Short Chain Fatty Acids Elizabeth Redmond, PhD, MMSc, RD - - PowerPoint PPT Presentation
Assessing Gut Issues: Short Chain Fatty Acids Elizabeth Redmond, PhD, MMSc, RD Chair-Elect Dietitians in Integrative and Functional Medicine DPG Education Specialist, Metametrix Laboratory, Georgia Short Chain Fatty Acids (SFCA) This session
Elizabeth Redmond, PhD, MMSc, RD
Chair-Elect Dietitians in Integrative and Functional Medicine DPG Education Specialist, Metametrix Laboratory, Georgia
This session will discuss: 1. What are SCFA ?
Predominant gut bacteria ferment dietary fiber and their monosaccharide components to acetate, propionate, and butyrate, and protein material to valerate, isovalerate and isobutyrate.
∗ C-2 Acetate ∗ C-3 Propionate Saccharolytic (carbohydrate) fermentation SCFA: >90% of SCFA ∗ C-4 Butyrate ∗ C-6 Caproate
∗ iC4 isoButyrate ∗ C-5 Valerate* ∗ iC5 isoValerate Proteolytic (Protein) fermentation SCFA: < 10% of SCFA ∗ iC6 hexanoate
An overview of the relationship between transit of food through the human gastrointestinal tract and the digestion of nutrients in the small intestine and fermentation in the cecum and colon.
Topping D L , Clifton P M Physiol Rev 2001;81:1031-1064
∗ More than 95% of SCFA are produced and absorbed within the colon. ∗ SCFA contribute to normal large bowel function and prevent pathology through their actions in the lumen and on the colonic musculature and vasculature, and through their metabolism by colonocytes.
Topping, D., Clifton, P. Physiol Rev July 1, 2001 vol. 81 no. 3 1031-1064
Acetate Butyrate Propionate Immune system Immune system Immune system Carcinogenesis Carcinogenesis Carcinogenesis Colonic function Colonic function Colonic function Adipogenesis Satiety Satiety Barrier function Neurological effects Visceral perception Cholesterol metabolism Insulin sensitivity Oxidative stress
Journal of AOAC International Vol. 95, No. 1, 2012
Neurogastroenterol Motil (2011) 23, 975–979
∗ Acts as a signal metabolite affecting epithelial cell proliferation, apoptosis, and differentiation. ∗ Affects several inflammatory parameters such as cytokines and myeloperoxidase activity, thus increasing antioxidant capacity. ∗ Provides barrier function: stimulates intestinal mucus production, mucosal repair, and decreases colonic epithelial permeability. ∗ Enhances the growth of lactobacilli and Bifidobacter sp. ∗ Increases mucosal blood flow. ∗ Increases in vitro crypt proliferation. ∗ Clinically can reduce inflammation and diarrhea. ∗ Possible protection against colonic carcinogenesis. ∗ Increases glutathione production.
∗ Decreases lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNFα) release from human neutrophils . ∗ Inhibits NF-κB reporter activity in human colon carcinoma cells. ∗ Intravenous administration increases peripheral blood antibody. ∗ Production of natural killer cell activity in cancer patients. ∗ Stimulates proliferation of normal crypt cells. ∗ Enhances ideal motility and increases colonic blood flow. ∗ May have a role in adipogenesis.
Neurogastroenterol Motil (2011) 23, 975–979
molecules, LPS-stimulated TNF-α
subjects
gamma
abnormalities in rats, similar to those detected in human autism.
Neurogastroenterol Motil (2011) 23, 975–979
∗ Acetate has been shown to increase cholesterol synthesis. ∗ Propionate has been shown to inhibit cholesterol synthesis. ∗ Treatments that can decrease the acetate/propionate ratio have been proposed as a way to reduce serum lipids.
J Clin Gastroenterol. 2006 Mar;40(3):235-43.
Valerate is0butyrate isovalerate inhibitory effects on cytokine release strong pungent cheesy
increase of glutathione (GSH) proposed that it is the anticonvulsant agent in valerian induce histone hyperacetylation major component of the cause of unpleasant foot
inhibitory effects on cytokine release excellent substrate for colonic oxidation, similar to butyrate
Journal of AOAC International Vol. 95, No. 1, 2012
∗ Proteins (from foods , albumin, blood, muscle, secretions) must be broken down to peptides and amino acids before bacteria can metabolize them. ∗ Proteins get broken down by bacterial proteases and peptidases, and pancreatic endopeptidases. ∗ The end product of the breakdown is SCFA, BCFA and organic acids.
Metabolism of N-containing substrates in the large gut, and the physiologic significance of the end products.
Fecal pH Diet BMI Predominant bacteria Location/Environment Immune Inflammation Race Gender Transit time
Concentration (mmol g dry wt bacteria)
pH 6.8 pH 5.5 Free amino acids Acetate 10.6 11.7 Propionate 2.8 3.2 Butyrate 1.8 3.2 Valerate 1.9 0.9 ibutyrate 0.5 0.5 ivalerate 2.6 0.9 Total 20.5 20.4 SCFA grown in mixed cultures of intestinal bacteria from amino acids, with a change in pH value.
High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health.
M (mmol/L) - -> Total SCFA acetate propionate butyrate valerate isovalerate isobutyrate maintenance 108.3 61.97 21.10 16.93 2.07 1.14 1.60 high-protein /moderate- carbohydrate (HPMC) 100.6 55.79 17.41 14.83 2.49 1.85 2.28 high-protein /low- carbohydrate (HPLC) 73.59 39.61 14.71 8.54 1.90 1.62 2.01 P <0.001 <0.001 <0.001 <0.001 <0.083 <0.001 <0.002 Short-chain fatty acids (SCFAs) detected in feces of 17 volunteers given 3 different diets. Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072
20 40 60 80 100 120 Maintance HPMC HPLC * **= <0.001; *= 0.001; ^=.01 ^
Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072
20 40 60 80 100 acetate propionate butyrate valerate isobutyrate isovalerate Saccharolytic fermentation Proteolytic fermentation HPLC HPMC Maintanance
Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072
**= <0.001; *= 0.001; ^=.01 ** ** * * ^ Percent
Diet/supplements Effects on SCFAs or their derivatives in inflammatory conditions Diet with resistant starch (1.53 kg/10 kg of diet) Improvement of symptoms; epithelial cell proliferation; regeneration of laminin; growth of intestinal bacteria Diet supplemented with cellobiose (9%) Reduction of weight loss; diminished tissue edema; attenuation of inflammatory cytokine concentrations Fiber supplementation (5%) Reduction in MPO and NO synthase activities; restoration of colonic glutathione levels; diminished TNF- concentrations Oral butyrate (10 mg/kg) Improvement of mucosa lesion and attenuation of the inflammatory profile of intestinal mucosa and local lymph nodes in a model of DSS-induced colitis. Nutrients 2011, 3
The amount of protein entering the colon depends on the amount of protein and the digestibility of the protein eaten.
∗ Decreased digestibility = increased protein fermentation. ∗ Digestibility of proteins from animal sources exceeds 90%; plant proteins range from 70–90%. ∗ On a normal mixed diet, the amount of protein has a stronger effect on the amount reaching the colon.
Topping D L , Clifton P M Physiol Rev 2001;81:1031-1064: http://physrev.physiology.org/content/81/3/1031.full
(NSP). NSP resist digestion by intrinsic human intestinal digestive enzymes completely, their intakes do not account for calculated human SCFA production (the “carbohydrate gap”).
products of small intestinal starch digestion are thought to contribute the
and/or NSP but not for RS. This means that dietary intakes can be calculated for the former but not the latter, and direct comparison may be difficult. Thus health authorities have been able to make dietary recommendations for fiber but not yet for RS.
Percentage of carbohydrate loss in relation to GI [adapted from Jenkins et al.]
Wong J M W , Jenkins D J A J. Nutr. 2007;137:2539S-2546S; http://lpi.oregonstate.edu/infocenter/phytochemicals/fiber/ http://lpi.oregonstate.edu/infocenter/phytochemicals/fiber/
20 40 60 80 100 120 BMI 18-24.9 BMI 25-30 BMI 30+ *
Mean SCFA (mmol/l)
Obesity (2009) 18, 190–195.
Percent SCFA for three BMI levels
* *
Percent of total SCFA
Obesity (2009) 18, 190–195.
20 40 60 80 acetate butyrate propionate valerate isobutyrate isovalerate >30 25-30 18-24.5
Percent SCFA for three BMI levels
Predominant bacteria, or normal indigenous microflora, have co-evolved with their host, and play a major role in health. They provide: ∗ Colonization resistance against potentially pathogenic organisms ∗ Aid in digestion and absorption ∗ Produce vitamins and SCFAs ∗ Stimulate the GI immune system ∗ Are able to activate innate and adaptive immunity
Acetate Propionate Butyrate Lactate Bacteroides x x X (D) Bifidobacteria x X (L) Lactobacilli x X (D/L) Clostridia x x x X (L) Faecalibacteria x X (D) Fusobacteria x x Prevotella X
Anaerobes dominate the gut.
Bacteroidetes ∗ Bacteroides spp. ∗ Prevotella spp. Firmicutes ∗ Clostridia spp. ∗ Mycoplasma spp. ∗ Lactobacillus spp. Proteobacteria ∗ Escherichia coli. Fusobacteria ∗ Fusobacteria spp. Actinobacteria ∗ Bifidobacter spp. ∗ Streptomyces spp.
10 20 30 40 Bacteroides Lachnospiraceace Roseburia
HPLC HPMC Maintanance ** * ** p= <.001; * p< .05
Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072
CT – Control diet ; HF – High fat diet HF-Cell – High fat with non-fermentable fiber HF-OFS – High fat with fermentable fiber
aberrant crypts per/ cm 2
J Nutr. 1999 Jul;129(7 Suppl):1483S-7S
Dietary levels of oligofructose and Bifidobacter sp. resulted in a decrease in aberrant crypts in RATS
OF – Oligofructose (inulin) SBO – Soybean oligosaccharide; WBO – Wheat bran oligosaccharide
PNAS August 17, 2010 vol. 107 no. 33 14691-14696
PNAS August 17, 2010 vol. 107 no. 33 14691-14696
SCFA-producing bacteria could help to prevent establishment of some potentially pathogenic intestinal bacteria. Quantification of SCFAs in fecal samples from BF and EU populations by SPME-GC-MS.
Comparative study in children from Europe (EU) and rural Africa (BF)
51.17% 13.64% 33.92% 1.20% 69.54% 8.30% 20.10% 1.70% 0% 20% 40% 60% 80% 100% Acetate Butyrate Propionate Valerate EU BF
PNAS August 17, 2010 vol. 107 no. 33 14691-14696
40.2 31.2 148.6 14.2 66.7 73.9 290 8.4 50 100 150 200 250 300 protein fat carbohydrate* fiber EU BF Grams of macronutrients
PNAS August 17, 2010 vol. 107 no. 33 14691-14696
Comparative study in children from Europe (EU) and rural Africa (BF)
Frequency of genes relayed to butyrate, acetate and propionate production in the fecal metagenome of 27 subjects. Nature, 2012; http://www.nature.com/nature/journal/vnfv/ncurrent/extref/nature11319-s1.pdf
Fecal Short Chain Fatty Acids in Children with Inflammatory Bowel Disease White bars= controls; black = severe UC; grey= inactive/mild UC
50 100 150 200 250 acetate butyrate propionate isobutyratelactate IBS Healthy (*P<0.05). * * Open Biochem J. 2010; 4: 53–58. Amount of SCFAs in each population
Colonic contents of the primary SCFA in African Americans, Caucasian Americans, and Native Africans.
O'Keefe S J D et al. J. Nutr. 2009;139:2044-2048
Patient symptoms ∗ belching ∗ flatulence ∗ bloating ∗ abdominal pain ∗ diarrhea ∗ fatigue
∗ Diet history - vegetarian diet - tries to avoid dairy ∗ Symptom questionnaire- meets criteria for IBS ∗ Symptom history ∗ Laboratory assessment of GI function
∗ Do a stool test ∗ Look to see if the patient has vitamin D, B12, or iron
∗ Consider getting these or other fat soluble vitamins ∗ Also consider amino acids
Acetate / Propionate = 48/4.5= 10.66 Average A/P ratio = 3.075 Total cholesterol: 209 HLD: 41 and Lp(a): 75
12.66 87.27 7.63 92.37 4.76 91.77 7.3 92.7 20 40 60 80 100 Proteolytic fermentation Saccharolytic fermentation Percent Case HPLC Maintenance Normal BMI
(Isobutyrate + isovalerate + valerate)
∗ Use of butyrate
∗ Butyrate functions as the major energy source for colonocytes and modulates several cellular processes
∗ Changes in dietary habits
∗ Increasing fiber intake of soluble fibers (fermentable) is more effective than insoluble (non-fermentable), which can increase SCFAs (butyrate). ∗ Decrease total protein intake, or shift to more plant protein. This will result in a shift from proteolytic to saccharolytic fermentation. ∗ Exclude dairy and casein
∗ Use of prebiotics
∗ Specifically inulin ∗ Product Klaire labs Biotagen ∗ Increase diet sources: artichoke hearts, banana, agave, garlic, onion, wild yam, chicory
Elizabeth Redmond, PhD, MMSc, RD
eredmond@metametrix.com
Metametrix Laboratory, Georgia Chair-Elect Dietitians in Integrative and Functional Medicine DPG