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 will discuss: 1. What are SCFA ? 2. What do SCFA do? 3. What affects SCFA production? 4. Review of the synergistic relationship of SCFAs and gut bacteria. 5. Possible treatments and case study.

Putrefactive SCFA 1. What are short chain fatty acids (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

1. What do SCFAs do? ∗ 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

Butyrate has been shown to: ∗ 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. Neurogastroenterol Motil (2011) 23, 975–979

Acetate has been shown to: ∗ 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

Propionate has been shown to: • Inhibits proinflammatory eicosanoids, nuclear factor- κ B, adhesion molecules, LPS-stimulated TNF- α • Regulates and inhibits proliferation of activated lymphocytes • Growth arrest and differentiation of human colon cancer cells • Induces colorectal cancer apoptosis • Lowers blood glucose and alters lipid metabolism in healthy human subjects • Increases satiety - Increases production of leptin • Upregulates peroxisome proliferator activated receptor (PPAR)- gamma • Activates G protein-coupled receptor and inhibits lipolysis • Intraventricular infusions can impair social behavior and cause brain abnormalities in rats, similar to those detected in human autism. Neurogastroenterol Motil (2011) 23, 975–979

Other clinical uses of SCFA: acetate/propionate ratio ∗ 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 strong pungent cheesy cytokine release or sweaty smell increase of glutathione proposed that it is the (GSH) anticonvulsant agent in valerian induce histone major component of the hyperacetylation cause of unpleasant foot odor inhibitory effects on cytokine release excellent substrate for colonic oxidation, similar to butyrate Journal of AOAC International Vol. 95, No. 1, 2012

The breakdown of proteins and peptides Protein Breakdown by colonic microorganisms. ∗ 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.

What affects production of SCFAs? Fecal pH Diet BMI Predominant bacteria Location/Environment Immune Inflammation Race Gender Transit time

pH 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.

Diet High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. M (mmol/L) - -> Total acetate propionate butyrate valerate isovalerate isobutyrate SCFA maintenance 108.3 61.97 21.10 16.93 2.07 1.14 1.60 high-protein 100.6 55.79 17.41 14.83 2.49 1.85 2.28 /moderate- carbohydrate (HPMC) high-protein /low- 73.59 39.61 14.71 8.54 1.90 1.62 2.01 carbohydrate (HPLC) 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

Level of SCFA in three diet groups 120 100 80 60 40 20 0 ^ * Maintance HPMC HPLC **= <0.001; *= 0.001; ^=.01 Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072

Percent SCFA for three diet groups Proteolytic fermentation Saccharolytic fermentation ** isovalerate HPLC ** isobutyrate HPMC * valerate Maintanance * butyrate ^ propionate acetate 0 20 40 60 80 100 Percent **= <0.001; *= 0.001; ^=.01 Am J Clin Nutr May 2011 vol. 93 no. 5 1062-1072

Diet/supplements Effects on SCFAs or their derivatives in inflammatory conditions Diet with resistant starch Improvement of symptoms; epithelial cell (1.53 kg/10 kg of diet) proliferation; regeneration of laminin; growth of intestinal bacteria Diet supplemented with Reduction of weight loss; diminished cellobiose (9%) tissue edema; attenuation of inflammatory cytokine concentrations Fiber supplementation Reduction in MPO and NO synthase (5%) activities; restoration of colonic glutathione levels; diminished TNF- concentrations Oral butyrate Improvement of mucosa lesion and (10 mg/kg) attenuation of the inflammatory profile of intestinal mucosa and local lymph nodes in a model of DSS-induced colitis. Nutrients 2011 , 3

Factors affecting protein fermentation 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. Mol. Nutr. Food Res. 2012, 56, 184–196; November 1, 2010 vol. 299 no. 5 G1030-G1037

Carbohydrate Gap o Fiber is comprised principally of polysaccharides and non-starch polysaccharide (NSP). NSP resist digestion by intrinsic human intestinal digestive enzymes completely, their intakes do not account for calculated human SCFA production (the “carbohydrate gap”). o Some of the deficit may be filled by oligosaccharides (OS), but starch and products of small intestinal starch digestion are thought to contribute the most. This fraction is termed resistant starch (RS). o A particular problem is that assay procedures are well-established for fiber 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. Topping D L , Clifton P M Physiol Rev 2001;81:1031-1064: http://physrev.physiology.org/content/81/3/1031.full

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/

BMI Percent SCFA for three BMI levels 120 * * 100 80 60 Mean SCFA BMI 18-24.9 (mmol/l) 40 BMI 25-30 20 BMI 30+ * 0 Obesity (2009) 18, 190–195.