Last month we saw that ulcerative colitis (UC) patients suffer continuing diarrhoea, (unrelieved by over-the-counter medications), and often pass blood and puss in their stool (Ref)

This article was inspired by ground-breaking UC research done in 1980 by Australian Associate professor William Roediger now at the University of Adelaide. Up until this work researchers had been unable to:

1. Find any ‘microbe causing the mucosal changes’ seen in UC
2. Offer a satisfactory explanation for UC’s causation

Then Roediger’s work gave us our first insight into a possible cause.

Initially, let’s define a few terms:

1. Epithelial cells are all the different cell-types that make-up our body’s mucous coverings
2. Stem cells are primordial (undifferentiated) cells that live in most tissues. When any adult tissue-cells die, these need to be replaced with new adult cells. Stem cells receive a signal to divide, to make new baby cells which then develop (differentiate) to become the adult cells that need to be replaced. Tissue stem cells can generally differentiate into most of the different cell-types that a tissue requires to function properly.
3. Goblet-cells are adult cells – living in mucosal tissue e.g. the colon. They make and secrete the mucus that covers and protects the all mucosal cells from microbes
4. Mitochondria are tiny organelles inside cells. Their job is to burn fuels (carbs, proteins, fats) to make the energy that allows all cells to function.

When scientist examine the mucous membranes of UC patients colons, they find that:

1. Mitochondria inside mucosal/epithelial cells have difficulty making energy
2. Stem cells of the colonic mucosa have difficulty becoming mature goblet cells,
3. A lack of goblet cells leads to a depletion in the protective mucous covering, giving microbes access to “unprotected” mucosal cells

Both the process of:

1. Mucous stem-cells becoming adult goblet cells and
2. Adult goblet cells making protective mucus

requires mitochondria to make huge amounts of energy.

In 1980 Roediger was the first to show that the colonic mucosal cells of UC patients have lost their ability to make energy from their normal fuel – a fat called butyrate, which is made by the colonic bacteria as they ferment fibre.

UC had up until this point had been defined as an “autoimmune disease”. Roediger’s findings lead him to redefine UC as an “energy deficiency disorder” that specifically affects the mucosal cells that line the large intestine.

In a bit more detail for those people that may be into it…

Energy production via respiration is the most efficient form of energy production in virtually all body cells. Respiration involves cells burning fuels such as carbs and fats using oxygen (that’s why It’s called aerobic respiration) and producing carbon dioxide in the process. Roediger found the following:

1. The cells harvested from non-ulcerated normal tissue found between UC ulcer-lesions, in patients suffering acute UC, had great difficulty utilizing oxygen to burn glucose or butyrate. In short, these cells had difficulty using respiration to make cellular energy. Whilst colonic cells harvested from normal control patients and UC patients in remission used normal levels of oxygen to make energy.
2. Butyrate is the preferred fuel for energy production by (most) colonic mucosal cells. Colonic cells harvested from patients:
   1. not suffering UC – utilised butyrate easily to make energy
   2. in remission from UC – were only able burn half the normal amount of butyrate
   3. suffering acute UC – were almost completely unable to burn butyrate for energy.

This finding suggests that energy production of UC patients has become abnormal.

1. Normally, when healthy colonic mucosal cells use butyrate for energy production, in doing so, they produce ketone bodies, which are a type of fat. The amount of ketone bodies produced by colonic mucosal cells therefore shows how well they make energy from butyrate. Colonic cells harvested from patients:
   1. not suffering UC – produced normal levels of ketone bodies
   2. in remission from UC – produce significantly less ketone bodies
   3. suffering acute UC – produced very little ketone bodies

This finding again suggests that energy production of UC patients has become abnormal.

1. Unlike healthy patients, colonic mucosal cells of both UC patients in remission, and UC patients with acute UC, appear to only be able to use glucose (not butyrate) as a fuel and both produce excessive levels of lactic acid. The importance if this finding is that Lactic acid is produced mainly when cells metabolise glucose non-aerobically (i.e. when glucose is not burnt in mitochondria using oxygen). This finding suggests that colonic mucosal cells both from UC patients in remission & from UC patients suffering acute UC, have difficulty burning fuel aerobically i.e., they cannot utilize respiration for energy production because their mitochondria aren’t working properly.

All the above findings suggest that colonic mucosal cells from UC patients seem to rely largely on anerobic energy production, with the cells from acute UC patients even more reliant on anerobic energy production than those from UC patients in remission.

Importantly, anerobic energy production is very inefficient and produces far less energy than aerobic energy production (about 18 times less energy per molecule of glucose). So, by definition, when the colonic mucosal cells of UC patients use anerobic metabolism to produce energy, they will produce far less energy from the same fuel compared to colonic mucosal cells of normal control patients. This, by definition, means that colonic mucosal cells from UC patients are energy deficient compared to cells from normal healthy patients.

According to Roediger, the key to the mystery of why the mitochondria of colonic mucosal cells from patients suffering acute or quiescent UC cannot make enough energy, has to do with a molecule called co-enzyme-A. Colonic mucosal cells can only burn fuels such as butyrate and glucose aerobically (i.e. via respiration using oxygen) when levels of co-enzyme-A are sufficiently high. Next month we will a look at why coenzyme A levels may be low in patients suffering from UC.

References

Roediger, W. E. W. (1980). The colonic epithelium in ulcerative colitis: an energy-deficiency disease?. The Lancet, 316(8197), 712-71.  https://sci-hub.se/10.1016/S0140-6736(80)91934-0

Sünderhauf, A., Hicken, M., Schlichting, H., Skibbe, K., Ragab, M., Raschdorf, A., … & Sina, C. (2021). Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis. Cellular and Molecular Gastroenterology and Hepatology, 12(1), 229-250. https://www.sciencedirect.com/science/article/pii/S2352345X21000230#bib3

Article Written + Submitted by:

Andreas Klein Nutritionist + Remedial Therapist from Beautiful Health + Wellness
P: 0418 166 269