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Microbiome > MHD5 short-fatty acids in health and disease > Flashcards

MHD5 short-fatty acids in health and disease Flashcards

1
Q

Why do we need to consume dietary fibre?

A

To promote regeneration of intestinal cells - keeping the intestinal barrier healthy and reducing the risk of developing colon cancer

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2
Q

How do we digest dietary fibre if we do not possess the correct enzymes?

A

Our gut bacteria do

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3
Q

What benefits does dietary fibre have?

A

Short-chain fatty acids (SCFAs) that provide fuel for our intestinal cells.
- Anti-inflammatory
- Anti-cancer effects
May also have systemic effects, influencing glucose homeostasis and even the brain

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4
Q

What are dietary fibres?

A

Non-digestible carbohydrates and lignin, that are intrinsic and intact in plants

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5
Q

Why are fibre-containing foodstuff the major fermentable substrates for gut microbiota?

A

Because almost 100% of it reaches the large intestine intact

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6
Q

How are SCFAs formed?

A

The fermentation of dietary fibres
resistant starches
other polyoligosaccharides and oligosaccharides that escape digestion in the stomach and small intestine and which release the large intestine (colon) intact

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7
Q

What are the three main SCFAs produced by the gut microbiota in the colon?

A
  • acetate
  • propionate
  • butyrate
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8
Q

Describe the structure of:

  • acetate
  • propionate
  • butyrate
A

Conjugate bases of their respective acids
(one oxygen double bonded to a carbon and another oxygen single bonded to the same carbon but that oxygen has a negative charge + a side chain)
-acetate: Two carbons including one bound to oxygens
-propionate: 3 carbons “
-butyrate: four carbons “

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9
Q

What condition determines whether SCFAs can be produced or not?

A

Oxygen availability: there must be an absence of oxygen for the fermentation process

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10
Q

Describe the varying pH levels and oxygen levels moving through the digestive tract from the mouth to the anus

A

Oral cavity: pH7, aerobic & anaerobic microniches
Stomach: pH 1-4, aerobic, microaerophilic pO2 77mm Hg
Small intestine: pH 5-5.5, facultatively anaerobic pO2 33mm Hg
Colon: pH 5.5-7.5, anaerobic, pO2 <33mm Hg
Anus: pH 5.5-7.5, anaerobic, pO2 <1mm HG

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11
Q

how many anaerobic bacteria reside in colon?

A

Largest amount than anywhere else 10^10

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12
Q

What other products other than SCFAs are there?

A
  • Carbon dioxide
  • Methane
  • Hydrogen
  • Hydrogen Sulphide
  • Increased amounts of bacterial cell mass
  • Heat
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13
Q

What is one of the main processes that contributes to the breakdown of fibres and the generation of SCFAs?

A

Cross-feeding

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14
Q

What is cross-feeding?

A

A process where one species of bacteria uses the product(s) of one or more other species to produce a different product

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15
Q

What are the two distinct cross-feeding mechanisms in the gastrointestinal tract?

A

1) Due to the consumption of fermentation end products (lactate, succinate, acetate)
2) Due to cross-feeding of partial breakdown products from complex substrates

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16
Q

What do both the cross-feeding mechanisms contribute to?

A

The production of butyrate and propionate, causing increasing intestinal levels of both these SCFAs

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17
Q

The production of butyrate leads to?

A

The butyrogenic effect (increased intestinal concentrations of butyrate and relative abundance of butyrate-producing bacteria such as Roseburiaspp. and Faecalibacterium prausnitzii).

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18
Q

What is the most abundant SCFA in the colon?

A

Acetate - formed by nearly all anaerobic gut bacteria that use organic materials

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19
Q

How is acetate formed?

A

By fermentation or reductive acetogenesis

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20
Q

What is reductive acetogenesis? What % of acetate is made this way?

A

A process by which acetate is produced directly from carbon dioxide and an electron source. A third occurs in colon.

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21
Q

What species forms acetate and how?

A

Blautia productaforms acetate from hydrogen and carbon dioxide

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22
Q

How does acetate formation benefit bacteria?

A

Because it results in energy generation by substrate-level phosphorylation of ADP to ATP

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23
Q

What are the three main pathways that propionate can be formed?

A
  • Succinate pathway
  • Acrylate pathway
  • Propanediol pathway
    Propionate can be formed directly from sugars in a single species or indirectly by cross-feeding from succinate and lactate producers in the human gut
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24
Q

How does propionate formation benefit bacteria?

A
  • The disposal of reducing equivalents, especially NADH

- ATP synthesis

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25
Q

What are reducing equivalents?

A

Any number of chemical species that transfer the equivalent of one electron in redox reactions

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26
Q

What is the most abundant route for propionate production?

A

Succinate pathway

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27
Q

How does the succinate pathway work?

A

Bacteroides spp. produce acetate and succinate from polysaccharides and peptides.
succinate>propionate: by Bacteroides spp. & cross-feeding bacteria
acetate>butyrate: by cross-feeding bacteria

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28
Q

In what bacteria is the acrylate pathway found?

A

found only in two groups of low-abundance bacteria (Negativicutes, Lachnospiraceae).

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29
Q

What bacteria use the succinate pathway?

A

Negativicutes, Verrucomicrobia, Bacteriodales

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30
Q

What bacteria use the propanediol pathway?

A

Lachnospiraceae

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31
Q

How abundant is the propanediol pathway and how does it work?

A 
Widespread and relatively abundant.
deoxy sugars (e.g. rhamnose &amp; fucose) > 1,2-propanediol
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32
Q

What is fucose and where can it be found? What is the significance of this?

A

Fucose is a major component of host-derived glycans Found on mucin lining the intestinal epithelium. Therefore, gut bacteria can produce SCFAs from host-associated carbohydrates (e.g. glycans) as well as dietary substrates.

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33
Q

What genus and species do over 90% of the butyrate-producing bacteria come from?

A

genus: Roseburia
species: Faecalibacterium prausnitzii
(both phylum Firmicutes)

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34
Q

What two factors influence butyrate concentrations in the gut?

A
  • Amount of dietary carbohydrate
  • Variations in the dominant metabolic type of butyrate-producer among individuals or variations in diet can influence butyrate supply in the colon
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35
Q

What types of bacteria can convert acetate to butyrate in the colon by cross-feeding?

A

Acetate-utilizing bacteria, such as Roseburiaspecies, Faecalibacterium prausnitzii, Coprococcussp. strain L2-50 and Anaerostipes caccae

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36
Q

Where does much of Faecalibacterium prausnitzii and Roseburia species butyrate carbon come from?

A

It is generated from acetate via the Coenzyme A (CoA) transferase route.

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37
Q

What is required for the formation butyrate from acetate via the Coenzyme A (CoA) transferase route, and why?

A

An energy source such as glucose, probably to provide a source of reducing power for butyrate synthesis from acetylCoA as well as energy for growth

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38
Q

How has it been shown that there is cross-feeding between intestinal bacteria?

A
  • Co-culture experiments
  • oligofructose (a prebiotic) used as the energy source, with Roseburia intestinalis and Anaerostipes caccae converting the acetate produced by Bifidobacterium longum to butyrate.
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39
Q

Most human-derived gut bacteria that possess genes for __________ synthesis lack genes associated with _________ formation

A

Most human-derived gut bacteria that possess genes for butyrate synthesis lack genes associated with propionate formation

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40
Q

Butyrate and propionate represent alternative ‘

______’ whose pathways have evolved in different groups of bacteria

A

‘hydrogen sinks’

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41
Q

What do hydrogen sinks do? Why is this important?

A

Reduce intestinal hydrogen gas (H2) concentration. It has to be removed from the intestinal tract to maintain the thermodynamic equilibrium that allows continuous biodegradation of organic compounds.

42
Q

What microbes are the most active H2 sinks?

A
  • Archaea, sulfate-reducing bacteria

- Acetogens

43
Q

Where are concentrations of SCFA greatest?

A

Caecum and the ascending colon (131 mmol/kg digesta)

44
Q

Why do SCFA concentrations fall during the passage through the small intestine?

A

95% of SCFAs are absorbed across the large intestinal wall, before which they pass through the portal blood and liver and then peripheral tissues

45
Q

What is the molar ratio of acetate, propionate and butyrate?

A

57:22:21

46
Q

What happens to pH levels as the amount of SCFA production increases? why?

A

They drop: acids and hydrogen ions are generated

47
Q

What is an indirect way that SCFA production is protective? Against what?

A

Low pH faecal stool samples are correlated to a lower incidence of colorectal cancer, SCFA production does this by maintaining a low pH in the gastrointestinal tract.

48
Q

What are healthy levels of circulating peripheral blood acetate, propionate and butyrate?

A

a: 22-42uM
p: 0.9-1.2uM
b: 0.3-1.5uM

49
Q

What other organic acids are found in much smaller quantities in the intestine?

A 
lactate
succinate
formate
valerate
caproate
branched chain fatty acids generated from amino acids
50
Q

What strange product is produced in minor amounts as a by product of carbohydrate fermentation?

A

Ethanol

51
Q

What is exogenous acetate production defined as?

A

colonic production (produced by gut microbiota) after accounting for intestinal retention

52
Q

What percentage of SCFA from carbohydrate fermentation does exogenous acetate production make up?

A

60-75%

53
Q

What is the principal way by which energy from carbohydrates, not absorbed by small intestine, is obtained?

A

Exogenous acetate is taken up by the intestinal epithelium, appears in hepatic portal blood and eventually passes through the liver to peripheral tissues, where it is metabolised

54
Q

How is acetate used in the liver?

A

Acetate is used as a substrate for the synthesis of cholesterol and long-chain fatty acids and as a co-substrate for glutamine and glutamate synthesis

55
Q

What tissues is acetate metabolised by?

A

heart, adipose tissue, kidney, and muscles.

56
Q

What impact does acetate have on health, as shown through human and mice studies?

A
  • Causes significant weight loss in humans after drinking 1.5g a day for 12 weeks
  • In mice it can cross blood brain barrier where it is metabolised and promotes appetite suppression & increased production of lactate and gamma-aminobutyric acid.
  • It is unknown if acetate has a hypothalamic effect in humans
57
Q

What is endogenous acetate?

A

Acetate produced by host cells

58
Q

50% of propionate acts as a precursor for _____ _____

A

hepatic gluconeogenesis

59
Q

What does microbiota-produced propionate reduce?

A

cancer cell proliferation in the intestine and liver and induces apoptosis.

60
Q

What are the levels of propionate in the blood and intestinal circulation?

A

20–26 μM in intestinal contents to 1 μM in systemic circulation

61
Q

Once in the circulation, what does propionate contribute to?

A

Improving glucose tolerance and insulin sensitivity
Reduction of high-density lipoprotein
Increase in serum triglyceride concentrations
More stable metabolic homeostasis

62
Q

How does propionate play a role in lipid metabolism?

A

By reducing hepatic use of acetate for fatty acid and cholesterol synthesis

63
Q

How does propionate directly influence satiety?

A

Stimulates leptin, GLP-1 and PYY production.
Propionate increases production of gut-derived satiety hormones, making you feel less hungry and reducing your desire to eat.

64
Q

What does propionate protect the blood brain barrier from?

A

Inflammatory stimuli, suggesting it plays an important role in the microbiome–gut–brain axis

65
Q

Name the disease that is an inborn error of metabolism associated with propionyl-CoA decarboxylase, is the most frequent (but rare) disorder of organic acid metabolism in humans.

A

Propionic acidaemia

66
Q

What are individuals affected by Propionic acidaemia unable to do?

A

unable to convert propionate to methylmalonyl CoA through propionyl-CoA.

67
Q

When do symptoms of propionate acidaemia occur?

A

Immediately after birth, and include poor feeding, lethargy, vomiting, dehydration, acidosis, seizures and poor muscle tone. Left untreated, the condition is fatal.

68
Q

What does treatment for propionic acidaemia involve?

A

placing an affected individual on a low-protein diet free of methionine, threonine, valine, and isoleucine, and providing carnitine supplements.

69
Q

What are patients with propionic acidaemia given in order to suppress gut microbial activity associated with propionate production?

A

antibiotics 10 days per month

70
Q

What are intestinal epithelial cells called?

A

colonocytes

71
Q

What is the principal source of energy for colonocytes?

A

Butyrate

72
Q

What does butyrate do?

A
  • essential in maintaining tissue homeostasis in the colonic epithelium
  • plays roles in suppressing intestinal inflammation and in lipid metabolism
  • exhibits a range of anti-tumorigenic effects on many cancer cell lines
73
Q

What percentage of energy does butyrate provide to the colonic mucosa?

A

40-70%

74
Q

Where is butyrate taken up from? via which transporter?

A

Butyrate is taken up from the colon via monocarboxylate transporter 1 (MCT1) and used to produce energy for intestinal cells.

75
Q

In the progression from normal to malignant cells in the human colon, what happens to the expression of MCT1 and intracellular concentrations of butyrate?

A

Significantly reduces

76
Q

A reduction in MCT1-mediated butyrate uptake has also been linked to what?

A

Reduced levels of butyrate oxidation observed in intestinal inflammation, relevant to conditions such as inflammatory bowel disease in which a significant reduction in butyrate-producing bacteria is seen in patients.

77
Q

In patients with inflammatory bowel disease, explain why only a small amount (< 1 μM) of butyrate is detected in the blood

A

Remaining butyrate not used as fuel by intestinal cells is mostly oxidised in the liver, to prevent toxic systemic concentrations.

78
Q

What do the SCFAs (Acetate, Propionate and Butyrate) activate?

A

Members of the free fatty acid receptor (FFAR) family of G protein-coupled receptors;

A,P&B -> activate FFAR2 (formally known as GPR43), at millimolar to micromolar concentrations

P&B -> activate FFAR3 (formerly known as GPR41) at micromolar concentrations.

79
Q

Where are both FFAR2 and FFAR3 expressed? What does this suggest?

A

Human colonic tissue, white adipose tissue, skeletal muscle and liver
-> suggesting SCFAs influence substrate and energy metabolism directly in peripheral tissues

80
Q

Where is FFAR2 expressed and not FFAR3?

A

Immune cells such as monocytes, B-lymphocytes, and polymorphonuclear cells

81
Q

FFAR3 has recently been shown to be expressed where?

A

Human brain endothelial cells, where it is likely activated by propionate and butyrate

82
Q

Where is hydroxycarboxylic receptor 2 (HCAR2, GPR109a) expressed?

A

gut epithelial cells
adipocytes
immune cells

83
Q

What is hydrocarboxylic receptor 2 activated by?

A

Butyrate

84
Q

What do acetate and propionate activate, expressed in kidney and vascular smooth muscle cells, to contribute to modulation of blood pressure?

A

Olfactory receptor 51E2 (OR51E2),

85
Q

In the large intestine, what do SCFAs produced from dietary substrates by the gut microbiota, bind to?

A

FFAR3 (GPR41) and FFAR2 (GPR43)

86
Q

What does SCFAs produced from dietary substrates by the gut microbiota binding to FFAR2 and 3 lead to?

A

The production of the gut-derived satiety hormones PYY and GLP-1 and (GLP-2?), affecting satiety and glucose homeostasis.

87
Q

Propionate and butyrate might also induce intestinal gluconeogenesis and sympathetic activity, what would this do?

A

Improving glucose and energy homeostasis.

88
Q

When some SCFAs taken up from the gut get into systemic circulation what else may they affect?

A

May also directly affect peripheral adipose tissue, liver and muscle substrate metabolism and function.

89
Q

How might circulating acetate influence the microbiome–gut–brain axis?

A

It might be taken up by the brain and regulate satiety via a central homeostatic mechanism

90
Q

Are metabolic effects mainly explained by direct effects of SCFAs or indirectly via gut-derived signalling molecules?

A

It remains unclear.

91
Q

What does PYY and GLP-1 and GLP-2 increase leads to a feeling of what?

A

reduced appetite
improved gut barrier function
improved glucose homeostasis (e.g. insulin sensitivity)
reduction in inflammation

92
Q

Where did the first suggestion that the gut microbiota influenced brain chemistry come from?

A

In 1986; demonstrated significant differences in hypothalamic histamine levels between germ-free and conventionally raised animals.

93
Q

What are the four major pathways by which the gut microbiota and the brain interact?

A

1) Direct modification of vagal or sympathetic sensorimotor function.
2) Inflammatory/immune activity.
3) Neuroendocrine crosstalk.
4) Gut-derived microbial metabolites interact directly with the blood–brain barrier.

94
Q

How do SCFAs contribute to the gut brain axis?

A

SCFAs are recognised by FFAR2 &3 expressed at the surface of enteroendocrine L-cells in the intestinal wall, producing GLP-1, GLP-2, and PYY. These peptides send signals to the brain that lead to reduced appetite, improved gut barrier function, improved glucose homeostasis (e.g. insulin sensitivity), and a reduction in inflammation.

95
Q

Propionate produced by gut microbes in the large intestine induces intestinal gluconeogenesis via FFAR3 where?

A

in the periportal afferent neural system (a gut–brain neural circuit)

96
Q

What does inducing intestinal gluconeogenesis via this gut–brain neural circuit improve?

A

various features of energy metabolism (e.g. insulin sensitivity)

97
Q

Increased intestinal propionate has also been associated with what?

A

reduced stress behaviours and reward pathway activity in mice and humans, respectively.

98
Q

Where is FFAR3 present? What does this mean?

A

Brain endothelial cells; SCFAs in the blood can interact with this receptor. Propionate is a highly potent FFAR3 agonist - having close to optimal ligand efficiency for this receptor.

99
Q

In vitro, what has propionate has been shown to protect?

A

The human blood–brain barrier from inflammation caused by lipopolysaccharide (LPS) and against oxidative stress

100
Q

What is exogenous acetate production defined as?

A

Colonic production after accounting for intestinal retention and is responsible for the majority of circulating SCFAs in human blood

101
Q

What is the gut-brain axis?

A

Complex multidimensional, bidirectional communication network of gut microbiome, the gut and the enteroendocrine system, linking emotional and cognitive centres of the brain with peripheral intestinal functions

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