Posts Tagged ‘Nicotine’

Diverticular Disease and Nicotine Metabolism

Tuesday, June 13th, 2023

Colon diverticular disease (DD), previously a curiosity, increased in significance in Western countries in the 20th century. The earliest indications of colon abnormality were changes in the sigmoid colon which was shortened, thickened and corrugated. The longitudinal muscles appeared in a contracted  form like after defaecation, unable to relax.

Internal pressure increased, eventually producing blow-out hernia through hardened circular muscle giving grape-like appendages on the outside of the colon – the diverticula. At this stage a diagnosis of diverticulosis could be made when the diverticula were seen by scans, colonoscopy or during surgery. A clinical appraisal alone would not separate easily any symptoms from those of any other bowel disease. An attack of diverticulitis or severe pain however, often lead to diverticula recognition in the hospital setting and it is here where statistics on DD and its ramifications are generated, more often on elderly patients.

Early researchers recognized that the affected colon muscles responded differently to drugs such as acetylcholine, morphine, carbachol and neostigmine, also to physiological stimulation. Parks (1) considered a pharmacological stimulus that would cause such a change, would be uncommon in real life. The ‘nicotinic’ receptors in the autonomic nervous system were a missed clue. Birkitt (2) also recognized an environmental factor was responsible for the diseases in affluent countries compared with Africa. Unfortunately, he attributed non-infective disease of the bowel to diet. DD was supposedly caused by low levels of fibre. Also in the 1970s Painter (3) professed “The factors which cause this acquired disease (DD) are operating more and more effectively and that diverticulitis in young patients will become a greater problem in the future.” In 2023 this has happened (4,5). Hospital admissions continued to endemic proportions and diagnosis in younger people is rising. Diet has never explained the neuromuscular changes in the colon at the beginning of DD which has now been accepted (6,7).

Birkitt’s “geographic medicine” data was in fact the epidemiology in the 1970s which pointed to DD as one of the 20th century ‘Western’ diseases, in time and place these correspond to the use of ‘Western’ cigarettes. Mortality statistics (8) show DD goes hand in hand through the 20th century with lung and other cancers, cardiovascular disease and appendicitis for example. Does Crohn’s disease follow the same pattern? In cigarettes there are the carcinogens and nicotine. Nicotine is the pharmacological stimulus. Globally, DD appearance correlates with the marketing of ‘Western’ cigarettes from the beginning of the 20th century. Firstly, in the USA, UK and Australia, in Europe after WW11 and in eastern countries after the US 1974 Trade Act with a rapid rise of DD in Japan. There is very little in African countries so far. The Japanese smokers merely changed their brands, not diet, as did Japanese immigrants in Hawaii. 

Nicotine is a drug and banned toxic pesticide. Addictive property means nicotine and active metabolites are in the body continuously, often for many years. Chronic effects are predictable. The action of nicotine on post-synaptic neurons is classic pharmacology. It stimulates then blocks normal acetylcholine transmission, leaving muscles contracted for longer. Its effects on the nitric oxide relaxation system may be complicated by nitrate levels in ‘Western’ cigarettes. Nicotine promotes fibrosis and changes to a firmer structure of collagen and elastin in the colon walls, like in the skin with smoker’s wrinkles and rigidity of walls in cardiovascular disease. In the colon walls, these are the neuromuscular precursors of diverticula and DD progression.

Nicotine is metabolized in the liver by enzyme CYP2A6 and its many variants which have ethnic differences in smoking diseases. Faster nicotine metabolism in females increases addiction and smoking habits and gender differences in smoking related diseases. Clinical results suggest that with DD, females have earlier and more extensive colon neuromuscular damage than males. Compared with males, females have more affected colon segments which increase with age (9). They are more at risk of persistent symptoms after sigmoidectomy (10) and diverticula are more scattered along the colon (11). More diverticula results in females having more episodes of diverticulitis and chronic complications and at a younger age (12). They had more chronic diverticulitis and strictures but less bleeding than men (13). Chronic complications such as sepsis, obstruction or pelvic fistula were more likely causes of death in women whose DD mortality rates have exceed men in the UK since WW11 (14,15). Gender differences must question the use and value of male only research cohorts. For example, male health professionals with only 10% smokers have been studied extensively since 1986 and resulted in a significant dietary treatment advice for all with DD irrespective of different disease progression and the basis of no gender differences in DD and diverticulosis rare before the age of 40 (16).

Research data from western countries shows DD usually in the sigmoid area of the colon. Muscles affected by nicotine in colon parts with mixing (ascending) or drying (transverse) movements would have different appearance and symptoms. Right sided disease is found in Eastern countries such as Japan. CYP2A6 polymorphism may be responsible for this difference. CYP2A6*4 variant produces different nicotine metabolic products, far less cotinine and less lung cancer. NakaJima (17) compared the frequency of CYP2A6*4 and other variants with reduced activity, with ethnicity. The table shows some possible association of CYP2A6*4 with the frequency of right-sided DD.

CYP2A6*4 and other liver enzymes have been demonstrated to affect the metabolism of nicotine with ethnic variations in smoking, also in drug and disease research. The long-term damage by nicotine in the autonomic nervous system has had less attention than cancer. How many smokers and non-smokers have DD depends on symptoms bad enough to be investigated. A familial pattern has been recognized which may be genetic or passive smoking. There are many unanswered questions. Nicotine as the cause of colon neuromuscular damage of DD is suggested by epidemiology, pharmacology and the link between genetics and environment. Many research reports show there is no doubt that smoking negatively affects all clinical aspects of DD.

The neuromuscular colon damage in DD is permanent. Lifestyle changes can alleviate some symptoms but there are no drug treatments except antibiotics and surgery. Anticholinergic side effects of drug treatments for other complaints might influence symptoms. Only prevention can make an impact on DD. The current situation with cheap, available, promoted nicotine products to reduce cigarette smoking seems to be producing a new generation of nicotine addicts without knowing long term effects. This is very reminiscent of 70 years ago with cigarettes and a frightening outlook for DD.

% of CYP2A6*4 in ethnic group Ref (17) % with DD in right colon   Reference
JAPANESE   50.5 67 (18)
KOREAN     42.9 85.2 (19)
BLACKS      21.9 18.3 (20)
WHITES        9.1 2.7 (20)


© Mary Griffiths 2023


  1. Parks T G. The pathogenesis of large bowel diverticula. Ulster Med J. 1971, 41, 45. PMID 5150065.
  2. Birkitt D P. Epidemiology of large bowel diseases: the role of fibre. Proc. Nutr. Soc. 1973, 32, 145.  DOI:  10.1079/pns19730032
  3. Painter N.S. Diverticular disease of the colon- a deficiency disease of Western civilisation. 1975. William Heinemann Medical Books Ltd. London. ISBN 0 433 24660x
  4.  Fialo A. et al. Analysis of the epidemiological trends on inpatient diverticulosis admissions in the USA: a longitudinal analysis from 1997-2018. Cureus. 2023, 15, e34493. DOI:10.7759/cureus.34493
  5. Broad J B. et al. Diverticular disease epidemiology: acute hospitalisations are growing fastest in young men.  Tech Coloproctol. 2019, 23, 713. DOI:10.1007/s10151-019-02040-8
  6. Kupcinskas J. et al. Pathogenesis of diverticulosis and diverticular disease. J Gastrointestin Liver Dis. 2019, 28, suppl.4. DOI:10.15403/jgld-551
  7. Schafmayer C. et al. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut. 2019, 68 854. DOI:10.1136/gutjnl-2018-317619
  8. National Statistics. Twentieth century mortality. 100 years of mortality data in England and Wales by age, sex, year and underlying cause. Crown Copyright 2003. CD ROM ISBN 0 11 621665 4.
  9. Eide T J. et al. Diverticular disease of the large intestine in Northern Norway. Gut. 1979,20, 609. DOI:10.1136/gut.20.7.609
  10. Choi K K. et al. After elective sigmoid colectomy for divertiulitis, does recurrence-free mean symptom-free? Am Surg. 2020, 86, 49. PMID 32077416
  11. Parks T J. Post mortem studies on the colon with special reference to diverticular disease. Proc R Soc Med. 1968, 61, 932. PMID 5679019
  12. Lightner A L. et al. Use of the Rochester epidemiology project for clinical research in colon and rectal surgery. Clin Colon Rectal Surg. 2019, 32, 8. DOI:1055/s-0038-1673349
  13. McConell EJ et al. Population-based incidence of complicated diverticular disease of the sigmoid colon based on gender and age. Dis Colon Rectum. 2003, 46, 1110. DOI:10.1007/s10350-004-7288-4
  14. Sell N M. et al. Are there variations in mortality from diverticular disease by sex. Dis Colon Rectum. 2020, 63, 1285. DOI:10.1097/DCR0000000000001711
  15. Kang J Y. et al. Diverticular disease of the colon – on the rise: a study of hospital admissions in England between 1989/1990 and 1999/2000. Aliment Pharmacol Ther. 2003, 17, 1189. DOI:10.1046/j.1365-2036.2003.01551.x
  16. Strate L L. et al. Nut, corn and popcorn consumption and the incidence of diverticular disease. JAMA 2008, 300, 907. DOI:10.1001/jama.300.8.907
  17. Nakajima N. et al. Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin Pharmacol Ther. 2006, 80, 282. DOI:10.1016/j.clpt.2006.05.012
  18. Takano M. et al. An analysis of the development of colonic diverticulosis in the Japanese. Dis Colon Rectum. 2005, 48, 2111. DOI:10.1007/s10350-005-0111-z
  19. Lee K M. et al. Clinical significance of colonic diverticulosis associated with bowel symptoms and colon polyps. J Korean Med Sci. 2010, 25,1323. DOI:10.3346/jkms.2010.25.9.1323
  20. Golder M. et al. Demographic determinants of risk, colon distribution and density scores of diverticular disease. World J Gastroenterol. 2011, 17 1009. DOI:10.3748/wjg.v17.i8.1009

Diverticular Disease: Progression, Smoking and Nicotine

Sunday, April 14th, 2019


Diverticular disease (DD) can progress from changes in the gut nerves and muscles to formation of diverticula (diverticulosis), to symptoms of colon dysfunction, to infections and inflammation (diverticulitis), to chronic symptoms, and to serious abdominal complications. The number of sufferers along this pathway diminishes greatly at every stage, only a minority ever need surgical treatment. On the other hand, progression and ageing go hand in hand.

The causes and risk factors of progression after diverticulosis are as varied as the people with DD.  Nobody knows what brings on diverticulitis which can be a gateway to problems. Historically, a diet low in fibre was thought to be responsible for all of the disease spectrum and could be easily remedied. This is no longer accepted. In the second half of the 20th century nobody considered an effect of smoking on the gut. Most Western adults smoked despite the risks of lung cancer and heart disease. Cigarettes had calmed the soldiers of the war, they were glamorous and macho, and nicotine was strongly addictive.

Cigarette use was aligned much closer to the appearance of DD in the world than diets which were variable and often assumed. Articles on this website in 2012 and 2013 have details of this epidemiology and also explain the pharmacology of nicotine where chronic use can cause the damage to the colon characteristic of DD.


IBS, Smoking, E-cigarettes and Nicotine

Thursday, November 13th, 2014

IBS and other diseases of the digestive system, including diverticular disease, are affected by cigarette smoking. Tobacco smoking is rapidly being replaced by the use of e-cigarettes known as ‘vaping’. This system is clamed to be safer than tobacco cigarettes, giving the pleasurable effects of nicotine with only trivial side effects. However, the pharmacological effects of nicotine are still relevant to all nicotine delivery systems.

This article appeared in Gut Reaction, the magazine of the IBS Network, Issue 93, Oct 2014

IBS sufferers are well aware that diet and the passage of food residues through the gut can influence their problems. Similarly, worry and stress affect the digestive system through nerve connections between the head brain and gut brain. Less attention is paid to substances which reach the bowel through it’s blood supply to modify nerve and muscle behaviour. Drugs and their side-effects are an example.

Cigarette smoking delivers many chemicals into the blood stream (more…)

Diverticular Disease And Colon Cancer

Thursday, April 3rd, 2014

Does having diverticular disease (DD) increase the risk of colon cancer (CC)?  One expert would say “yes” and another would answer “no”. Much depends on the design of studies, choice of patients, what data is fed into the computer for statistical analysis, interpretation of the results and what opinions and conclusions are made.

Research can be based on the occurrence of the two separate diseases, how many people with DD have CC and how many people with CC have DD (1). Comparison can be made with the levels of CC and DD which would be expected in the general population. Information can be expanded by including different types of cancerous lesions and their position in the colon. The diagnosis of DD is not so stable. Diverticulitis but not diverticulosis was indicated to be in a long-term causal relationship with increased risk of left-sided CC (2). However, these conditions at diagnosis can change. Diverticulitis can revert to diverticulosis with few further problems, or, diverticulosis can later progress to diverticulitis or even further to serious complications. This is a basic problem in DD research. (more…)

Cigarette Smoking: The Cause Of Diverticular Disease?

Wednesday, June 19th, 2013

Two previous articles relate to this theory of the cause of diverticular disease (DD). “Colon wall muscles in diverticular disease” and “Diverticular disease: updated epidemiology” can be found on this website. Because of the length of this article, many details with supporting references have not been included and a summary is provided.



The worldwide epidemiology of diverticular disease (DD) is the same as that of the smoking epidemic used by many organisations and charities to show the relationship between smoking and lung cancer and many Western diseases. The grouping of countries by the timing and extent of DD correspond historically with the introduction of “Western” cigarettes. The types of tobacco and additives in the Western products and their promotion are related to the pattern of disease and they are designed to deliver the maximum amount of nicotine into the body. The changes in the colon wall with DD reflect the pharmacological action of nicotine in the chronic dosing produced by cigarette smoking. Ethnic differences in the metabolism of nicotine and different sensitivity in longitudinal and circular colon wall muscles could explain differences in the sites of disease particularly between Eastern and Western countries. Changes in the colon wall structure with DD are similar to those found in blood vessels caused by smoking. Such changes are found in the lungs of children subjected to passive smoking. Could DD also start this early in life?


There is a plethora of reports of research and opinions on what might be the cause of diverticular disease (DD). Research is often carried out in the hospital situation where the diagnosis of diverticulosis, diverticulitis or the treatment of complications takes place. Patients can then be surveyed to find out why they came to be in that situation. This tends to result in the cause of symptoms being blamed for the disease which is not the same as why or when the disease started in the first place. The formation of diverticula, the basis of diagnosis, is a later stage in its progression.


Diverticular Disease: Updated Epidemiology

Thursday, May 3rd, 2012


“Ideas, like living organisms, have their natural history, growing from conception through a more or less tumultuous adolescence and reproductive maturity to an old age, when they act as a bar to further progress. During this time they become so modified that their origin is obscured” Sir Richard Doll (1)


Looking at the occurrence of a disease in time and place, and assessing what might have influenced changes, is known as the science of epidemiology. The theory, that diverticular disease (DD) was caused by low levels of fibre in the diet, has been prominent for about 40 years. This was based on the rarity of DD in Uganda compared with Western countries such as Great Britain or the USA. It was assumed that high levels of fibre in the Ugandan diet protected people from DD and that an increase in dietary fibre would prevent DD and its symptoms would be eliminated. This was a conclusion too far. It ignored the rarity of DD in people eating very little fibre (2,3) and that vegetarians can get DD (4,5). There is no evidence that a high fibre diet prevents DD. The theory is so entrenched that if DD appears in a country then it is assumed that its inhabitants have changed from their normal to a low fibre western diet. This is particularly incongruous when applied to right-sided DD in the caecum and ascending colon. Even the theory’s originators thought low fibre levels could not be relevant to this area (6)

Data from post-mortems, mortality statistics and surveys can provide information on the occurrence of DD, each aspect contributing to the overall picture. Song et al. (7) showed how colonoscopy findings, over time, could plot a rising prevalence of DD in Korea. Jun and Stollman in 2002 (8) collected results from research papers on the % of patients with DD in series of examinations by colonoscopy or barium enema Xray. They used these results to show that changes in the prevalence of DD varied greatly in time and between countries. Searching through later research reports mainly in the PubMed website gives this type of information for many more countries. (References to these sources are too numerous to include here). The results fall into 4 distinct patterns of when DD appeared and how numbers have changed over time until 2010. (more…)