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Monday, August 5, 2019

Pooh poohing the obesity microbiome theory

Nutrition has fashions and the most attractive fashions are those that promise the most in terms of beneficial effects. An important determinant of durability of a nutrition fashion is the challenges it poses to experimental challenge. At present, the best example of a long living nutrition fashion is the human gut microbiome which represents all of the bacteria we house in our lower gut. Their main evolutionary basis was the extraction of energy from food carbohydrates that are not amenable to digestion by our digestive enzymes. However, in recent times these bacteria have been associated with many diseases. If you get the wrong bacteria in your gut you increase the risk of many diseases such as (non-exhaustive list: depression, anxiety, autism, cancer of the lung and colorectum, pancreatitis, liver disease and many gut disorders such as irritable bowel syndrome, Crohn’s disease and ulcerative colitis. Of particular importance is infection of the gut with Clostridium difficile which can be fatal in up to 30% of cases. Considerable success has been achieved using faecal transplants of such patients with encapsulated bacteria  from a healthy donor.

Another condition which receives considerable attention in relation to the gut microbiome is obesity The gut microflora of obese persons differ from those with a normal weight and when obese persons lose weight their gut microbe population moves in the direction of normal. But the big question is cause and effect. Does an adverse microbiome population cause obesity or does obesity cause an adverse microbiome population? In an attempt to answer that question, a recent study examined the impact of faecal transplantation of people with severe obesity (but who were metabolically healthy, with no sign of type 2 diabetes, fatty liver or the metabolic syndrome) with a capsule containing filtered faecal extract from a healthy normal weight female[1]. Twenty severely obese subjects (BMI 35+,Kg/M2) were randomly assigned to either the treatment arm (encapsulated faecal transplant) or a placebo arm (similar capsules with glycerol and colouring matter). The treatment arm began with a booster level of transplantation which was then followed by a reduced maintenance dose. They were told to eat normally and were closely monitored throughout the 12 week treatment period. Probiotics were not permitted for the study duration and for 4 weeks prior to treatment. Antibiotic treatment was not permitted for 8 weeks prior to the treatment and then throughout the treatment.

The obese patients did not lose weight. So, if the microbiome theory of obesity is correct, why not? The first question : “did the faecal transplant alter the gut microbiome composition’? And the answer is ‘yes, it did’. Faecal samples were taken at several instances during the intervention and the gut microbiome quickly resembled that of the healthy lean donor and that was sustained throughout the study. The gut-microbiome theory also states that the underlying effect is a change in the type of bile acids secreted with less taurocholic acid type bile in faeces. So did the faecal transplant cause a reduction of faecal taurocholic acid? Again, yes it did. And finally, central to the obesity-gut microbiome theory is that the obese type is that the obesity type microbiota alters the production of a gut hormone which plays a role in weight regulation, the hormone glucagon-like peptide (GLP). Did the change with treatment? No it didn’t.

Now, just as one swallow never made a summer, one experiment never copper fastened a scientific theory. But it opens the debate. It challenges the theory and that is what drives scientific enquiry. Flaws can be found in this study and the authors list a few. Maybe it wasn’t long enough for weight loss to occur. Maybe, but I doubt it since weight loss can rapidly respond to treatment. Maybe the faecal transplant dose wasn’t strong enough. Maybe, but I doubt this also, since the dose in use in the study changed the composition of the microbiota.

So I’m left with the view that more studies like this need to be completed to properly address this question. But let me leave you with my final thought. Obesity is a consequence of overeating and the caloric balance theory of obesity is to the microbiome theory what the Mona Lisa is to graffiti. To paraphrase Bill Clinton: It’s the calories, stupid.  

[1] Allegretti J et al (2019) Effects of Fecal Microbiota Transplantation With Oral Capsules in Obese Patients. Clinical Gastroenterology and Hepatology (In press, available online)

Tuesday, April 23, 2019

The genetics of obesity

The genetics of obesity

Obesity is a very complex condition and involves a multitude of metabolic pathways, each regulated by  several genes. A disorder of one gene can lead to severe obesity but the rate of occurrence of these single gene defects is so low that they cannot explain the current pandemic of obesity.  For example, a rare defect in the gene which encodes for a protein, bearing the awkward title melanocortin-4 receptor (MC4-R) can lead to obesity. But even among morbidly obese persons, this gene defect is only found in 4% of this population. Thus a single gene defect is never going to explain the obesity issue.

However, twin studies have repeatedly shown that obesity is highly heritable to a level of about 70%. So if one gene defect can’t explain this inherited susceptibility to obesity, maybe data on multiple genes might assist us. A recent study by UK and US scientists[1], has begun to throw some light on how we might begin to predict the susceptibility to obesity based on our genes.

The first step in their quest was to explore a published database on 300,000 individuals whose body-weight was known and who had their entire genetic code searched for over 2.1 million common genetic variants. No single variation explained any significant risk of obesity. Thus the next step was to take all of these 2.1 million common genetic variants and see if they could compute a polygenic score which would be predictive of obesity. They used advanced computational methodologies to devise 6 candidate scoring systems. To determine which was best, they turned to the UK Biobank which has full genetic data and body weight data on over 120,000 subjects. Their best performing scoring system could now be put to the test.

They used four different data sets to explore the predictability of their polygenic score  in quite different groups. To understand their scoring system, they could first dismiss all those common gene variants which had simply no link with obesity. Thus our hair and eye colours are genetically determined and different genetic variants explained redheads from blondes to brunettes. So they were scrapped along with lots of others. They were left with genes that had a very, very minor effect on obesity right up to some genetic variants with a more significant link with obesity but still, on their own, would have no real predictive power. The more of the higher linked variants you had, the higher your polygenic score. So every individual in the UK Biobank got a score ranging from low to high. They divided the 300,000 subjects into ten groups (deciles) with increasing polygenic scores and they showed a very strong link between the score and body weight.  Half the people with the lowest score had a normal body mass index whereas among those in the top 10% of the polygenic score, only 17% were of normal weight. Conversely, among those classified as obese, only 9% belonged to the lowest scoring decile while 38% were at the top end of the score. Across the ten deciles of polygenic score there was a linear increase in  bodyweight, BMI and the incidence of severe obesity.

The next data sets they turned to were ones that included subjects who underwent bariatric surgery for the treatment of their morbid obesity. A high polygenic score was associated with a 5.0-fold increased risk of severe obesity treated with bariatric surgery. To understand the evolution of obesity over time, they then turned to the Framingham Offspring and Coronary Artery Risk Development in Young Adults (CARDIA). This gave data on 3,722 individuals who at baseline had no case of severe obesity. Over the next 27 years they were weighed 8 times. Over that period some subjects went on to develop severe obesity. Among those in the lowest 10% of the polygenic score just over 1% went on to develop severe obesity. In contrast, those in the top 10% of the polygenic score, 16% went on the become severely obese. The final database they used was one of UK babies born in the years 1991-1992 who were followed up to their 18th birthday (Avon Longitudinal Study of Parents and Children). The difference in birthweight between the top and bottom 10% of the polygenic score was just 0.06 kg. By 8 years of age the difference was 3.5 kg and by 18 years of age the difference had risen to 12.3 kg.  

This has shown that we are fast becoming capable of defining genetic profiles which predicts the likelihood development of a normal weight or a severe obesity problem. But before you jump up and down and blame your genes, remember the key saying: “Genes load the obesity gun. But only the environment pulls the trigger”. That said, a knowledge of the likely risk of sever obesity might motivate people with a high score to watch their calories more closely than most

[1] Khera et al., 2019, Cell 177, 587–596

Saturday, December 22, 2018

A . brief history of Christmas fare

Christmas fare: A brief history
In order to understand Christmas fare, we need to appreciate the seasonality of food in mid-winter. Hay was harvested in summer and by November, when frost and snow began to fall, stock were moved into barns and more often than not there was not enough hay for all the stock so some would be slaughtered for meat. At the same time, landowners now had time on their hands and so they turned to hunting, especially hunting birds: Pheasant, partridge, grouse, guinea fowl, pigeons, duck & geese. The story of the turkey follows later. Medieval winter has been described as an avian slaughter. Preserving meat was a tiresome task and so the mince meat pie was invented. It bears simply no resemblance to today’s mince pies.

To begin with, pies were baked in communal ovens to reduce the risk of fires in cottages roofed in thatch. These pies used a bread dough, with a thickness of at least an inch if not more, with the base made like a mini coffin. That was the original use of the word before the undertakers hijacked it and it became an unmentionable object in polite circles. The ‘coffin’ was then loaded with chopped meat from hunted fowl and some beef and mixed with seasonal dried fruits and nuts and topped with  a generous dollop of strong liquor, all in the interests of preservation.  The lid of the coffin-like pie was overlaid on top of the contents and the sides and top sealed by pressing the dough together.

Quite frequently, en route to Church on Christmas morning, families would stop at the bakers and place their pie in the oven which was half way between a modern barbecue and a pizza oven. Lots would have been drawn to determine who got which position in the communal oven. Four or five hours later, the pie was reclaimed by the household and laid on the table. The bread dough formed a very hard crust and usually, the bottom part was burned. In households with servants, the latter would get this burned crust while the gentry got the ‘upper crust’! Some of these pies were enormous and there was a general tendency in all areas of Christmas fare for the landed gentry to outdo one another in outlandish dishes. This is the recipe for a famous Yorkshire mince pie:

First make a good standing crust and let the wall and bottom be very thick”. The recipe then goes on to propose that a turkey, a goose, a guinea fowl, a partridge and a pigeon be boned and place in the pie with the turkey breasts on top. On one side a chopped hare could be piled and on the other side some minced beef. Dried fruit, sugar, nuts, spices and port were added along with four pounds of butter. ‘Then lay on the lid which must be very thick and bake in a very hot oven for four hours’. The crust alone would require a bushel of flour, that is all of over four stone of flour and the pie would often weigh up to ten stone!

The transition from the meat-dominated crusty mince pie to today’s mince pie required the mastery and popularisation of pastry which differs from crusty dough with the addition of fat. The pastry pie is tasty but not a strong as crusty pies. So adaptations were made and the advent of fruit in mince pies began with Queen Elizabeth  The First’s love of pies made with orangeado, a candied orange peel. In time other fruits were candied as sugar became more available and together with port and dried fruit, the recipes for modern meatless mince pies came into vogue. Of course, the crude thick  crusts of former pies were replaced with various types of pastries from shortbread to puff pastry and the delicate nature of pastry miniaturised the size of the now sweet  pie, still retaining the title mince pie.  

Now the mince pies of Christmas were the subject of a very serious political edict in England. Cromwell and the Puritans banned Christmas in 1645, believing it to be a sin-laden papish Catholic festivity. One strict protestant , Philip Stubbes writing in his famed book ‘The Anatomie of Abuses’  noted that “More mischief is that time committed than in all the year besides ... What dicing and carding, what eating and drinking, what banqueting and feasting is then used ... to the great dishonour of God and the impoverishing of the realm”. The minced pie was banned as was all Christmas fare. It was only restored when King Charles the second  took over from Cromwell that the ban was lifted.

As I pointed out, winter time was the season for the hunting of wild fowl and, again, because preservation was not possible, a disproportionate consumption ensued. For landowners, hunting brought pheasant, woodcock, pigeon, guinea fowl and the like but not of course turkey. The meaning of turkey then and now is very different. Colonial explorers of the day discovered in In Madagascar, a bird that was like a guinea fowl, only much larger. Its meat was delicious with ample white breast meat and tasty brown leg meat. It was seen as a real luxury back in the day. It was imported into Europe either through Turkey or India. Thus ,what the English called turkey was just a big exotic bird imported from Madagascar via Turkey, originally called Turkey bird and then just turkey. The French regarded the same bird as having its origins in India which became ‘Oison d’Inde’, Goose from India, abbreviated to Dinde, the modern French word for turkey. Either way fowl dominated Christmas fare except for the very lower classes who ate beef.

In England, Goose was regarded as a significant social step up above lowly beef. The goose also provided superb feathers for pillows, the finest quills for writing and, most importantly, the tail and wing-tip feathers for arrows to guide flight. The inn keepers of England ran  Goose clubs for its patrons beginning with the purchasing of young geese to be communally raised on local commonage via  a weekly subscription to the club.   But for the landed gentry, it was this exotic imported bird from Turkey together with a range of hunted domestic fowl that they focused on for Christmas and, for them, the social ladder required as much culinary ostentation as possible. One way to impress was to go as for as possible in the process of engrastation, nowadays called ‘stuffing’.  It would not be uncommon to have the flesh of a partridge stuffed into the cavity of a pigeon and for the whole pigeon to be stuffed into the cavity of a goose and then to top it all to stuff the multi-stuffed goose into the turkey.

The obsession with fowl at Christmas served as a secretive way to pass on Catholic catechism across generations at a time when all things Catholic were proscribed. The carol, The Twelve days of Christmas celebrates the period of the birth of Christ, December 25th to the arrival of the Magi from the East on January the 6th. Note that on the 7th day, representing the Sabbath, the song describes what “My true love gave to me” and ‘My True Love’ represents Christ. Thereafter the parade of wild fowl provides guidance to young children about issues of Catechism. Thus here is what was meant by the gifts of the 7th day of Christmas:

The partridge in a pear tree
Christ, since the mother partridge will feign injury to lure predators away from defenceless nestlings.  
Two Turtle Doves
The old and New Testaments
Three French Hens
The 3 gifts of the Magi
Four Calling Birds
The 4 gospel evangelists: Mathew, Mark, Luke and John
Five Gold rings
Rings have no beginning or end and are thus representative of eternity. Five depicts the first 5 books of the Jewish Torah: Genesis, Exodus, Leviticus,  Numbers and Deuteronomy.
Six Geese a-laying.
The 6 days  of Creation
Seven Swans a-swimming
The 6 days of creation and the 7th day of rest.
Eight Maids a milking
The 8 beatitudes
Nine ladies dancing
The 9 Angelic choirs
Ten Lords a-leaping
The 10 commandments
The eleven pipers playing
The 12 apostles minus Judas
The twelve drummers drumming
The 12 precepts of the apostle’s creed

Will it ever sound the same to you again?

Let me return to the turkey. When the colonial settlers reached the North-Western US territories they encountered a new bird that lived in covered forests but with field breaks to allow this bird with limited flight, to escape temporarily from the forest in search of prey. This ‘undocumented bird’ if I may call it so,  looked just like the bird that was imported at Christmas from Africa via Turkey back in the homeland and by then simply called, turkey,  and so this new “undocumented” bird was also called a turkey. It was first introduced into Europe in Spain, spreading northwards and assumed the title of Turkey in England and Dinde in France. Turkeys were domestically farmed and would be herded great distances from farming areas to towns and cities creating the early days of the turkey Christmas market. In time, the bird lost its already limited ability to fly and was ideal for fattening for Christmas in Europe and in Thanksgiving in the US. We haven’t looked back.

But we are not quite finished with engastration or stuffing. In the Cajun region of the US, Paul Prudhomme, the famous Louisiana chef, whilst working at a carvery, decided that the turkey was boring. He set out in the mid 80’s to improve it and invented and patented the now famous Cajun treat, the Turducken. This is a Duck stuffed with a Hen and in turn the stuffed duck is stuffed into the Turkey ~ Turkey-Duck-Hen, “Turducken”. I have a good friend, a very famous nutritionist, who annually hosts a New Year’s Eve party in her home in Washington where the piece-de-resistance is her Cajun Turducken. The Turducken wasn’t the first phenomenon of stuffing smaller de-boned birds into bigger de-boned birds. In 1807 The French food critic, Grimod de La Reyni√®re (one of the first of this species! ) described “roast without equal"—a bustard stuffed with a turkey, a goose, a pheasant, a chicken, a duck, a guinea fowl, a teal, a woodcock, a partridge, a plover, a lapwing, a quail, a thrush, a lark, an ortolan bunting and a garden warbler: 17 birds in all!
When all the savoury meats and stuffings, the potatoes and vegetables are gone, its time to switch course and focus on the sweet side of Christmas dinner. Pride of place is the Plum Pudding but to understand the plum pudding we need to go back in time. Offal,  fat, spices and fruits (the best preservatives of their day) were mixed with meats, grains and vegetables and packed into cow’s stomachs as meat puddings (as opposed to meat pies) so they would keep as long as possible. This also had the advantage that it could be cooked at home by boiling over the home fire and emerged in rural areas where bakers communal ovens weren’t available. In the 1700s, dried fruit became more plentiful as in currants (dried grapes from the Corinth region of Greece), sultanas (from the Sultans of the Izmir region of Turkey), raisins (called after racemus meaning a bunch of grapes) and of course dried local plums. As sugar became more plentiful from the Caribbean, candied fruit peelings were also added to the mix. In time, the meat component of the old savour puddings  fell away, just as with  mince pies. The use of animal stomachs was abandoned in favour of muslin cloths. However, the now sweet tasting pudding retained the tradition of exposure to the gut by incorporating suet, the fat which surrounds the kidney, into the recipe. In fact  tradition holds that there should be thirteen ingredients in a Christmas plum pudding representing  Christ and the twelve apostles.

Finally we turn to crackers which are part of the fun of Christmas dinner. Believe it or not, Christmas crackers have their origins in food, specifically boiled sweets. What was special about these Christmas sweet treats is that were wrapped in pretty paper wrapping  which, back in the day,  was itself quite a novelty. The progression from wrapped sweets to Cracker Bonbons, brings us back to cap guns that became popular in the US after the Civil War. A tiny amount of explosive material was placed in a container of a toy gun  and when the trigger was pulled the firing pin was released to make a bang. I grew up with cap guns and can still recall the smell of the explosive and the tiny wisp of smoke that accompanied the bang. I was The Cisco Kid! Well, in the 1860’s,  Tom Smith an entrepreneurial confectioner, decided to remove the sweet from the cracker bonbon, enlarge it, insert two strips of material each connected to one end of the cracker  and meeting in the middle in a simple mechanism the glides an explosive material across and an abrasive material. Little poems and trinkets and  party hats. Were inserted into the cracker.  When each end is pulled, the tiny explosive on one strip is rubbed against an abrasive part of the other strip and the cracker bangs just as it opens, always unevenly. The larger part has the goodies. Much more fun than boiled sweets.

Happy Christmas and Bon Appetit!

There’s much more to Christmas traditions beside food: from Christmas trees, to stockings, to boxing day, to carols and of course St Nick himself. Mark Forsyth’s “A Christmas Cornucopia- the hidden stories behind our Yuletide traditions” tells it all. I have also consulted many volumes from the Edible Series of Reaktion Books and of course Wikipedia, to which I make a financial contribution.

 Michael J Gibney, Dublin, December 2018. ©