly type 1 and type 2 stools (Bristol Stool Chart)
• Having to strain during during evacuation and may have bloating,discomfort and pain
Chronic constipation. Nat Rev Dis Primers 3, 17096 (2017). https://doi.org/10.1038/nrdp.2017.96
Integria Healthcare Symposium 2021Restoring the Seat of Health 4
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Constipation: Underlying Considerations
https://www.grepmed.com/images/13083/differential-constipation-diagnosis-causes
Concomitant Considerations
• Mechanical: Colon, rectal or anal stricture, megacolon rectocele, intestinal pseudoobstruction, injured tissues, diverticulosis, abnormal narrowing of intestine or rectum
• Organic stenosis: Cancer or cancer-related causes, diverticulitis, sigmoid or caecalvolvulus, intestinal masses, inflammatory and ischemic or surgical stenosis
• Psychological conditions: Depression, anxiety, eating disorders
• Enteric neuropathies: Hirschsprung disease
• Neurological disorders: MS, Parkinson’s, stroke, spinal cord injury, paraplegia,spina bifida, autonomic neuropathy
• Endocrine/metabolic conditions: T2D, hypercalcaemia, porphyria,hypo/hyperthyroidism, pregnancy
• Myopathic disorders: Scleroderma and amyloidosis
• Connective tissue disorders: Lupus
Forootan M, Bagheri N, Darvishi M. Chronic constipation: A review of literature. Medicine. 2018;97(20). doi: 10.1097/MD.0000000000010631
Integria Healthcare Symposium 2021Restoring the Seat of Health 5
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Medication Considerations and Subtypes of Constipation
Forootan M, Bagheri N, Darvishi M. Chronic constipation: A review of literature. Medicine. 2018;97(20). doi: 10.1097/MD.0000000000010631
Bristol Stool Chart
Slow
transit
Rapid
transit
• Types 1, 2 and 3 are hard or
impacted
• Types 4 and 5 are normal
and optimal
• Type 6 is subnormal
• Type 7 is diarrhoea
• Colour and shape can be
red flags
Integria Healthcare Symposium 2021Restoring the Seat of Health 6
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
FC More Than Just Poor Stool Output
Social Work Mood Health
Functional Axis of Constipation
Integria Healthcare Symposium 2021Restoring the Seat of Health 7
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Kastl Jr AJ, Terry NA et al. The structure and function of the human small intestinal microbiota: current understanding and future directions. Cell Mol Gastroenterol Hepatol.
2020;9(1):33-45. doi.10.1016/j.jcmgh.2019.07.006
Grenham S, Clarke G et al. Brain–gut–microbe communication in health and disease. Front. Physiol. 2011;2:94. doi 10.3389/fphys.2011.00094.
Factors that Support GIT Motility
• Factors that are vital to normal GIT motility are:
• Immune function
• Nervous system function
• Bile acid metabolism and mucus secretion
• GIT microbiota
• GIT fermentation
• An imbalance or dysfunction in any of these components may contribute to:
• Altered gut motility
• Symptoms of constipation
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Integria Healthcare Symposium 2021Restoring the Seat of Health 8
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Colonic Transit is Linked to Gut Microbiota Diversity and Microbial Fermentation
Müller M, Hermes GD et al. Distal colonic transit is linked to gut microbiota diversity and microbial fermentation in humans with slow colonic transit. Am J Physiol Gastrointest Liver Physiol. 2020;318(2):G361-9. doi.10.1152/ajpgi.00283.2019
Constipation and Gut Microbiome
• Study 1: FC patients had:
• Relative decrease in obligate bacteria(Lactobacillus, Bifidobacterium/Bacteroides spp.)
• Parallel increase of potentially pathogenic microorganisms(Pseudomonas aeruginosa/Campylobacter jejuni)
• Study 2: FC patients had:
• Decreased Prevotella and increased representation in several generaof Firmicutes
• No change in genera Lactobacillus and Bifidobacteria
1. Zhao Y, Yu YB. Intestinal microbiota and chronic constipation. Springer plus. 2016;5(1):1130. doi:10.1186/s40064-016-2821-12. Ahmadi S, Nagpal R et al. Prebiotics from acorn and sago prevent high-fat-diet-induced insulin resistance via microbiome–gut–brain axis modulation.
J Nutr Biochem. 2019;67:1-3. doi.10.1016/j.jnutbio.2019.01.011
Integria Healthcare Symposium 2021Restoring the Seat of Health 9
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Gut Dysbiosis Complications
Fukui H. Gut microbiome-based therapeutics in liver cirrhosis: basic consideration for the next step. J Clin Transl Hepatol. 2017;5(3):249. doi.10.14218/JCTH.2017.00008
Stress and heightened emotional
states can affect GIT motility (as
well as increase abdominal pain and
the ANS modulates these effects).
The long-term effects of stress have
functional effects; altering GIT
motility and secretions, reducing the
capacity of gastrointestinal mucosa
to regenerate, which in turn can
impact on the health of the gut
microbiome.
Constipation and Gut-Brain Axis
Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat Rev Gasteroenterol Hepatol. 2009;6(5). doi: 10.1038/nrgastro.2009.35
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Integria Healthcare Symposium 2021Restoring the Seat of Health 10
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Constipation, Gut-Brain Axis and Gut Microbiome
• It is now recognised that the gut-brainaxis plays a pivotal role in:
• Stress related disorders andgastrointestinal motility
• This may be related to the gutmicrobiome
Carco C, Young W et al. Increasing evidence that irritable bowel syndrome and functional gastrointestinal disorders have a microbial pathogenesis. Front. Cell. Infect. Microbiol. 2020. doi.10.3389/fcimb.2020.00468
Microbiota Regulation of Neuroinflammation and HPA Axis Activity
Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23-33. doi.10.1016/j.ynstr.2016.03.001
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Integria Healthcare Symposium 2021Restoring the Seat of Health 11
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Words for figure
• Schematic for microbiota regulation of neuroinflammation and HPA axis activity.Communication within the microbiota-gut-brain axis involves the complex co-ordination ofa number of factors and systems. The microbiota can govern events in the periphery andCNS by various means of communication including vagal nerve activation, cytokineproduction, neuropeptide and neurotransmitter release, SCFA release and microbial by-products, and by utilising the lymphatic and systemic circulation. Once these signalspenetrate the blood brain barrier and reach the brain, they can influence the maturationand activation state of the microglia. Once activated, microglia play a key role in immunesurveillance, synaptic pruning and clearance of debris. They also facilitate a number ofeveryday functions in the brain, including the regulation of HPA axis activation state. Therelease of glucocorticoids (cortisol) as a consequence of HPA axis activation can in turnregulate the activation state of brain microglia, as well as influence cytokine release andtrafficking of monocytes from the periphery to the brain. HPA Hypothalamic-Pituitary-Adrenal; BDNF Brain derived neurotrophic factor; LTP Long term potentiation; BBB Blood-brain barrier; GC Glucocorticoids; GR Glucocorticoid receptor; FFAR Free fatty acidreceptor; SCFA Short chain fatty acid; NP Neuropeptide; NT Neurotransmitter; DCDendritic cell; EEC Enteroendocrine cell.
Rea K, Dinan TG, Cryan JF. The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23-33. doi.10.1016/j.ynstr.2016.03.001
Gut-Metabolic Axis
Moreno-Indias I, Cardona F et al. Impact of the gut microbiota on the developmhttps://doi.org/10.3389/fmicb.2014.00190ent of obesity and type 2 diabetes mellitus. Front. Microbiol. 2014;5:190. doi 10.3389/fmicb.2014.00190
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Integria Healthcare Symposium 2021Restoring the Seat of Health 12
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Summary of Functional Constipation
Clinical insights:
• Diet: fibre, prebiotics, water
• Disrupted microbiome
• Neurological: acute anxiety
• Conditioning: neurological,childhood?
Vriesman, Mana H et al., 2020. Management of functional constipation in children and adults. Nature reviews. Gastroenterol Hepatol, 17(1), pp.21–39.
Impact of Dietary Fibre and Polyphenols
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Integria Healthcare Symposium 2021Restoring the Seat of Health 13
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Function of the Intestinal Microbiome
Grenham S, Clarke G et al. Brain–gut–microbe communication in health and disease. Front. Physiol. 2011;2:94. doi 10.3389/fphys.2011.00094.
Probiotics versus Prebiotics
Integria Healthcare Symposium 2021Restoring the Seat of Health 14
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Key Definitions
• Probiotics: microorganisms that alter the microflora of the host, availableas supplements or through diet1
• Prebiotics: nondigestible dietary components that selectively stimulate thegrowth and/or activity of host bacteria1
• Synbiotics: contain both probiotics and prebiotics1
• Postbiotics: According to the International Scientific Association ofProbiotics and Prebiotics (ISAPP), a postbiotic is defined as a “preparationof inanimate microorganisms and/or their components that confers ahealth benefit on the host” 2
1. Patel RM, Denning PW. Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence?Clinics in Perinatology. 2013;40(1):11-25. DOI: 10.1016/j.clp.2012.12.002.
2. Salminen, S., Collado, M.C. et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat Rev Gastroenterol Hepatol. 2021;18, 649–667. doi.10.1038/s41575-021-00440-6
Pre- Pro- and Postbiotics
Patel RM, Denning PW. Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence? Clinics in Perinatology. 2013;40(1):11-25. DOI: 10.1016/j.clp.2012.12.002.
Integria Healthcare Symposium 2021Restoring the Seat of Health 15
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Effect of Prebiotics on Gut Function and Health
Mohajeri, M.H., Brummer. et al. The role of the microbiome for human health: from basic science to clinical applications. Eur J Nutr. 2018;57,1–14. doi.10.1007/s00394-018-1703-4
Dietary Fibre & Prebiotics
• The human body needs a variety of fibre for:
1. Transit time support
2. Microbiome composition support (prebiotic)
• If the microbiome only has access to fibre from a single source such asrefined flour, there will be a reduction in microbiome diversity and someGIT issues
• The fruit and vegetables in the diet also provide an importantprebiotic that is not a chained CHO (polyphenols)
Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics (2017)
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of
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Integria Healthcare Symposium 2021Restoring the Seat of Health 16
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Variety of Fibre is Essential
Low-Residue and Low-Fiber Diets in Gastrointestinal Disease Management - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Overview-of-possible-effects-of-different-fibers-on-gastrointestinal-digestion-and_fig1_283790366 [accessed 3 Aug,
2021]
Impact of Dietary Fibre, SCFAs & Inflammation
Keshteli AH, Madsen KL, Dieleman LA. Diet in the pathogenesis and management of ulcerative colitis; A review of randomized controlled dietary interventions. Nutrients. 2019;11(7):1498. doi.10.3390/nu11071498
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Integria Healthcare Symposium 2021Restoring the Seat of Health 17
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Dietary Fibre & SCFAs Influence Detoxification
Spanogiannopoulos P, Bess EN et al. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14(5):273-87. doi.10.1038/nrmicro.2016.17
Dietary Fibre, SCFAs & Systemic Circulation
Dalile B, Van Oudenhove L et al. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gasteroenterol Hepatol. 2019;16(8):461-78. doi.10.1038/s41575-019-0157-3
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Integria Healthcare Symposium 2021Restoring the Seat of Health 18
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Metabolic Effects of Dietary Fibre & SCFAs
Li X, Watanabe K, Kimura I. Gut microbiota dysbiosis drives and implies novel therapeutic strategies for diabetes mellitus and related metabolic diseases. Front Immunol. 2017 Dec 20;8:1882. doi.10.3389/fimmu.2017.01882
Dietary Fibre & SCFAs Shape Gut-Brain Connection
Dalile B, Van Oudenhove L et al. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat
Rev Gasteroenterol Hepatol. 2019;16(8):461-78. doi.10.1038/s41575-019-0157-3
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Integria Healthcare Symposium 2021Restoring the Seat of Health 19
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Aim for Variety of Prebiotics/Polyphenols in Diet
• Process of “Cross-feeding”
• Products produced from fermentation of a polysaccharide by one bacterialspecies provide substrates for growth of other bacteria
• Dietary fibre promotes extensive metabolic interactions among bacterialspecies in the GIT microbiota
• Indirect stimulation of the growth of other microbes within the communitythrough the utilisation of by-products of other community members
• Dietary modulation of GIT microbiota via fibre or prebiotic consumption canresult in metabolic consequences that are different from results of singleculture-based experimentations that assess bacterial growth on isolatedsubstrates
Individual Responses to Prebiotics/Polyphenols
• Microbiota response to dietary modulation via fibre is influenced by:
• Host genetics
• Adequate dosages of the dietary polysaccharide of interest
• Individual microbiota composition
• Individuals could be categorised into responders and non-responders
• 2.5 g/d FOS or GOS did not increase Bifidobacteria, while doses of 10 g/d did
• Up to 7.5 g/day of agave inulin produced no response in people without Bifidobacteria
• Composition of individual microbiota and keystone species influences fibre fermentation
• Ruminococcus bromii had a reduced capacity to ferment the supplemented resistantstarch, resulting in 20–30% fermentability compared to 100% fermentability in thosewithout it
Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. 2017;8(2):172-184. doi:10.1080/19490976.2017.1290756
Integria Healthcare Symposium 2021Restoring the Seat of Health 20
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Importance of Fibre Polyphenol Ratio
• Consider fibre intake in context ofentire diet
• Dietary fibre per kilocalorie hasbeen shown to be positively relatedto both Bifidobacterium spp.abundance and faecal butyrateconcentrations
Makki K, Deehan EC, et al. The impact of dietary fiber on gut microbiota in host health and disease. Cell Host Microbe. 2018;23(6):705-15.
Chemical Structure of Polyphenols
• Dietary polyphenols arenatural compoundsoccurring in plants,including foods such asfruits, vegetables, cereals,tea, coffee and wine
• Chemically, polyphenolsare a large heterogeneousgroup of compoundscharacterized byhydroxylated phenylmoieties
Beconcini D, Felice F et al. (2020). Antioxidant and anti-inflammatory properties of cherry extract: nanosystems-based strategies to improve endothelial function and intestinal absorption. Foods. 2020;9(2):207. doi 10.3390/foods9020207.
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Integria Healthcare Symposium 2021Restoring the Seat of Health 21
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Polyphenols Interactions with the Gut
• Microbial glucuronidase andsulphatase activity may alsodeconjugate the phase II metabolitesextruded via the bile throughout theenterohepatic circulation, enabling theirreuptake and affect bioavailability
• Clostridium and Eubacterium involvedin metabolism of phenolics such asisoflavones, flavones and flavan-3-ols
• Firmicutes possess less glycan-degrading enzymes than Bacteroideteswhich also suggests that intake ofdifferent polyphenols could reshape thegut microbiota differently
Cardona F, Andrés-Lacueva C et al. Benefits of polyphenols on gut microbiota and implications in human health, J Nutr Biochem. 2013;24(8):1415-22. doi 10.1016/j.jnutbio.2013.05.001.
Polyphenols and Gut Microbiota• Phenolics alter gut microbiota and alter Bacteroides / Firmicutes balance1
• Catechin inhibits growth of Clostridium histolyticum and enhances growth of E. coli andmembers of Clostridium coccoides–Eubacterium rectale group, while growthof Bifidobacterium and Lactobacillus spp. remain relatively unaffected2
• Proanthocyanidin-rich extract from grape seeds given to healthy adults for 2 weeks wasable to significantly increase the number of Bifidobacteria3
• Monomeric flavan-3-ols and flavan-3-ol-rich sources (chocolate, green tea, blackcurrant,grape seed extracts may modulate the intestinal microbiota, producing changes inbeneficial bacteria such as Lactobacillus spp. but inhibiting other groups such asClostridium spp. in both in vivo and in vitro studies4
• A cocoa dietary intervention in a rat model showed a significant decrease in the proportionof Bacteroides, Clostridium and Staphylococcus genera in the faeces of cocoa-fedanimals5
Integria Healthcare Symposium 2021Restoring the Seat of Health 22
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
References for Previous Slide
1. Tzounis X, Rodriguez-Mateos A et al. Prebiotic evaluation of cocoa-derived flavanols inhealthy humans by using a randomized, controlled, double-blind, crossover interventionstudy. AJCN. 2011;93(1):62-72. doi.10.3945/ajcn.110.000075
2. Yamakoshi J, Tokutake S et al. Effect of proanthocyanidin-rich extract from grape seedson human fecal flora and fecal odor. Microb Ecol Health Dis. 2001;13(1):25-31.doi 10.1080/089106001750071672
3. Molan AL, Liu Z. Kruger M. The ability of blackcurrant extracts to positively modulatekey markers of gastrointestinal function in rats. World J MicrobiolBiotechnol. 2010;26(10):1735-43. doi 10.1007/s11274-010-0352-4
4. Viveros A, Chamorro S et al. Effects of dietary polyphenol-rich grape products onintestinal microflora and gut morphology in broiler chicks Poult Sci. 2011 Mar1;90(3):566-78. doi 10.3382/ps.2010-00889
5. Massot-Cladera M, Pérez-Berezo T et al. Cocoa modulatory effect on rat faecalmicrobiota and colonic crosstalk. Arch Biochem Biophys. 2012;527(2):105-12.doi 10.1016/j.abb.2012.05.015
Polyphenols Inhibit Pathogenic Microbes
• Variety of potential mechanisms of action of polyphenols on bacterial cellsand pathogenic species:
• Bind to bacterial cell membranes disturbing membrane function andinhibiting cell growth (catechins inhibit K. pneumonie, S. choleraesis,P. aeruginosa, S. aureus)
• Interfere with bacterial quorum sensing, which is achieved byproducing, releasing and detecting small signal molecules identified asautoinducers (green tea sensitises MRSA to B-lactum antibiotics, redwine/green tea polyphenols inhibit VacA in H.pylori)
• Inhibitory action on DNA and RNA synthesis (quercetin binds DNAE.coli subunits)
Cardona F, Andrés-Lacueva C et al. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem. 2013;24(8):1415-22. doi10.1016/j.jnutbio.2013.05.001
Integria Healthcare Symposium 2021Restoring the Seat of Health 23
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Polyphenols Reduce Inflammation
• Bacterial fermentation of cocoa fractions increases Bifidobacteria,Lactobacilli and butyrate production and reduces plasma triacylglyceroland CRP
• Regular intake of red wine polyphenols/cocoa decreases BP andtriglycerides, increases HDL and growth of Bacteroides, also decreasesuric acid levels
• Hypothesised that reduction in CRP is due to increase in Bifidobacterium
V. Fogliano, M.L. Corollaro, et al. In vitro bioaccessibility and gut biotransformation of polyphenols present in the water-insoluble cocoa fraction. Mol NutrFood Res, 55 (1) (2011), pp. 44-55
M.I. Queipo-Ortuño, M. Boto-Ordóñez, et al. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers
Summary
Kumar Singh A, Cabral C, et al. Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients. 2019;11(9):2216. doi 10.3390/nu11092216
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Integria Healthcare Symposium 2021Restoring the Seat of Health 24
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Summary - Polyphenols and Gut Health
• Bioavailability and effects of polyphenols greatly depend on theirtransformation by components of the gut microbiota
• Studies are determining gut microbiota transformation of particularpolyphenol types and identifying responsible microorganisms
• Dietary polyphenols and their metabolites exert prebiotic-like effects tomaintain gut health; stimulating growth of beneficial bacteria and inhibitingpathogenic bacteria
• New techniques of metagenomic and metabolomic studies will providemore insight into health effects of polyphenols
Insights from a Prebiotic Intervention Study on Functional Constipation
Integria Healthcare Symposium 2021Restoring the Seat of Health 25
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Clinical Study Rationale• Treatment with a polyphenol/prebiotic formulation for 3 weeks in a group of
people with:
1. Functional constipation and associated GIT symptoms and
2. Self-reported low intake of fruits, vegetables and whole grains
• Will result in positive health benefits including:
• Improved bowel motions (frequency and consistency)
• Reduction in GIT symptoms and improvement in QOL
• Gut microbiome modulating effects *
• Safe (RBC and E/LFT) and well tolerated
* Results are still being analysed
Constipation-related Symptoms
PAC-SYM questionnaire
• 12 questions about constipation
• The symptoms rated from none (0) to
severe (4)
• Symptom subscales:
• Abdominal (Q1-4)
• Rectal (Q5-8)
• Stool (Q9-12)
• Study: Baseline results:
• Average score: 17 (max 48)
Range of scores 7 to 33
Discomfort in your abdomen
Pain in your abdomen
Bloating in your abdomen
Stomach cramps
Painful bowel movements
Rectal bleeding during or after a bowel movement
Incomplete bowel movement, like you didn’t “finish”
Bowel movements that were too hard
Bowel movements that were too small
Straining or squeezing to try to pass bowel movements
Integria Healthcare Symposium 2021Restoring the Seat of Health 26
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Constipation-related Quality of Life
PAC-Q
• Specific effects of constipation on how people function in daily life
• PAQ has been validated against and correlates with the PAC-SYM
DASS
• Focusses on the symptoms of depression, anxiety and stress in the person
on that day (overall mood)
Clinic insight:
• Functional constipation has a significant impact on quality of life
• Higher prevalence of anxiety/stress in those with functional constipation
than general population
Constipationrelated
QOL
PAC-QOL
Physical discomfort 1. Felt bloated to the point of bursting?
2. Felt heavy because of your constipation?
3. Felt any physical discomfort?
4. Felt the need to have a bowel motion but not able to?
Psychosocial
discomfort
5. Been embarrassed to be with other people?
6. Been eating less and less because of not being able to have bowel movements?
7. Had to be careful about what you eat?
8. Had a decreased appetite?
9. Choose what you eat (for example, at a friend’s house)?
10. Been embarrassed about staying in the bathroom for so long when you were away from home?
11. Been embarrassed about having to go to the bathroom so often when you were away from home?
12. Your daily routine (for example, traveling, being away from home)?
Worries and concerns 13. Felt irritable because of your condition?
14. Been upset by your condition?
15. Felt obsessed by your condition?
16. Felt stressed by your condition?
17. Felt less self-confident because of your condition?
18. Felt in control of your situation?
19. Been worried about not knowing when you are going to be able to have a bowel movement?
20. Been worried about not being able to have a bowel movement?
21. Been more and more bothered by not being able to have a bowel movement?
22. Been worried that your condition will get worse?
23. Felt that your body was not working properly?
Treatment satisfaction 24. Had fewer bowel movements than you would like?
25. Satisfied with how often you have a bowel movement?
26. Satisfied with the regularity of your bowel movements?
27. Satisfied with the time it takes for food to pass through the intestines?
28. Satisfied with your treatment?
Co
ns
tip
ati
on
rela
ted
Q
OL
PA
C-Q
OL
Ph
ys
ica
l d
isc
om
fort
1.F
elt
blo
ate
dto
the
poin
tofb
urs
tin
g?
2.F
elt
heavy
because
ofyour
constipation?
3.F
elt
any
ph
ysic
ald
isco
mfo
rt?
4.F
elt
the
need
toh
ave
ab
ow
elm
otio
nbutnotable
to?
Ps
yc
ho
so
cia
l
dis
co
mfo
rt
5. B
ee
n e
mb
arr
asse
d to
be
with
oth
er
pe
op
le?
6. B
ee
n e
atin
g le
ss a
nd
le
ss b
eca
use o
f n
ot b
ein
g a
ble
to
ha
ve
bo
we
l m
ove
me
nts
?
7. H
ad
to
be
ca
refu
l a
bo
ut w
ha
t yo
u e
at?
8. H
ad
a d
ecre
ase
d a
pp
etite
?
9. C
ho
ose
wh
at
yo
u e
at (f
or
exa
mp
le, a
t a
frie
nd
’s h
ou
se
)?
10
. B
ee
n e
mb
arr
assed
ab
ou
t sta
yin
g in
th
e b
ath
roo
m fo
r so
lo
ng
wh
en
yo
u w
ere
aw
ay f
rom
ho
me
?
11
. B
ee
n e
mb
arr
asse
d a
bo
ut h
avin
g to
go
to
th
e b
ath
roo
m s
o o
fte
n w
he
n y
ou
we
re a
wa
y f
rom
ho
me
?
12
. Y
ou
r d
aily
ro
utin
e (
for
exa
mp
le, tr
ave
ling
, b
ein
g a
wa
y f
rom
ho
me
)?
Wo
rrie
s a
nd
co
nc
ern
s1
3. F
elt irr
ita
ble
be
ca
use
of yo
ur
co
nd
itio
n?
14
. B
ee
n u
pse
t b
y y
ou
r co
nd
itio
n?
15. F
elt o
bsessed b
y y
our
conditio
n?
16
. F
elt s
tre
sse
d b
y y
ou
r co
nd
itio
n?
17
. F
elt le
ss s
elf-c
on
fid
en
t b
eca
use
of yo
ur
co
nd
itio
n?
18
. F
elt in
co
ntr
ol o
f yo
ur
situ
atio
n?
19
. B
ee
n w
orr
ied
ab
ou
t n
ot kn
ow
ing
wh
en
yo
u a
re g
oin
g to
be
ab
le to
ha
ve
a b
ow
el m
ove
me
nt?
20
. B
ee
n w
orr
ied
ab
ou
t n
ot b
ein
g a
ble
to
ha
ve
a b
ow
el m
ove
me
nt?
21
. B
ee
n m
ore
an
d m
ore
bo
the
red
by n
ot b
ein
g a
ble
to
ha
ve
a b
ow
el m
ove
me
nt?
22
. B
ee
n w
orr
ied
th
at yo
ur
co
nd
itio
n w
ill g
et w
ors
e?
23
. F
elt th
at yo
ur
bo
dy w
as n
ot w
ork
ing
pro
pe
rly?
Tre
atm
en
t s
ati
sfa
cti
on
24
. H
ad
fe
we
r b
ow
el m
ove
me
nts
th
an
yo
u w
ou
ld lik
e?
25
. S
atisfie
d w
ith
ho
w o
fte
n y
ou
ha
ve
a b
ow
el m
ove
me
nt?
26
. S
atisfie
d w
ith
th
e r
eg
ula
rity
of yo
ur
bo
we
l m
ove
me
nts
?
27. S
atisfied w
ith the tim
e it ta
kes for
food to p
ass thro
ugh the inte
stines?
28
. S
atisfie
d w
ith
yo
ur
tre
atm
ent?
Integria Healthcare Symposium 2021Restoring the Seat of Health 27
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Clinical Aspects
1. Poor diet was a recognised probable cause (n=40; 66%)
2. Restricted diet (food sensitivities, major issue was dairy, gluten) (n=6, 10%)
3. Coffee used as a laxative (n=10, 13%) (why?)
4. Regular exercise (n=18, 29%) beneficial or not? Dehydration, electrolytes?
5. Possibly hormone related (n=3, 5%)
6. Experiencing stress and/or anxiety (n=21, 32%)
7. Wide variation in total energy intake (lowest 800 calories)
8. High consumption of foods that may increase constipation – gluten containingfoods, processed grains (bread, pasta, rice), milk and dairy products, red meat,fried or fast foods, alcohol
Study Design
• Study Group • Polyphenol/Prebiotic Formulation
Total Men Women
Prebiotic 28 8 (10.7%) 25 (89.3%)
Comparator 30 9 (30.0%) 21 (70.0%)
Ingredients Quantity
Partially hydrolysed Guar Gum (PHGG) 3 g
Acacia Gum 1 g
Slippery Elm 500 mg
Fruit Pectin 500 mg
Theobroma cacao (Cacao) 500 mg
Hylocereus polyrhizus (Red Dragon Fruit) 500 mg
Integria Healthcare Symposium 2021Restoring the Seat of Health 28
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Intervention Improves Stool Frequency
• Baseline • Day 21
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Av Baseline Av week 1 Av week 2 Av week 3
Stool frequency (weeks total)
Intervention Improves Stool Frequency
Group A – Prebiotic group Group B – Comparator group
Inte
rven
tio
n I
mp
roves S
too
l F
req
uen
cy
•B
ase
line
•D
ay 2
1
Integria Healthcare Symposium 2021Restoring the Seat of Health 29
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Intervention Improves Stool Frequency
Stool frequency
Baseline P-value W1 P-value W2 P-value W3 P-value
Prebiotic 2.8 (1-4)
0.397
3.3 (2-6)
0.022
3.9 (0-7)
0.014
4.6 (0-7)
<0.001Comparator 2.9 (2-4) 2.9 (2-4) 3.2 (1-6) 3.0 (2-5)
*Significance similar using ANOVA and Mann-Witney U test
Intervention Improves Stool Composition
Baseline Days 1-7 Days 8-14 Days 15-21
Prebiotic Min 1.3 - 5.3 1.0 - 5.0 2.0 - 5.6 1.7 - 5.6
Av. (SD) 2.8 (1.2) 2.8 (1.0) 3.2 (0.8) 3.3 (0.9)
Comparator Min 1.3 - 6.3 1.3 - 5.5 1.3 - 5.5 1.0 - 4.5
Av. (SD) 2.7 (1.2) 2.6 (1.2) 2.7 (1.1) 2.5 (0.8)
P-value 0.8471 0.5475 0.1592 0.0014
Based on the Bristol Stool Chart
The results were calculated by dividing the sum of the stool compositions in each week by number of stools recorded
in that week. i.e 3 stools of a consistency of Bristol Stool Type 2, 1, & 3 respectively is (2+1+3)/3 = 2.
P=<0.05, significant; probability assessed by T-test
Integria Healthcare Symposium 2021Restoring the Seat of Health 30
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
0.00
10.00
20.00
Significant reduction in symptoms and improvement in QOL in Prebiotic group (A) compared to comparator (B)
Intervention Improves QOL
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
PAC-SYM PAC-Q
Group A – Prebiotic group Group B – Comparator group
PAC-SYM Sub-scores Baseline and Day 21
Baseline Completion (Day 21)
Prebiotic Comparator P value Prebiotic Comparator P value
Sub-scores
Abdominal symptoms 6.8 + 3.3 6.6 + 3.5 0.784 2.3 + 2.2 5.7 + 2.5 <0.001
Rectal Symptoms 2.2 + 2.3 2.0 + 2.0 0.815 0.6 + 1.0 1.4 +1.2 0.004
Stool symptoms 7.6 + 3.5 8.0 + 4.2 0.669 0.5 + 0.5 0.2 + 0.4 0.022
Integria Healthcare Symposium 2021Restoring the Seat of Health 31
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Intervention Improves QOL: PAC-SYM
Prebiotic Prebiotic
PAC-SYMBaseline
n= 28 (total)
Week 3
n = 28 (total)
1. Discomfort in your abdomen 27 (96%) 17 (61%)
2. Pain in your abdomen 21 (75%) 13 (46%)
3. Bloating in your abdomen 27 (96%) 19(68%)
4. Stomach cramps 22 (79%) 8 (27%)
5. Painful bowel movements 18 (64%) 7 (33%)
6. Rectal burning during or after a bowel movement 15 (54%) 4 (14%)
7. Rectal bleeding or tearing during or after a bowel movement 10 (36%) 4 (14%)
8. Incomplete bowel movement, like you didn’t “finish” 25 (89%) 12 (43%)
9. Bowel movements that were too hard 24 (86%) 17 (61%)
10. Bowel movements that were too small 24 (86% 8 (27%)
11. Straining or squeezing to try to pass bowel movements 24 (86%) 16 (57%)
12. Feeling like you had to pass a bowel movement but you couldn’t (false alarm) 22 (79%) 12 (43%)
0.00
1.00
2.00
3.00
4.00
5.00
6.00
Baseline Final
Depression
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
4.00
4.50
5.00
Baseline Final
Anxiety
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
Baseline Final
Stress
Reductions in Depression, Anxiety and Stress
Group A – Prebiotic group Group B – Comparator group
Integria Healthcare Symposium 2021Restoring the Seat of Health 32
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Intervention Enhanced Diversity and Richness
ind
ex
Change Score = stool frequency
Outcome Summary
• Prebiotic treatment 16 g day:• More regular bowel motions and better formed stools• Reduced abdominal symptoms• Better quality of life• Better mood• Highly variable results observed
• Other Comments: Increased satiety/reduced hunger, reduced food intake,perceived weight loss, greater energy levels
• Link for prebiotics /polyphenols and neurological function and metabolism• Possibly through the gut microbiome (future analysis)
Integria Healthcare Symposium 2021Restoring the Seat of Health 33
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Too Much Fibre?
• The amount of fibre to support GIT health and healthy bowel motionsvaries from person to person
• Increasing fibre consumption may not make colonic transit normal
• Increasing fibre consumption may even worsen symptoms through theeffect of the fibre on microbiome metabolism and the gas produced withsymptoms of bloating, abdominal distension and pain
Plant based foods
Bulk fibre for stools
Contributes to fluid intake
Prebiotics to feed
microbiome
Polyphenols with positive
effects on GIT and
metabolism
Enhanced microbiome, diversity & richness
GIT symptoms & functional constipation
Improved sleep,
anxiety & stress
Altered microbiome, diversity
No improvement in GIT symptoms & functional constipation
No improvements in sleep, anxiety & stress
intake intake
Integria Healthcare Symposium 2021Restoring the Seat of Health 34
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Benefits of Prebiotics and Polyphenols for Functional Constipation
• Support transport time?
• Support gut health and reduceinflammation?
• Support gut microbiome diversity?
• Support neurological processes?
Polyphenol Prebiotic Powder
Integria Healthcare Symposium 2021Restoring the Seat of Health 35
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Polyphenol Prebiotic Powder
Partially hydrolysed Guar Gum (PHGG)
Acacia Gum
Slippery Elm
Fruit Pectin
Theobroma cacao (organic raw Cacao powder)
Hylocereus polyrhizus (Red Dragon Fruit)
Prebiotics PHGG & GA
• Emerging research from clinicaltrials evaluating prebioticproperties of partially hydrolysedguar gum (PHGG) and gum arabic(GA) suggest a potential benefit forthe treatment of constipation
• Increased beneficial microbes• Increased species diversity and
evenness• Reduced abundancies of
pathogenic bacteria in healthyhuman volunteers
Calame W, Weseler AR et al. Gum arabic establishes prebiotic functionality in healthy human volunteers in a dose-dependent manner. Br J Nutr. 2008;100(6):1269-75. doi: 10.1017/S0007114508981447.
Reider SJ, Moosmang S et al. Prebiotic effects of partially hydrolyzed guar gum on the composition and function of the human microbiota—Results from the PAGODA trial. Nutrients. MDPI AG; 2020;12(5):1257. doi.10.3390/nu12051257
Integria Healthcare Symposium 2021Restoring the Seat of Health 36
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Prebiotics Apple Pectin & Slippery Elm
• Slippery elm has been found to increaseLactobacillus spp. Bifidobacterium spp.,Bacteroides spp., and Eubacterium spp., anddecrease Klebsiella1
• Pectin influences the composition and diversity ofthe gut microbiota with in vitro studiesdemonstrating increases in Bifidobacterium andLactobacillus2
1. Peterson CT, Sharma V et al. Prebiotic potential of herbal medicines used in digestive health and disease. J Alt Comp Med. 2018;24(7):656-65.doi 10.1089/acm.2017.0422
2. Flint HJ, López Siles M et al. Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii can utilize pectin, uronic acids, and host-derived substrates for growth. App Environ Ecol, 2012;15;78(2):420-8. doi 10.1128/AEM.06858-11
Constituents of Dragon Fruit & Cocoa
Cocoa powder contains:
• Alkaloids theobromine (2%) andcaffeine (0.5%)
• Catechin and epicatechin are themain polyphenols in cocoa powder
• Procyanidins
Red Dragon fruit:
• The pigment responsible for the redcolour of red dragon fruit pulp isbetacyanin
• Polyphenols include phenolic acid(386.09±1.52 mg/100g), flavonoids(210.02±0.83 mg/100g) andanthocyanins (81.75±1.43 mg/100g),Gallic acid and catechins
Integria Healthcare Symposium 2021Restoring the Seat of Health 37
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Dragon Fruit Boosts Akkermansia
• Betacyanin from red dragon fruit increasesthe growth of Akkermansia muciniphila,which has been inversely associated withobesity, diabetes, inflammation, andmetabolic disorders1
• The antioxidant action of polyphenols in reddragon fruit also protects Akkermansiamuciniphila, which is vulnerable to attack byfree radicals2
1. Frugé AD, Van der Pol W et al. Fecal Akkermansia muciniphila is associated with body composition and microbiota diversity in overweight and obesewomen with breast cancer participating in a presurgical weight loss trial. J Acad Nutr Diet. 2020;120(4):650-9. doi 10.1016/j.jand.2018.08.164
2. Daglia M. Polyphenols as antimicrobial agents. Curr Op Biotechnol. 2012;23(2):174-81. doi 10.1016/j.copbio.2011.08.007
Cocoa Improves Microbiome Composition
• Cocoa polyphenols interact bidirectionally withthe intestinal microbiota as the microbiotametabolises polyphenols producing secondarybioactive metabolites, which in turn increasesbeneficial intestinal species1
• Cocoa polyphenols enhance the growth ofLactobacillus and Bifidobacteria, E coli,Bifidobacterium spp., Bacteroides spp., andEubacterium spp. while reducing pathogenicspecies such as Clostridium perfringens2
1. Sorrenti V, Ali S et al. Cocoa polyphenols and gut microbiota interplay: bioavailability, prebiotic effect, and impact on human health. Nutrients.2020;12(7):1908. doi 10.3390/nu12071908
2. Tzounis X, Rodriguez-Mateos A et al. Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study. AJCN. 2011;93(1):62-72. doi.10.3945/ajcn.110.000075
Integria Healthcare Symposium 2021Restoring the Seat of Health 38
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Polyphenol Prebiotic Powder
Clinical applications:
• Dysbiosis
• Irritable Bowel Syndrome (IBS)
• Metabolic disease
• Constipation
Ingredients actions:
• Increases microbial diversity
• Improves intestinal mucosalintegrity via short-chain fatty acid(SCFA) production and reducedintestinal inflammation
• Improves bowel regularity
• Improves metabolic parameters
Polyphenol Prebiotic Formulation Clinical Applications
• Support gut motility (constipation)
• Support diet of those with reduced fruit/veg intake and/or very low fibreintake, and low calorie/low carbohydrate diets (to help increase microbiotadiversity and richness with overall health benefits)
• Support weight through increased satiety before meals and direct effect ofpolyphenols on glycan-degrading capability of Bacteroides
• Support the mucous membranes against colonisation of undesirables inGIT and help prevent more serious GIT disorders
• Support immune system
• Support people with high anxiety traits
Integria Healthcare Symposium 2021Restoring the Seat of Health 39
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
FC Summary
• There are many pathophysiological factors in FC and careful investigationsare required before providing an individualised therapeutic strategy
• Establish the underlying cause or the contributing factors (if it is FC)
• Look for drug interactions especially in those with chronic pain
• Diet is a major factor in FC; fibre replaced by processed foods
• If FC has been present from childhood consider “conditioning” (trauma)
• A person with anxiety/stress/PTSD has a higher likelihood of FC
FC Summary
Low-Residue and Low-Fiber Diets in Gastrointestinal Disease Management - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Overview-of-possible-effects-of-different-fibers-on-gastrointestinal-digestion-and_fig1_283790366 [accessed 3 Aug, 2021]
Integria Healthcare Symposium 2021Restoring the Seat of Health 40
Investigating the Impacts of Polyphenols and Dietary Fibre on the Microbiome and Functional Gut HealthDr Elizabeth Steels
Polyphenol Summary
• Functional constipation associated with poor diet; low fiber intake; and alack of fruit and vegetables can be supported by addition of prebiotic fibresapprox. 12-16 g per day
• Prebiotic fibres and polyphenols have a specific role in modulating andsupporting a healthy gut microbiome, as well as other health benefits