Wednesday 27 November 2013

Could obesity be due to micro-organisms within us?

We have seen in a previous post that we are only 10% human, that micro-organisms on us and in us outnumber human cells by a factor of 10 to 1.

Most of the almost hundred trillion micro-organisms that inhabit our bodies live in the intestine. Not only are they by far the most numerous, also the most diverse and the least understood, but they seem to be of the greatest importance. Remember that about 95% of our faeces is composed of dead bacteria, with very little food waste.

It has been discovered that people with diabetes have different micro-organisms compared to the general population. This not yet understood but perhaps the intestinal micro-organisms as part of our “microbiome” have a significant role in our metabolism. There is much research for the future and perhaps our individual intestine micro-organisms are almost as individual as a fingerprint. There up to three million different genes in this vast number of bacteria, but their function, if any, is completely unknown. It is reasonable to anticipate that there is some genetic function, yet to be discovered. There is a suggestion that intestinal bacteria also have an influence on mental health, but the mechanism of this is completely unclear. 

The amino acid cysteine, sulphur atom highlighted
People with ulcerative colitis have a preponderance of bacteria that metabolise sulphur. They reduce sulphur with hydrogen, thereby forming hydrogen sulphide, whereas the usual metabolic process is reduction of carbon to methane. An important dietary source of sulphur is milk. The amino acid cysteine contains sulphur and it is the cysteine that enables milk to curdle. The sulphur atoms can bridge and loosely connect to each other and this is the mechanism of the curdle. It has been known for some time that avoidance of milk helps some people with ulcerative colitis and the sulphur now turns out to be the reason.

Obesity is a much more common problem. It can be the result of gluttony and this is of course undoubted. It is thought that this is in part due to the “thrifty gene". Some people or certain ethnic groups are able to survive with very little food and under this circumstance they have a survival advantage. When food is abundant they tend to become obese and sometimes grossly so. 

But there are many people who appear to gain weight and become obese over a surprisingly short period of time without having increased food intake. This has long been recognised but treated with scepticism - they must have been eating secretly! However it now turns out that obese people usually have different intestinal bacteria from non-obese people and this might be of great importance. 

Bacteria in the intestine are metabolically active. They digest the food residue that we cannot digest. The human intestine digests and absorbs very rapidly protein, fat, simple sugars and starches. However we are unable to digest fruit and vegetable. These become the residue of digestion and they pass into the colon, where they are acted on by the bacteria that inhabit in particular the caecum. The immediate result is the production of gases - think of the flatus that we pass each day, large volumes. The main gases are carbon dioxide and hydrogen, rapidly converted into methane and water. 


Methane, CH4 is a fundamental building block of organic chemistry and from it can be derived molecules such as butane and short-chain fatty acids such as butyrate. This can be produced in large quantities, as long as there is adequate vegetable intake. It is thought that butyrate is necessary for good health of the colon and that it is probably protective against colon cancer.

The fatty acids butyrate and propionate are readily absorbed by the colon and are then passed though the portal vein to 
the liver, where they enter the general metabolic pool. They might be used immediately for metabolic needs, otherwise they will be stored as fat. Fatty acids are the fuel for the heart muscle.

It might seem to be a bit far-fetched to blame obesity on intestinal bacteria rather than gluttony, but think of non-human animal species. Cattle eat grass, but from cattle we take large amounts of milk and meat, fat and protein. It is the bacteria within the intestine of cattle that produce fat and protein from water, methane and nitrogen. Glucose can be produced in the body from the fat and protein absorbed (gluco-neogenesis). The more grass eaten, the more bacteria, the more fat and protein. Do not underestimate the power of micro-organisms.

And it is not just cattle but also sheep and horses, and do not forget rhinoceros and elephant. They all grow to be very large animals by just eating grass and other vegetation, and drinking water. The ultimate size of the well-fed adult is obviously genetically determined, otherwise growth would never stop.

Perhaps the largest vegetarian animal has been diplodocus. Once again this is an example of how bacteria can feed us from within to a very large size even if we eat only grass, fruit, and vegetables.

The message for human obesity is that avoiding dietary fat and protein might not work. Lots of vegetables can be indirectly fattening. Water will not lead to weight gain or weight maintenance. We must eat to live, but just small amounts of meat, vegetables and fruit might be be adequate. If you have a weight problem do not overeat vegetables. If you do not have a weight problem then you will have the colonic bacteria that will allow you to eat lots of fruit, vegetables, and cereals without putting on weight.

There is something else on the horizon. Faecal transfer by enema is a way to change the bacteria in the colon. It is at present only a research area but it might come into clinical practice in about ten years’ time. It might have remarkable benefits in a variety of human conditions, including mental health as well as physical health.

In the meantime probiotics might be useful. These are bacteria or bacterial spores  that can be taken by mouth with a view to repopulating the intestine with bacteria that might have advantages, but it is not very scientific. 

The stomach contains strong hydrochloric acid and the function (purpose for creationists) is to kill bacteria and thereby sterilise food. Probiotics taken by mouth, for example live yoghurts, might not be expected to survive the acid of the stomach. However probiotics are available in a gelatin capsule. This should survive the stomach with contents then being released in the intestine.

To control weight gain by probiotics cannot be considered to be of predicted value, but many people will think it is worth a try. The main message is that you might not lose weight by eating just vegetables. Don’t forget the cow - all that it eats is grass. Our natural intestinal micro-organisms can also convert dietary vegetables into meat and fat.

Hugh Trowell

Dennis Burkitt
About forty years ago a number of interesting and thoughtful doctors - Dennis Burkitt  Hugh Trowell, TL Cleave, and the younger Kenneth Heaton - tried to understand western diseases, “diseases of civilization”, on the basis of dietary change to highly refined fibre-depleted carbohydrates. Treatment with high fibre diets and bran started, but if we look critically only a little was achieved and not a great deal. I found the ideas to be very attractive and in my younger days at the hospital I was called the local “Bran Man”. 

Burkitt and Trowell had worked in mission hospitals in Africa. They were convinced that faecal mass, stool size, was much larger in the Africans and they put this down to the higher fibre content of the diet. What they did not appreciate was the importance of intestinal bacterial mass - the more the better.

The number of intestinal micro-organisms is astounding. About 95% of faecal excretion is dead bacteria and it is this that is responsible for faecal mass. There is in reality only a very small amount of vegetable waste.

An afterthought - there is also a suggestion that intestinal worms can be an advantage to health, especially suppression of allergies.


Wednesday 13 November 2013

Osteoporosis : forget calcium and vitamin D - but what about HRT ?

Osteoporosis : forget calcium and vitamin D - but what about HRT ?

Osteoporosis is nothing to do with vitamin D, and so why is it that we see headlines such as:

And this was in the British Medical Journal! It also appeared on the inner pages of national newspapers. There is no biological reason to expect vitamin D to be helpful in the treatment of osteoporosis, and this had been demonstrated in an earlier trial.  

Osteoporosis is a serious, disabling, and chronic disease, especially in elderly women  whose number is increasing considerably. The absence of effective treatment of osteoporosis creates therapeutic desperation, and as a result the vitamin D trials came into being. The absence of benefit can hardly be attributed to be a so-called “failure” of vitamin D, but that is how it has appeared. 

It is important to understand osteoporosis, and to do so it is necessary to take a look at the biology of bone. Osteoporosis and vitamin D are both something to do with bone, but that is where the connection ends. But vitamin D has many benefits unconnected with bone.


Bone formation starts as the production of a fibrous substance called osteoid, which is laid down in a structural pattern called matrix. This is obviously of fundamental importance and is is this step that is impaired in osteoporosis. When matrix is inadequate the bones become brittle and they easily break.

Bone and its matrix are continually being regenerated - old bone is destroyed by cells called osteoclasts (= “bone destroyers”) and new osteoid matrix is created. At any one time about 10% of bone is being replaced. This occurs in ways that are not fully understood. In fact understanding is extremely poor otherwise the nature of osteoporosis would be clear, but it isn’t. 

Head and neck of femur - normal and osteoporotic bone

The pattern of matrix varies in different parts of the body depending on the physical stresses at particular parts of the skeleton. The density of matrix is much greater in weight-bearing parts, especially the neck of the femur and the vertebral bodies of the spine. It has been noted that as a result of weightlessness, astronauts lose bone density and develop osteoporosis. In healthy people this is rapidly reversed in normal physical circumstances. 

Ossification and osteomalacia

Matrix is converted into mature bone by specialised cells called osteoblasts (= “bone creators”). They add to the matrix a complex calcium-containing compound, a process that is called ossification. Osteoblasts are controlled by calcitriol, the active form of vitamin D. When vitamin D is deficient the ossification process fails. This means that bone remains prodominently osteoid matrix and therefore it is not rigid but can bend. This bone disease is called osteomalacia (“soft bone”). 

In osteoporosis there is not enough matrix, but the matrix that is present is fully ossified. This means that that the bone density is low - the bones are thin, delicate and prone to fracture. In practice bone density is measured as the density of calcium rather matrix, as usual measuring what it is easy to measure rather than what it is most important to measure.

On the other hand osteomalacia is completely different. There is normal matrix but it is not fully ossified. The bones are therefore soft rather than brittle. They can bend and deform especially during growth in childhood.

X-ray of tibia and fibula in rickets showing typical bend of soft bone
Bow legs, typical of rickets

Rickets is a disorder of vitamin D deficiency affecting growing bone and is thus seen as an active disease in children, the childhood form of osteomalacia.  Skeletal deformities can result and can persist into adult life. The characteristic deformity is bow-legs. A much more serious deformity is contraction of the pelvis due the thrust from the legs pushing the hip-joints inwards. When rickets was more common in the industrial cities during the 19th and early years of the 20th century,  the contracted pelvis in young women led to terrible problems and often death due to obstructed labour.

Vitamin D is vital for bone health especially in childhood.

Osteporosis in the 21st century

Now that we are in the 21st century osteoporosis will become a major problem. It is a condition found almost exclusively in elderly women and their number is increasing steadily. The main reason for this is that deaths from coronary heart disease, the major killer of the latter half of the 20th century, have virtually come to an end. Death rates from stroke have decreased substantially and those from cancer significantly. The major problem is now old age with associated infirmity, and this is causing great pressures on health services.

X-ray of spine showing vertebral collapse and osteoporotic bone
Osteoporosis results in brittle bones that fracture easily. This occurs most commonly in the spine. The vertebra can collapse vertically causing temporary pain but irreversible shortening of the trunk. This is accentuated by the intervertebral discs become dehydrated with increasing age, and they also lose their height. The vertebra may collapse asymmetrically, the front collapsing into what is called a “wedge fracture”. This causes shortening, but also a frontwards leaning. This leads to a curvature of the spine called a kyphosis, or historically a “Dowager’s hump”, indicating its characteristic appearance in elderly women.

X-ray of pinned neck of femur

Fractures can occur in any bone but the most serious is the neck of the femur. This can be a terminal event in very old people, but for the majority a “quick fix” can be given by  the surgical insertion of fixing pins, or even a total hip replacement.

The significance of the menopause

The synthesis of bone osteoid matrix is controlled to a significant extent by the sex hormones testosterone in men and oestrogen in women. Deficiency of these hormones can lead to reduction in the synthesis of bone matrix and thus osteoporosis. Testosterone deficiency in men is rare, but oestrogen deficiency in women is universal. 

As the ovaries cease to function at about the age of 50 years, oestrogen production inevitably comes to an end. This is the menopause, and it can occur naturally usually between the ages of 45 and 60. It obviously occurs earlier if the ovaries are surgically removed, and in some women spontaneously.

The menopause can be identified by the cessation of menstruation, but this is not obvious if hysterectomy has been performed. A women will probably identify night-time hot sweats and flushing as menopausal symptoms. Biochemical tests can also indicate menopause. 

The way in this works is as follows. The ovaries are stimulated by hormones produced in the pituitary gland, the time controller. The pituitary secretes the hormone FSH (follicle stimulating hormone) and this activates follicle maturation within the ovaries. This is followed by the secretion of LH (lutenising hormone) by the pituitary, and this leads to release of the ovum, the egg, from the follicle. The follicle secretes oestrogen, and this together with the failure of fertilisation of the ovum leads to inhibition of secretion of FSH and LH by the pituitary gland, which then comes to the end of its monthly cycle. Menstruation follows immediately and then the cycle starts again, with commencement of FSH secretion by the pituitary. 

When the ovaries ultimately fail, the blood levels of FSH and LH are maintained at a very high level, and this becomes evidence of the menopause. It is sometimes puzzling to women as to why when the ovaries stop working hormone levels in the blood increase, but these are only stimulating hormones and not active sex hormones. There is  a failure of what is called “feed-back inhibition”. The same thing happens with the thyroid in which organ failure, hyothyroidism or myxoedema, leads to an increase in the blood level of TSH, thyroid stimulating hormone also produced by the pituitary.

Post-menopausal osteoporosis

The development of osteoporosis
After the menopause a woman has low production of oestrogen, and this is not a good thing. It leads to osteoporosis. Before the menopause women have a distinct health advantage over men, but this is lost after the menopause. It is interesting to note that in a variety of mammals there is equality of susceptibility to infections and infestations between young males and females, but after puberty the females gain an advantage, again pointing to a benefit from oestrogen. Menopause occurs very rarely in non-human mammals and so its effect is not available for study. It is usual in nature for death of a female to occur shortly after, or perhaps before, the end of reproductive functions. 

In humankind, if a woman dies at the age of about 70 years she would have been deprived of oestrogen for just 20 years. This is long enough for osteoporosis to develop without it usually being a major problem. But now more than 40% of women die after the age of 85 years, and the proportion living to 100 is expected to increase substantially. The menopause can now be expected to occur at only half-way through a woman’s life. For a woman to live perhaps 50 years without oestrogen gives an extremely high risk of serious osteoporosis.

Prevention of osteoporosis

What can be done about this? First, physical exercise during earlier life can produce the natural stresses on the skeleton that will lead to optimum deposition of osteoid matrix. Second, sun exposure and vitamin D should be maximised to make certain that ossification of matrix is perfect. Third, diet should be good with adequate protein to help build up matrix. Fourth, avoidance of obesity avoids undue vertical pressure on bones, especially the spine and hips.

Treatment with corticosteroids, prednisolone, should be minimised but it is sometimes essential even intermittently for suppressing serious illnesses, especially chronic inflammatory conditions (eg asthma, ulcerative colitis, lupus). Prednisolone can lead to severe osteoporosis due to an imbalance of bone turnover, increased osteoclast activity or reduced synthesis of osteoid matrix. Its effect is additive to that of the menopause. It is recommended that older people who take steroids should also take calcium and vitamin D tablets. There is no evidence that these are of any benefit in osteoporosis but clearly vitamin D will be helpful if there is associated but unrecognised deficiency of vitamin D. Calcium and vitamin D tablets are prescribed widely, but unpleasant and ineffective, they are also very cheap. The vitamin D given will however improve health in several other ways.

A group of pharmaceuticals called biphosphanates can be helpful in perhaps minimising the progression of osteoporosis but not reversing it. Biphosphonate is often given as a single weekly dose of alendronate, although this can have detrimental effects on the oesophagus and much more serious but less common effects on the jaw.

Strontium can also be given in established osteoporosis, again to reduce deterioration rather than to reverse. It is probably equally effective as biphosphonates, but there are now concerns about its safety.

The guidance that doctors receive is that these pharmaceuticals should only be given when osteoporosis is established. This is reasonable considering long-term therapy with medicines that have significant undesirable effects. The presence of osteoporosis can be detected by bone density scans, but the usefulness of these is doubtful if we are interested in the prevention of osteoporosis, and we must be.

Hormone replacement therapy

The greatest benefit must lie in preventing osteoporosis. This is the role of HRT – hormone replacement therapy. This is started at the time of the menopause and it is usually used as short-term treatment for suppressing menopausal symptoms. However its value in preventing osteoporosis demands long-term use. HRT should most certainly be given to women who have an early menopause. In the woman with a menopause after the age of 50, how long HRT should be given is far from clear but perhaps until about 20 years before death. For most women this might mean until the age of 80 years! 

It is difficult to get our minds around this but we must remember two vitally important facts. This first is that osteoporosis cannot be reversed and can only be prevented. The second is the remarkable long lives that pre-menopausal women of today must expect. To have a long life-expectancy is wonderful, but only if health is maintained and serious disability with osteoporosis is avoided. 

Women who are 100 years old today were born at about the time of the First World War. The younger women who are approaching the menopause today were born in the latter half of the 20th century and they can expect to live to the age of 100. The decision as to whether to take HRT is very relevant for them and it cannot be put off. It is necessary to deal with judgement as the full information about the value of HRT is not likely to be available for perhaps another 20 years. What we must do in the meantime is assess the balance of risks. There is as usual a great deal of fear given to women, especially if "trying to interfere with nature". But if nature means either an early death or crippling osteoporosis then perhaps it is best to interfere with it. 

Breast cancer in younger women is usually oestrogen dependent. Part of the treatment and long-term suppression therapy is Tamoxifen, which  functions by blocking oestrogen receptors. This creates menopausal symptoms and most women are able to cope with these. It follows therefore that to give oestrogen-containing HRT to women with previous breast cancer or with a high family risk of breast cancer would be unwise - it should not be given. But be clear that HRT does not “cause” breast cancer.

There is potentially a huge amount to be gained by so many young women in the prevention of osteoporosis. Hopefully other methods of prevention will come available in the future. At the moment there is only HRT, and this means natural hormone levels. 

Stem cells

The failure to produce adequate bone matrix in the elderly is likely to be the result of insufficient stem cells with increasing age. Some tissues, such as the liver and bone marrow, are richly endowed with stem cells, and the supply is adequate for recovery from major damage and for a long life. However some tissues do not have such a rich supply of stem cells. This would apply to the heart and the brain, and so we have heart failure and brain failure occurring commonly in old age. 

It would appear that osteoporosis is similar, age-related bone matrix failure resulting from the bone running out of stem cells. Somehow this is exacerbated by oestrogen depletion. At present there is no therapeutic opportunity for stem cell replacement, but there is a huge amount of basic science research taking place in respect of stem cell biology. Hopefully effective treatment will follow.