Short-chain Fatty Acids

Blood, 18 June 2009, Vol. 113, No. 25, pp. 6440-6448.
Prepublished online as a Blood First Edition Paper on April 20, 2009; DOI 10.1182/blood-2008-09-171728.
RED CELLS, IRON, AND ERYTHROPOIESIS

Short-chain fatty acid–mediated effects on erythropoiesis in primary definitive erythroid cells
Himanshu Bhatia1, Jennifer L. Hallock2, Amrita Dutta1, Shay Karkashon1, Lauren S. Sterner2, Toru Miyazaki3, Ann Dean2, and Jane A. Little1
1 Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; 2 Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; and 3 Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

Short-chain fatty acids (SCFAs; butyrate and propionate) up-regulate embryonic/fetal globin gene expression through unclear mechanisms. In a murine model of definitive erythropoiesis, SCFAs increased embryonic β-type globin gene expression in primary erythroid fetal liver cells (eFLCs) after 72 hours in culture, from 1.7% (± 1.2%) of total β-globin gene expression at day 0 to 4.9% (± 2.2%) in propionate and 5.4% (± 3.4%) in butyrate; this effect was greater in butyrate plus insulin/erythropoietin (BIE), at 19.5% (± 8.3%) compared with 0.1% (± 0.1%) in ins/EPO alone (P < .05). Fetal -globin gene expression was increased in human transgene-containing eFLCs, to 35.9% (± 7.0%) in BIE compared with 4.4% (± 4.2%) in ins/EPO only (P < .05). Embryonic globin gene expression was detectable in 11 of 15 single eFLCs treated with BIE, but in0 of 15 ins/EPO-only treated cells. Butyrate-treated [65.5% (± 9.9%)] and 77.5% (± 4.0%) propionate-treated eFLCs were highly differentiated in culture, compared with 21.5% (± 3.5%) in ins/EPO (P < .005). Importantly, signaling intermediaries, previously implicated in induced embryonic/fetal globin gene expression (STAT5, p42/44, and p38), were not differentially activated by SCFAs in eFLCs; but increased bulk histone (H3) acetylation was seen in SCFA-treated eFLCs. SCFAs induce embryonic globin gene expression in eFLCS, which are a useful short-term and physiologic primary cell model of embryonic/fetal globin gene induction during definitive erythropoiesis.

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THE IDEA THAT DRUGS MIGHT SAFELY SWITCH ON NONWORKING GENES RECEIVED
ABOOST FROM RESEARCHERS DEVELOPING TREATMENTS FOR A GROUP OF GENETIC
BLOODDISORDERS


THE BLOOD DISORDERS INVOLVE RED BLOOD CELLS' FAILURE TO PRODUCE
HEMOGLOBIN OR PRODUCTION OF A DEFECTIVE FORM OF THE OXYGEN CARRYING
PROTEIN.
THE DISORDERS INCLUDE SICKLE CELL ANEMIA WHICH MOSTLY AFFLICTS
AFRICAN AMERICANS AND COOLEY'S ANEMIA WHICH MOSTLY AFFLICTS ITALIANS
GREEKS AND OTHER MEDITERRANEAN GROUPS.


BLOOD SPECIALISTS HAVE BEEN TRYING FOR A DECADE TO FIND A NEW WAY TO
TREAT THESE DISORDERS BY TURNING ON A HEMOGLOBIN GENE THAT ORDINARILY
QUITS WORKING AFTER BIRTH.
THE FEW DRUGS THAT HAVE PULLED OFF THIS TRICK HAVE BEEN
TOO TOXIC FOR THE LIFETIME USE THAT THE ANEMIC PATIENTS WOULD REQUIRE.


NOW A TEAM OF RESEARCHERS IN OAKLAND CALIF REPORTED PRELIMINARY
RESULTS IN WHICH A FOOD ADDITIVE A FATTY ACID CALLED ARGININE BUTYRATE
APPEARED TO STIMULATE THE NONWORKING GENE TO BEGIN MAKING NORMAL
HEMOGLOBIN IN SIX PATIENTS THEIR REPORT APPEARS IN THIS WEEK'S ISSUE
OF THE NEW ENGLAND JOURNAL OF MEDICINE.


THE MAIN PROBLEM IS THAT THE DRUG MUST BE GIVEN INTRAVENOUSLY BUT ONE
OF THE RESEARCHERS SAID AN ORAL FORM OF THE DRUG IS BEING DEVELOPED.


THE TWO ANEMIAS ARE IDEAL CANDIDATES FOR GENE ACTIVATION THERAPY.
BOTH INVOLVE DEFECTS IN HEMOGLOBIN THE IRON CONTAINING PROTEIN THAT
RED BLOOD CELLS USE TO CARRY OXYGEN TO BODY TISSUES.
OF THE TWO GENES CAPABLE OF MAKING HEMOGLOBIN ONE FUNCTIONS ONLY
DURING FETAL LIFE WHEN THE FETUS MUST PULL OXYGEN CARRYING BLOOD
ACROSS THE PLACENTA.
 THIS FETAL GENE TURNS OFF AFTER BIRTH AND A SECOND ADULT GENE TAKES
OVER.


IN COOLEY'S ANEMIA ALSO KNOWN AS BETATHALASSEMIA THE DEFECTIVE ADULT
GENE PRODUCES LITTLE OR NO HEMOGLOBIN.
THOSE BORN WITH THE DEFECT MUST RECEIVE REPEATED BLOOD TRANSFUSIONS TO
SURVIVE.
IF THE FETAL GENE COULD BE REAWAKENED AND PUT BACK TO WORK THE
PATIENT'S RED CELLS WITH A NEW ENDOWMENT OF PERFECTLY FUNCTIONAL FETAL
HEMOGLOBIN WOULD ENLARGE REDDEN
AND REGAIN VIABILITY EXPLAINED H FRANKLIN BUNN IN AN EDITORIAL
COMMENTINGON THE NEW RESEARCH.
DR BUNN WHO IS AT THE BRIGHAM AND WOMEN'S HOSPITAL IN
BOSTON IS ALSO WORKING ON GENESWITCHING TREATMENTS FOR THE
BLOODDISORDERS


IN SICKLECELL ANEMIA THE ADULT HEMOGLOBIN GENE FUNCTIONS BUT IS
DEFECTIVE AND THE DEFECTIVE HEMOGLOBIN IT PRODUCES LEADS TO A RIGID
SICKLE SHAPED RED BLOOD CELL.
THIS SICKLING EFFECT DOESN'T OCCUR IF FETAL HEMOGLOBIN IS ALSO
PRESENT.


IN THE LATEST RESEARCH ALL SIX PATIENTS THREE WITH COOLEY'S ANEMIA AND
THREE WITH SICKLECELL ANEMIA EXPERIENCED INCREASES IN FETAL HEMOGLOBIN
PRODUCTION FOLLOWING INFUSIONS OF AN ULTRAPURE FORM OF ARGININE
BUTYRATE REPORTED A TEAM OF RESEARCHERS HEADED BY SUSAN P PERRINE OF
CHILDREN'S
HOSPITAL OAKLAND RESEARCH INSTITUTE IN OAKLAND CALIF.
THE TEAM INCLUDEDSCIENTISTS FROM A HALF DOZEN MEDICAL CENTERS IN THE
US AND CANADA.


INCREASES IN THE OUTPUT OF FETAL HEMOGLOBIN RANGED FROM 6 TO 45 ABOVE
PRETREATMENT LEVELS THE RESEARCHERS REPORTED.
IN TWO PATIENTS THE PRODUCTION OF FETAL HEMOGLOBIN CONTINUED FOR A
MONTH AFTER TREATMENT STOPPED.
SIDE EFFECTS WERE ALMOST NONEXISTENT THEY SAID.


THE RESULTS ALTHOUGH HIGHLY PRELIMINARY INDICATE THAT THE
ADMINISTRATION OF ARGININE BUTYRATE REPRESENTS A NOVEL AND POTENTIALLY
EFFECTIVE THERAPY FOR THESE PREVALENT MOLECULAR DISORDERS THE REPORT
DECLARED.


IN A TELEPHONE INTERVIEW DR PERRINE SAID SHE HAD TO COMPOUND THE
ARGININE BUTYRATE USED IN THE TEST.
THE TEAM SHE SAID HAS SINCE DEVELOPED SOME VARIATIONS OF THE FATTY
ACID THAT COULD BE GIVEN ORALLY.
THE RESEARCHERS HOWEVER ARE LOOKING FOR A DRUG MANUFACTURER WHO WOULD
TAKE OVER DEVELOPMENT
OF THE DRUGS AND TAKE THEM THROUGH THE US FOOD AND DRUG ADMINISTRATION
PROCESSES FOR MARKETING

"Butyrate production is largely determined by the content of a
particular type of carbohydrate in the diet"
"Eat plenty of sources of fibre - such as fruit and vegetables"
"Butyrate is produced in the gut when the bacteria ferment the
carbohydrate present in food."


Very Low Carbohydrate Diets May Disrupt Long-term Gut Health
ScienceDaily (Jun. 20, 2007) -- Scientists at Aberdeen's Rowett
Research Institute have shown that a very low carbohydrate weight-loss
diet results in a four-fold reduction in the numbers of certain types
of bacteria in the gut of obese men.
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This is a significant finding because these gut bacteria produce a
substance called butyrate, which has been shown to be important for
keeping the gut healthy including helping to prevent colorectal
cancer. The study raises questions about the impact of the prolonged
use of very low-carbohydrate weight-loss diets on gut health.


Very low-carbohydrate weight-loss diets (such as the so-called 'Atkins-
type diets) are popular with people struggling to lose weight and are
used in some weight-loss clinics. Nutritionists have raised concerns
about the low fruit and vegetable content of such diets as these
contain nutrients that help protect against a number of diseases and
cancers within the body. Less attention has been paid to the
consequences of the low carbohydrate intake on the bacteria within the
gut and how this might alter the release of either beneficial or
harmful compounds from the food.


In this study, 19 healthy, obese men were given three diets containing
different levels of carbohydrate (high, medium and low). Two of the
diets also contained a high proportion of protein, as this is known to
help reduce appetite and is used in a number of diets that help
produce weight loss. Indeed, the volunteers lost similar amounts of
weight and body fat on these two diets. Stool samples were analysed
for the amount and type of bacteria, and for butyrate.


"The changes in butyrate production that we observed in this study are
the largest ever reported in a human dietary trial. The results
provide strong evidence that butyrate production is largely determined
by the content of a particular type of carbohydrate in the diet that
the bacteria in our guts can utilise," said Professor Harry Flint who
led the research at the Rowett Institute.


"We can't be sure from this study about the impact of butyrate
production on gut health, but there has been quite a lot of work done
which shows that butyrate stops cancer cells from growing, and so
helps prevent colorectal cancer.


"If low carbohydrate diets are to be consumed for long periods of
time, it may be important to ensure that there is enough of the right
sort of carbohydrate in the diet which can be used by the bacteria to
produce compounds such as butyrate, which are beneficial for human
health. This means making sure you continue to eat plenty of sources
of fibre - such as fruit and vegetables," said Professor Harry Flint.


What is butyrate?


Butyrate is what is known as a short chain fatty acid, and is produced
in the gut when the bacteria ferment the carbohydrate present in food.
It can be used by the bacteria as a source of energy and also is used
by the cells which line the gut wall. Studies have shown that butyrate
can prevent cancer cells in the gut from continuing to grow and so
reduce the risk of colorectal cancer.


The composition of the three diets was as follows:


Normal (maintenance) diet: 13% protein, 52% carbohydrate, 35% fat, as
calories;


Medium carbohydrate diet: 30% protein, 35% carbohydrate, 35% fat. as
calories


Low carbohydrate diet: 30% protein, 4% carbohydrate, 66% fat, as
calories.


The work is published in Applied and Environmental Microbiology,
73:1073-8.


Adapted from materials provided by Rowett Research Institute.

"Butyrate output was increased by 40 % "

Lupin kernel fibre foods improve bowel function and beneficially
modify some putative faecal risk factors for colon cancer in men.

Full Papers

British Journal of Nutrition. 95(2):372-378, February 2006.
Johnson, Stuart K. *; Chua, Veronica; Hall, Ramon S.; Baxter, Amynta
L.
Abstract:
Consumption of some dietary fibres may benefit bowel health; however,
the effect of Australian sweet lupin (Lupinus angustifolius) kernel
fibre (LKFibre) is unknown. The present study examined the effect of a
high-fibre diet containing LKFibre on bowel function and faecal
putative risk factors for colon cancer compared to a control diet
without LKFibre. Thirty-eight free-living, healthy men consumed an
LKFibre and a control diet for 1 month each in a single-blind,
randomized, crossover study. Depending on subject energy intake, the
LKFibre diet was designed to provide 17-30 g/d fibre (in experimental
foods) above that of the control diet. Bowel function self-perception,
frequency of defecation, transit time, faecal output, pH and moisture,
faecal levels of SCFA and ammonia, and faecal bacterial [beta]-
glucuronidase activity were assessed. In comparison to the control
diet, the LKFibre diet increased frequency of defecation by 0[middle
dot]13 events/d (P = 0[middle dot]047), increased faecal output by 21
% (P = 0[middle dot]020) and increased faecal moisture content by
1[middle dot]6 % units (P = 0[middle dot]027), whilst decreasing
transit time by 17 % (P = 0[middle dot]012) and decreasing faecal pH
by 0[middle dot]26 units (P < 0[middle dot]001). Faecal butyrate
concentration was increased by 16 % (P = 0[middle dot]006), butyrate
output was increased by 40 % (P = 0[middle dot]002) and [beta]-
glucuronidase activity was lowered by 1[middle dot]4 [mu]mol/h per g
wet faeces compared to the control diet (P < 0[middle dot]001).
Addition of LKFibre to the diet incorporated into food products
improved some markers of healthy bowel function and colon cancer risk
in men.


Copyright(C) 2006 The Nutrition Society

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Nitrogen reduces short-chain fatty acid production .


"As nitrogen was increased the valeric acid decreased"


This is the effect of the different consumption of meat on nitrogen.


No meat - 54 nitrogen
60 g meat- 52 nitrogen
240 g meat - 159 nitrogen
420 g meat - 199 nitrogen


More meat .. higher nitrogen .. therefore fewer short-chain fatty
acids..


http://carcin.oxfordjournals.org/cgi/content/full/22/1/199


Carcinogenesis, Vol. 22, No. 1, 199-202, January 2001
(c) 2001 Oxford University Press


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SHORT COMMUNICATION


Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation
R. Hughes1, A.J. Cross1, J.R.A. Pollock2 and S. Bingham3
1 Medical Research Council, Dunn Human Nutrition Unit, Welcome Trust/
MRC Building, Hills Road, Cambridge CB2 2XY and
2 Pollock and Pool Ltd, Ladbroke Close, Reading RG5 4DX, UK


Abstract
 
Human male volunteers were studied in a metabolic facility whilst they
were fed randomized controlled diets. In eight volunteers there was a
significant increase in faecal apparent total N-nitroso compounds
(ATNC) and nitrite excretion (P < 0.0001 and P = 0.046, respectively)
when randomized doses of meat were increased from 0 to 60, 240 and 420
g/day over 10 day periods. Mean (± SE) faecal ATNC levels were 54 ± 7
µg/day when the diets contained no meat, 52 ± 11 µg/day when the diets
contained 60 g meat/day, 159 ± 33 µg/day with 240 g meat and 199 ± 36
µg/day with 420 g meat. Higher concentrations of NOC were associated
with longer times of transit in the gut (r = 0.55, P = 0.001) and low
faecal weight (r = -0.51, P = 0.004). There was no significant decline
in levels in individuals fed 420 g meat for 40 days. The exposures
found on the higher meat diets were comparable with other sources of N-
nitroso compounds (NOC), such as tobacco smoke. Many NOC are known
large bowel initiators and promotors in colon cancer, inducing GA
transitions in codons 12 and 13 of K-ras. Endogenous NOC formation,
combined with prolonged transit times in the gut, may explain the
epidemiological associations between high meat/low fibre diets and
colorectal cancer risk.


Abbreviations: ATNC, apparent total N-nitroso compounds; MTT, mean
transit time; NOC, N-nitroso compounds; PABA, p-aminobenzoic acid.


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"As the level of added nitrogen was increased the level of valeric
acid in the flasks decreased."

http://academic.research.microsoft.com/Paper/12012042.aspx


 

Do you got a link of this one : "NOW A TEAM OF RESEARCHERS IN OAKLAND CALIF REPORTED PRELIMINARY
RESULTS IN WHICH A FOOD ADDITIVE A FATTY ACID CALLED ARGININE BUTYRATE
APPEARED TO STIMULATE THE NONWORKING GENE TO BEGIN MAKING NORMAL"

hi dori,
hope you're well!
i found these:
http://www.springerlink.com/content/q36382564v875g44/
http://asheducationbook.hematologylibrary.org/cgi/content/full/2005/1/38
hope these help