Are Certain Bacteria Associated With Development of Colorectal Cancer?


The gut microbiome may play an important role in the development of colorectal cancer, according to a study published in the Journal of Gastrointestinal Oncology. Study author Jessica D. Dahmus, MD, of the Thomas Jefferson University Hospital, and colleagues sought to analyze the potential carcinogenic associations of five strains of sulfidogenic bacteria based on prior published research.

Sulfidogenic bacteria was focused on due to its production of hydrogen sulfide, which has been shown to cause DNA damage. This can result in genomic instability, notably found in more than 80% of sporadic colorectal cancers. The authors suggested that hydrogen sulfide affects mitochondrial function in intestinal epithelial cells, resulting in hyperproliferation in the Ras/MAPK pathway. Colorectal cancer is one of many malignancies for which this pathway is a known mechanism of carcinogenesis.

Researchers analyzed Streptococcus bovis, Fusobacterium nucleatum, Helicobacter pylori, Bacteroides fragilis, and Clostridium septicum. S. bovis seems to be associated with higher rates of both adenomas and carcinomas. Patients with colorectal cancer have been shown to have high concentrations of F. nucleatum and less microbial diversity than control groups. H. pylori infections appear to be associated with a 1.4-fold risk increase for colorectal cancer, although the authors mentioned that data may be controversial due to publication bias from the original research. The subtype Enterotoxigenic Bacteroides fragilis produces a toxin that has been shown to affect the development of colorectal cancer. Finally, C. septicum has not been associated with the initial appearance of colorectal cancer, but it does appear to have a mutually beneficial relationship with malignancies in progress.

“Future research may focus on whether the detection of certain bacterial concentrations within stool or biopsied polyps could serve as adjuncts to current screening modalities to help identify higher risk patients,” the authors concluded.

Epidemiology, clinical impacts and current clinical management of Helicobacter pylori infection


Summary
  • Helicobacter pylori infection is a major cause of morbidity and mortality worldwide. More than 50% of the global population is estimated to be infected.
  • Differences in prevalence exist within and between countries, with higher prevalence seen among people with lower socio-economic status.
  • Most transmission of infection occurs early in life, predominantly from person to person in the family setting.
  • H. pylori is the cause of most peptic ulcer disease, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma and causes symptoms in a subset of patients with functional dyspepsia.
  • Choice of diagnostic test depends on the clinical context; urea breath tests and endoscopy with biopsy are the major diagnostic tools.
  • Evidence-based indications for eradication of H. pylori infection are well documented.
  • The most widely used and recommended eradication therapy in Australia is triple therapy comprising a proton pump inhibitor, amoxycillin and clarithromycin, usually for 1 week. Effective alternative regimens are available for patients with proven allergy to penicillin.
  • Antimicrobial resistance is the major determinant of the outcome of eradication therapy. Trends in antibiotic resistance need to be monitored locally, but individual patient susceptibility testing is not usually necessary as it rarely guides the choice of therapy.
  • The outcome of treatment should be assessed not less than 4 weeks after therapy. This is usually done with a urea breath test if follow-up endoscopy is not required.
  • When first-line therapy fails, several proven second-line therapies may be used. Repeat first-line therapy and ad hoc regimens should be avoided. Overall cumulative eradication rates should approach 99%.

Helicobacter pylori infection is a major cause of morbidity and mortality worldwide. Infection invariably causes active chronic gastritis. In many people this may be clinically silent throughout life, but in a significant minority it results in gastroduodenal diseases, especially peptic ulcer disease, non-cardia gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection increases the risk of ulceration and bleeding in patients taking non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, and is responsible for symptoms in a subset of patients with functional dyspepsia. The seminal recognition of H. pylori by Marshall and Warren1 in 1982 was acknowledged by the award of the Nobel Prize in Physiology or Medicine in 2005.

Prevalence of Helicobacter pylori infection in Australia and New Zealand

It is estimated that more than 50% of the world’s population is infected with H. pylori.2 However, significant differences in the prevalence of infection exist within and between countries. In general, people in developing nations and residents of developed countries with low socio-economic status have a higher prevalence of infection.24

In most populations, including in Australia and New Zealand, the prevalence of H. pylori infection increases with age (Appendix).510 While acquisition of infection was initially believed to occur throughout life, it is now accepted that the increase in prevalence of H. pylori infection with increasing age reflects the passage through the population of distinct age cohorts whose acquisition rates of H. pylori in childhood were higher than those today. For example, in a study conducted in 2002, the prevalence of H. pylori infection in children aged 1–4 years was 4.0%, while the prevalence progressively increased in subsequent age cohorts, up to 23.3% in those aged 50–59 years.6 Given that acquisition occurs in childhood, these results and those of other studies in Australia indicate that the prevalence of H. pylori infection is decreasing in Australia (Appendix).

Based on studies conducted between 1988 and 2006, the overall prevalence of H. pylori infection in asymptomatic non-Indigenous Australians ranged from 15.4% to 30.6% (Appendix).6,11 In contrast, Indigenous Australian populations and migrant populations resident in Australia have significantly higher prevalence levels of H. pylori infection (Appendix).12,13 In a study conducted in Western Australia, not only was the prevalence of H. pylori infection significantly higher in Indigenous populations (76%) than in non-Indigenous populations (30%), but differences in the prevalence of infection between rural and urban Indigenous populations (91% v 60%) were observed.12 Similarly, residents of Australia born in high prevalence countries have been reported to have higher rates of infection than those born in Australia. For example, in one study of Australian residents, the overall prevalence of infection in adults born in western Europe, the United States and Canada (all 29.9%), southern Europe (51.3%), southern Africa and South America (both 46.2%) was higher than for those born in Australia or New Zealand (18.3%).13 Children born in Australia to parents who were born in countries with a high prevalence of infection also have higher prevalence rates.14 Further, extremely high prevalence rates of H. pylori infection have been reported in African refugee children in WA, ranging from 69% in those aged < 5 years to 91% in those aged > 10 years.15

A systematic review of studies conducted in New Zealand that investigated the prevalence of H. pylori infection in asymptomatic adults from four birth cohorts (1926–1940, 1941–1955, 1956–1970 and 1971–1985) of Maori, Pacific and European participants found the prevalence in Pacific Islanders to be significantly higher than that in Europeans.16

Origin and natural history of infection

Current evidence suggests that the close association between humans and H. pylori originated in Africa. It has been estimated that H. pylorihas been associated with humans for the past 88 000–116 000 years, with acquisition of H. pylori infection possibly occurring by a host jump from an unknown source.17

Once established within the gastric mucosa of its host, H. pylori persists for life unless the infection is treated with antibiotics.2 In the early years of life, before infection is established, transient infection with H. pylorimay be common; however, acquisition and loss of infection appear to differ in children from different ethnic backgrounds. For example, in a study involving white and African American children matched for socio-economic class, loss of infection over a 12-year period was significantly higher in the white children (50%) than the African American children (4%), the latter group remaining infected or becoming reinfected.2,18True reinfection with H. pylori after successful eradication is uncommon in adults, the rate of reacquisition being reported as < 1% in many developed and some developing countries.19 In contrast, in other developing countries, it has been reported to be > 10%.19 However, this high rate is commonly due to recrudescence, in which antibiotic therapy suppresses, rather than eradicates, the H. pylori infection. In this scenario, after treatment is ceased, the number of bacteria increase over time, leading to recurrence of symptoms.

Transmission of infection

Transmission of H. pylori infection predominantly occurs from person to person within the family setting, with mothers playing a key role in transmitting H. pylori infection to their children.2,3 Evidence supporting this view comes from epidemiological studies showing that children with an infected mother have an increased risk of infection, and from studies comparing the genetic make-up of H. pylori strains present in the index child and his or her parents. For example, a Japanese study found that for children with H. pylori-positive mothers, the relative risk of acquiring infection was 5.3 times that of children whose mothers were H. pylori-negative.20 Further evidence from Japan showed that in 60% of children, the genetic make-up of H. pylori strains isolated from index paediatric patients matched the strains in their mothers, while 27.5% matched the genetic make-up of both parents.21

Although controversial, a further possible risk factor for person-to-person transmission is attendance at day care centres. A recent study reported the prevalence of H. pylori infection in Portuguese children attending day care centres for more than 3 years to be significantly increased (40.2%) compared with children who had never attended day care centres (13.2%).22 This finding is supported by a systematic review and meta-analysis of 16 studies, which showed the frequency of child care attendance to be a risk factor for H. pylori infection, particularly in settings with a high prevalence of infection.23

While investigations into the role of breastfeeding in the acquisition of H. pylori infection have produced conflicting results, a systematic review of epidemiological studies conducted between 1984 and 2007 reported breastfeeding to be protective against H. pylori infection, particularly in low and middle income countries.24

The most controversial area of H. pylori epidemiological research relates to its route of transmission. Given that H. pylori infection is located in the stomach and that H. pylori has a basic need for gastric-type mucosa for in vivo proliferation, ingestion appears to be the most likely means of acquisition. However, whether H. pylori reaches the oral cavity via the gastro–oral, oral–oral or faecal–oral route remains unclear.2,3

Currently, any role for water, pets or houseflies as possible transmission routes for H. pylori remains unproven.2,3,25

Risk factors associated with acquisition ofHelicobacter pylori infection

Studies conducted in both developed and developing countries have identified low socio-economic status as being strongly associated with the acquisition of H. pylori infection, with socio-economic status during childhood being of particular importance.24 Socio-economic status encompasses a range of factors, including density of living, level of hygiene, sanitation and educational opportunities. In particular, low levels of education, high density of living, lack of sanitation and low hygiene levels are reported to increase the acquisition of infection within a population.24

This view is supported by the high prevalence rates reported in socio-economically disadvantaged Indigenous Australian communities12 and by the finding that Australians classified in the lowest quartile of socio-economic status (Q1) have a significantly higher prevalence of H. pyloriinfection (32.9%) than those in higher socio-economic quartiles (Q2–4: 18.4%, 19.9% and 20.8% respectively).13

Number of siblings and household crowding are also significant predictors of H. pylori infection.13 In New Zealand, household crowding among children born between 1971 and 1985 was shown to contribute to 44% of H. pylori infections in Pacific Islanders, 36% in Maori people and 14% in Europeans.16

Clinical impacts of Helicobacter pyloriinfection

Gastric cancer and MALT lymphoma

The risk of developing intestinal-type gastric adenocarcinoma depends on several interacting factors, including H. pylori virulence, H. pylori genetic ancestries, host genetics, dietary factors, essential micronutrients and the gastrointestinal microbiota.26 In susceptible infected hosts, active chronic gastritis results in gastric mucosal atrophy with intestinal metaplasia. In a small proportion of people, these pre-malignant mucosal changes lead to dysplasia and early (clinically silent), then advanced, gastric cancer. Gastric cancer mostly presents at an advanced, symptomatic stage and is associated with a poor prognosis. H. pyloriinfection has been estimated to confer an individual lifetime risk of gastric cancer of 1%–2%, irrespective of the population prevalence.27 Higher risk of gastric cancer relates to a greater risk of infection and genetic susceptibility. In Australia, this includes migrants from high prevalence areas, older people and those with a family history of gastric cancer. Uncomplicated longstanding dyspepsia is not an indication of the presence of gastric cancer. New onset of symptoms at an older age or alarm symptoms (including unexplained iron deficiency anaemia, overt bleeding, weight loss or dysphagia) at any age are indications for prompt endoscopy. However, if these symptoms are due to gastric cancer, they usually signify advanced disease with a poor prognosis.

Some well resourced countries with a high prevalence of gastric cancer conduct population screening for H. pylori infection and adverse gastric histology.28 In Australia, where other cancers are more common, population screening for H. pylori infection or precursor mucosal changes is not advocated, although case-by-case selection of individuals at higher risk (eg, those with a family history of gastric cancer) is appropriate. When gastric mucosal atrophy and intestinal metaplasia have been identified, endoscopic surveillance may be of benefit in individual cases, but an overall reduction in mortality is yet to be demonstrated. When dysplasia is found, focal areas of high-grade dysplasia may be removed endoscopically, while more extensive changes require surgery.

Gastric MALT lymphoma is a rare manifestation of H. pylori infection. Eradication of H. pylori when the lymphoma is at a low grade stage usually results in regression and cure.29

Peptic ulcer disease

H. pylori infection has been shown to cause most duodenal ulcers and about two-thirds of gastric ulcers. However, with decreasing prevalence of infection in Australia and increasing cure of ulcer patients, the proportion of all peptic ulcers due to H. pylori is falling. Without definitive treatment, peptic ulcer disease is a chronic relapsing and remitting disease that causes major morbidity and mortality from pain, bleeding and perforation. Eradication of H. pylori infection heals most active peptic ulcers and prevents further relapse, thus effectively curing the disease. For complicated ulcer disease (such as bleeding ulcers) or large gastric ulcers that may be slow to heal even after eradication of H. pyloriinfection, a short course of proton pump inhibitor (PPI) therapy is usually also given. Additional treatment with a PPI is not usually required for uncomplicated duodenal ulcer disease, as long as successful eradication is confirmed. Asymptomatic patients with a past history of peptic ulcer disease should be tested for H. pylori infection and treated to prevent further relapses.

NSAIDs, including aspirin, cause most other ulcer disease and an increasing proportion of all ulcers. H. pylori and NSAIDs act synergistically to increase the risk of ulcers and bleeding.30 As eradication of H. pylori infection markedly reduces this risk,31 guidelines advocate testing for and treating H. pylori infection before commencing chronic NSAID therapy.32 When a patient with an ulcer who is taking NSAIDs is found to also have H. pylori infection, both risk factors must be addressed. Following ulcer bleeding and when NSAIDs are still required, eradication therapy is appropriate, but PPIs are also needed to reduce the risk of recurrent bleeding. Low dose aspirin use increases the risk of peptic ulceration and bleeding, and H. pylori infection adds to this risk. In patients known to have previously had ulcer disease or bleeding, H. pylori should be tested for and treated before aspirin is used.33

H. pylori-associated dyspepsia

H. pylori gastritis is commonly associated with upper gut symptoms. However, only up to a third of infected patients with functional dyspepsia will have sustained relief of symptoms after eradication therapy, because functional dyspepsia is a heterogeneous condition. H. pylori may be causal in some patients and incidentally present in others. However, the proportion of infected patients whose symptoms abate after eradication therapy is greater than for those given empirical acid suppression therapy.34 Furthermore, patients may benefit from a reduced lifetime risk of ulcer disease and cancer, especially if they are treated before adverse histological changes have developed in the gastric mucosa.30 For both reasons, it is recommended to offer these patients eradication therapy.28,32,35

A recent revised classification of gastritis has recognised H. pylori-associated dyspepsia as a distinct entity, and this will be incorporated into the 11th revision of the International Classification of Diseases.28 The classification also highlights the significance of H. pylori gastritis as the precursor lesion that leads to peptic ulcer disease and gastric cancer, irrespective of whether symptoms are present.

H. pylori infection has been associated with a variety of other conditions. In most cases, the association has not been shown to be causal, and common conditions will inevitably coexist in some patients. There are modest data linking H. pylori to immune thrombocytopenic purpura, and eradication therapy is often tried, with variable results.35

Diagnosis

The choice of diagnostic test depends on the clinical context. For uncomplicated upper gut symptoms in younger patients, a non-invasive “test and treat” strategy using the stable carbon isotope 13 (13C) or radioactive carbon 14 (14C) urea breath test is appropriate, with recourse to endoscopy if this strategy fails to relieve symptoms.32Validated breath tests are highly sensitive and specific. Tests with indeterminate results should be repeated after several weeks. Faecal antigen tests have also been used but are less convenient and somewhat less accurate. Serology is the least sensitive and specific test and, while useful in epidemiological studies, is not considered sufficiently accurate for individual clinical decision making.36 Moreover, as antibodies may persist for years, serological testing is not appropriate to determine the outcome of therapy. When endoscopy is indicated, H. pylori infection is readily diagnosed by biopsy. Use of two diagnostic modalities, usually histology and a rapid urease test, with biopsy samples taken from two topographical locations in the stomach (antrum and corpus) maximises accuracy. Biopsy for culture is not used as a primary diagnostic test.

As failure of eradication therapy is not uncommon,37 the outcome of therapy should be assessed. This is usually done with a urea breath test not less than 4 weeks after cessation of therapy. When endoscopy is required, such as to ensure the healing of gastric ulcers and to exclude neoplasia, the outcome of therapy may be assessed using repeat biopsy samples taken at that time. The finding of active chronic gastritis without any organisms identified should prompt suspicion for undetected infection and further testing.

False negative results from urea breath tests, faecal antigen tests and biopsies may occur when there has been recent antibiotic use (within 4 weeks) or recent use of PPIs (within 1–2 weeks). Hence, when possible, PPIs should be withheld before testing to maximise diagnostic accuracy.38

Treatment and drug resistance

The decision to treat or not to treat H. pylori infection must be an active one, taking an individual patient’s circumstances and risks into consideration. The decision to test for H. pylori infection is therefore made with therapeutic intent. Recommended indications for treatment are summarised in Box 1.

The major determinant of successful eradication is the presence or absence of pre-treatment antimicrobial resistance. Lack of adherence with treatment and smoking are also factors.40 The choice of therapy is based on local antibiotic usage, documented antibiotic resistance and outcome data (Box 2). Thus, recommended therapies will vary regionally. The most widely used and recommended treatment (including in Australia) is triple therapy comprising a PPI, amoxycillin and clarithromycin, usually for 1 week.41 In countries where clarithromycin has been widely used as monotherapy for other infections, resistance to it is often high (> 20%), which greatly reduces the effectiveness of this therapy — often to below the acceptable benchmark eradication rate of > 80%. This has led to calls to abandon this therapy as first-line treatment and instead use a variety of other combinations and dosing. These so-called concomitant, sequential or hybrid regimens combine these three drugs with a nitroimidazole or other agents and increase the duration of therapy to 10–14 days. However, in Australia, clarithromycin resistance has been repeatedly documented to be low (6%–8%),37,42 so this advice may not be relevant to the Australian situation and has not been tested locally. Fortunately, resistance to amoxycillin is virtually non-existent and does not develop after treatment failure. Conversely, metronidazole resistance in Australia is known to be very high (45%–50%), almost certainly due to widespread, long term use of nitroimidazoles as monotherapy.43 Therefore, clarithromycin remains an effective component of triple therapy in Australia, while adding metronidazole to this combination will add adverse effects, adherence difficulties and cost, while adding only modestly to predicted outcomes. Such a regimen has not been formally tested in Australia, and studies from abroad vary in quality and outcomes. The option of extending the duration of standard triple therapy has similarly not been tested in Australia, but such studies are needed as there is anecdotal evidence that current local results do not match those from randomised controlled trials published years ago.

For patients who are allergic to penicillin (Box 3), metronidazole may be substituted for amoxycillin, although pre-treatment metronidazole resistance reduces the efficacy of this regimen. A penicillin-free, bismuth-containing quadruple therapy may be used instead (see below). Alternatively, formal penicillin allergy testing may be done for the many patients with a remote or unlikely history of allergy. Up to 80% of such patients have been found not to be allergic to penicillin and may be treated with standard therapy.44

The main role of culturing endoscopic biopsy samples is to monitor changes in antimicrobial resistance over time. When therapy fails, individual antibiotic sensitivity testing from cultured biopsy samples is seldom helpful, as it has little role in clinical decision making. Secondary clarithromycin resistance frequently follows failure of first-line therapy and is therefore assumed in this scenario. Repeat treatment with a clarithromycin-containing combination has a very low rate of success (about 10%). Moreover, in vitro sensitivity of other antibiotics does not infer in vivo efficacy, and ad hoc regimens designed in this way should also be avoided.

Proven second-line or salvage eradication therapies are well documented, but some of the components of these combinations are not registered for use and are not readily available in Australia. They may be obtained from abroad after approval from the Therapeutic Goods Administration through the Special Access Scheme, but second-line therapy should remain the domain of the interested and informed practitioner. In Australia, three evidence-based options for second-line therapy have been evaluated (Box 2). Levofloxacin-based triple therapy (PPI, amoxycillin and levofloxacin) has been shown to result in high eradication rates irrespective of the number of prior treatment failures.45 Quadruple therapy of bismuth subcitrate, a PPI, tetracycline and metronidazole, while clumsy in terms of dosage, is also effective, as metronidazole resistance is overcome by this four-drug regimen.37 Rifabutin-based triple therapy may also be used but is less effective, and the occasional occurrence of neutropenia tends to limit its use.46 These combinations may be used sequentially for repeated treatment failures, if necessary. In experienced centres, final eradication rates with judiciously chosen therapy should approach 99%.

Helicobacter pylori and Cancer


Key Points
  • Helicobacter pylori (H. pylori) is a type of bacterium that is found in the stomach of about two-thirds of the world’s population.
  • H. pylori infection is a major cause of gastric (stomach) cancer, specifically non-cardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus). H. pylori infection also causes gastric mucosa-associated lymphoid tissue (MALT) lymphoma.
  • H. pylori infection is associated with a decreased risk of some other cancers, including gastric cardia cancer (cancer in the top portion of the stomach) and esophageal adenocarcinoma.
  1. What is Helicobacter pylori?Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that grows in the mucus layer that coats the inside of the human stomach.To survive in the harsh, acidic environment of the stomach, H. pylori secretes an enzyme called urease, which converts the chemical urea to ammonia. The production of ammonia around H. pylori neutralizes the acidity of the stomach, making it more hospitable for the bacterium. In addition, the helical shape of H. pylori allows it to burrow into the mucus layer, which is less acidic than the inside space, or lumen, of the stomach. H. pylori can also attach to the cells that line the inner surface of the stomach.Although immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pylori infection, they are unable to reach the stomach lining. In addition, H. pylori has developed ways of interfering with local immune responses, making them ineffective in eliminating this bacterium (12).

    H. pylori has coexisted with humans for many thousands of years, and infection with this bacterium is common. The Centers for Disease Control and Prevention (CDC) estimates that approximately two-thirds of the world’s population harbors the bacterium, with infection rates much higher in developing countries than in developed nations.

    Although H. pylori infection does not cause illness in most infected people, it is a major risk factor for peptic ulcer disease and is responsible for the majority of ulcers of the stomach and upper small intestine. More information about H. pylori and peptic ulcer disease is available from the National Institute of Diabetes and Digestive and Kidney Diseases.

    In 1994, the International Agency for Research on Cancer classified H. pylori as a carcinogen, or cancer-causing agent, in humans, despite conflicting results at the time. Since then, it has been increasingly accepted that colonization of the stomach with H. pylori is an important cause of gastric cancer and of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (see Questions 2–5,7,9). Infection with H. pylori is also associated with a reduced risk of esophageal adenocarcinoma (see Questions 4–6).

    H. pylori is thought to spread through contaminated food and water and through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Infection is more likely in children living in poverty, in crowded conditions, and in areas with poor sanitation.

This Scientist Let a Flea Live Inside Her In Order to Study It | Smart News


The history of science is filled with stories of curious folks, who, for one reason or another, thought it would be a great idea to experiment on themselves: Benjamin Franklin with his lightning rod kite, Isaac Newton, stabbing himself in the eye with a needle to see what would happenJonas Salk, giving himself (and his family) his experimental polio vaccine. But these are tales of a bygone era, when curiosity took charge and basic lab safety standards hadn’t taken hold.

Or not.

From Science magazine, we learn the much more modern story of Marlene Thielecke, a budding medical researcher who decided to let a sand flea live in her foot. Why? She wanted to answer a question:

Where, exactly, does the sand flea have sex? On the dusty ground, where it spends the first half of its life? Or already nestled snugly in its host—such as in a human foot—where it can suck the blood it needs to nourish its eggs?

Thielcke was already researching a disease, known as tungiasis, which often results from a sand flea infection, says Geekosystem. But, scientists don’t really know how the critters reproduce. So, “upon discovering a flea living in her foot, Thielecke – instead of reacting with the appropriate terror response –  decided to study the creature, in the hopes it might help science.”

Science:

At first, the flea didn’t bother Thielecke and she noted that it seemed to grow normally. But she soon realized it wasn’t laying any eggs—unusual for an embedded and otherwise apparently mature flea. It also lived much longer than usual; after 2 months, it was still regularly expelling liquid from its abdomen, a sign it was still alive—but still no eggs. At that point, Thielecke says, the spot was itchy, painful, and prevented her from walking normally. “I started to get uneasy” about leaving it in for so long, she says, so she extracted it.

So what’s the verdict? Sand fleas probably have sex inside you. (Which luckily didn’t happen to Thielecke.)

And, by the way, Thielecke’s tale of self-experimentation isn’t actually as rare as you’d think. At the end of his life Ralph Steinman, the Nobel prize winner in 2011, tested his own pancreatic cancer treatments on himself. James Logan swallowed a hookworm, and a tiny camera, to see what happened. And, in the 1980s, Barry Marshall drank a soup of Helicobacter pylori bacteria to give himself an awful case of stomach ulcers, just to prove that the bacteria were to blame. Or, perhaps our personal favorite, Donald Unger, who cracked the fingers on his left hand, but not his right, to show that cracking your knuckles won’t cause arthritis.

Gut Bacteria May Exacerbate Depression.


The digestive tract and the brain are crucially linked, according to mounting evidence showing that diet and gut bacteria are able to influence our behavior, thoughts and mood. Now researchers have found evidence of bacterial translocation, or “leaky gut,” among people with depression.

Normally the digestive system is surrounded by an impermeable wall of cells. Certain behaviors and medical conditions can compromise this wall, allowing toxic substances and bacteria to enter the bloodstream. In a study published in the May issue of Acta Psychiatrica Scandinavica, approximately 35 percent of depressed participants showed signs of leaky gut, based on blood tests.

The scientists do not yet know how leaky gut relates to depression, although earlier work offers some hints. Displaced bacteria can activate autoimmune responses and inflammation, which are known to be associated with the onset of depression, lower mood and fatigue. “Leaky gut may maintain increased inflammation in depressed patients,” which could exacerbate the symptoms of depression if not treated, says Michael Maes, a research psychiatrist with affiliations in Australia and Thailand and an author of the paper. Currently leaky gut is treated with a combination of glutamine, N-acetylcysteine and zinc—believed to have anti-inflammatory or antioxidant properties—when behavioral and dietary modifications fail.

microscope slides of gut microbes


Causes of Leaky Gut

Regular use of painkillers

Regular use of antibiotics

Infections (such as HIV)

Autoimmune disorders

Alcohol abuse

Inflammatory bowel disease

Gluten hypersensitivity

Severe food allergies

Radiation therapy

Inflammatory disorders

Psychological stress

Exhaustion


Ulcer Bacteria Linked to Cognitive Decline
One type of harmful bacteria escaping the gut might be Helicobacter pylori, the main cause of stomach ulcers. H. pylori may contribute to cognitive impairment or Alzheimer’s disease, according to a study published in the June issue of Psychosomatic Medicine. Compared with uninfected individuals, people who tested positive for H. pylori performed worse on cognitive tests, including ones assessing verbal memory. Some laboratory evidence indicates that H. pylori cells can escape the gut and sneak into the brain. There the cells aggregate with the amyloid proteins characteristic of Alzheimer’s and instigate the buildup of plaque, suggests study co-author May Baydoun, a staff scientist at the National Institute on Aging. The National Institutes of Health estimates that about 20 percent of people younger than 40 and half of adults older than 60 are infected with the bacteria, which can be treated with antibiotics.


Bugs That Influence the Brain
Preliminary research suggests that these common gut microbes can also affect our thoughts and feelings.

1. Helicobacter pylori: Children infected with this ulcer-causing bacterium performed worse on IQ tests, suggesting a possible link between H. pylori infection and cognitive development.

2. Lactobacillus helveticus and Bifidobacterium longum: Healthy human volunteers who consumed a probiotic mix of these bacteria exhibited less anxiety and depression.

3. Probiotic bacteria B. animalis subsp. lactis, Streptococcus thermophilus, L. delbrueckii subsp. bulgaricus, L. lactis subsp. lactis: Healthy women who consumed yogurt containing these bugs showed less activity in brain regions that process emotions and physical sensations. Researchers do not yet know whether these effects were beneficial; they also have not discovered the mechanism underlying the observed shift in brain activity.

4. Lactobacilli: Healthy students had fewer of these bacteria present in their stool during a high-stress exam time compared with a less stressful period during the semester. The findings suggest a potential link between stress and gut microbes, but the exact relation remains unknown.

Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy.


Abstract

Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings.

Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy.

Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.

Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.

 

Source: BMJ

 

 

H. Pylori Eradication Might Reduce Recurrent Gastric Cancer After Surgery.


 

Thirty-six months after subtotal gastrectomy for gastric cancer, patients who were H. pylori-free had less glandular atrophy and intestinal metaplasia than infected patients.

Intestinal metaplasia (IM) and glandular atrophy (GA) have been identified as preneoplastic conditions in patients infected with Helicobacter pylori. The role of H. pylori eradication in improving these conditions after subtotal gastrectomy for gastric cancer is unclear.

To investigate this issue, researchers in Korea randomized 190 patients with gastric cancer and H. pylori infection to receive 7 days of proton-pump inhibitor–based triple therapy or placebo prior to surgery. The greater and lesser gastric curvatures were biopsied prior to surgery and at 12 and 36 months after surgery and evaluated according to the updated Sydney criteria. H. pylori infection was determined by both a rapid urease test and histologic examination of endoscopic biopsies. Histological findings of GA and IM were scored to indicate presence and severity (absent, 0; mild, 1; moderate, 2; severe, 3).

At 36 months, 75% of patients in the treatment group were free of H. pylori compared with 41% of the placebo group. The mean GA and IM scores did not differ between the two groups. However, compared with H. pylori-infected patients, those without H. pylori had less atrophy (P=0.005) and IM (P=0.03).

COMMENT

The lack of difference in glandular atrophy or intestinal metaplasia between study groups at 36 months might be explained by a type II error. Histological scores for both were lower in the treatment group, but these differences did not reach statistical significance, possibly because of the low eradication rate in the treatment group, the high spontaneous remission rate in the placebo group, or the relatively large number of patients lost before the final analysis. As the authors concluded, the findings suggest that successful H. pylori eradication might reduce the preneoplastic changes in the gastric remnant after gastric surgery, but the clinical significance of the histologic changes remains to be determined.

Source: NEJM

Acid Suppression and Effectiveness of Ampicillin for Helicobacter Pylori.


At a low pH, H. pylori bacteria stopped dividing, making ampicillin ineffective. More sustained acid suppression might be useful for refractory infections.

Standard therapy for treating Helicobacter pylori infection typically includes ampicillin, a second antibiotic, and a proton-pump inhibitor (PPI). However, the effectiveness of this regimen has been decreasing with increasing antibiotic resistance. Because ampicillin acts on bacterial cell walls and requires actively dividing bacteria to be effective, investigators examined whether H. pylori growth — and, consequently, ampicillin effectiveness — was affected by gastric pH level.

H. pylori were incubated in dialysis chambers with 5 mM urea and varying pH levels with or without ampicillin for 4, 8, or 16 hours. Changes in the expression of genes associated with bacterial growth, viability, and survival were determined.

Ampicillin was bactericidal at pH levels of 4.5 or 7.4, but at a pH level of 3.0, the bacteria seemed to become dormant, with decreased expression of a host of genes associated with cell envelope biosynthesis. In this environment, ampicillin did not affect bacterial viability or survival.

The authors suggest that PPIs are associated with nocturnal acid breakthrough that might reduce the pH level, rendering ampicillin ineffective, and that more persistent acid reduction could potentially improve the clinical effectiveness of amoxicillin therapy.

Comment: This paper provides a compelling argument for the importance of PPI therapy in antibiotic treatment of H. pylori. It further suggests that sustained acid reduction should be the goal to improve the effectiveness of ampicillin or other drugs that require bacterial growth. The frequency of nocturnal acid breakthrough is likely overstated, and the ability of PPI therapy to maintain a pH of 4.5 is likely better than the authors suggest. The decreasing eradication rate is associated with antibiotic resistance, often to the second antibiotic (e.g., clarithromycin). Knowing the patterns of antibiotic resistance in a population will allow for more effective therapy. In refractory cases, higher PPI doses to sustain a high pH might be a reasonable approach to optimizing the effectiveness of the antibiotic that requires active cell growth.

Source: Journal Watch Gastroenterology

No Evidence of Cancer Risk from Long-Term PPI Therapy.


Hormonal and histologic changes observed with long-term use of proton-pump inhibitors do not seem to translate into an elevated risk for mucosal gland atrophy or cancer.

Prolonged use of proton-pump inhibitors (PPIs) has been associated with an increase in serum gastrin levels, which could drive proliferation of enterochromaffin-like (ECL) cells in the gastric mucosa and contribute to mucosal gland atrophy in the presence of Helicobacter pylori infection. Two recent studies evaluated the long-term effects of PPI use on gastric mucosa.

In a multicenter study, Fiocca and colleagues randomized 554 patients with chronic gastroesophageal reflux to receive 20 mg of esomeprazole daily or undergo laparoscopic antireflux surgery. Gastric biopsies and serum samples for gastrin and chromogranin A were taken at baseline and at 1, 3, and 5 years. Biopsies from each time point were available for 338 participants. In the esomeprazole arm, ECL cell hyperplasia increased between time points, mucosal inflammation decreased (only in those with H. pylori infection), and serum gastrin and chromogranin A levels increased moderately. No atrophy or intestinal metaplasia occurred. The authors concluded that despite moderate increases in gastrin and chromogranin A levels, 5 years of esomeprazole therapy did not cause dysplastic or neoplastic changes and decreased inflammation in patients with H. pylori infection.

Brunner and colleagues report the longest follow-up results to date of efficacy, safety, and tolerability in 142 patients who received pantoprazole for a mean of 9.2 years to treat peptic ulcers or reflux esophagitis. Gastric biopsies and serum gastrin levels were obtained at baseline, during healing (until week 12), every 6 months during the first 5 years, and annually during the subsequent 10 years. The ECL cell density increased moderately during the first 3 years and then stabilized. Investigators observed no clinically relevant changes in the gastric mucosa or increase in intestinal metaplasia. Serum gastrin levels rose to moderate levels and subsequently remained constant but showed high variability between patients. In patients with H. pylori infection, antral gastritis regressed after eradication of the infection. The authors concluded that maintenance therapy with pantoprazole for up to 15 years is well tolerated, with no evidence of increased risk for gastric cancer.

Comment: Both studies confirm that long-term PPI treatment increases serum gastrin levels and is associated with an increase in ECL cells. Serum gastrin levels rose to a moderate level early in treatment and then remained constant for the duration of follow-up. The absence of histologic evidence of intestinal metaplasia or other precancerous mucosal changes suggests that the risk for gastric cancer is probably not increased by PPI therapy. However, both of these prospective studies were small and underpowered to detect a small increase in risk.

Source: Journal Watch Gastroenterology

 

Is Helicobacter pylori Eradication Sufficient for Bleeding Ulcers?


A prospective study suggests that peptic ulcer rebleeding is very unusual after H. pylori eradication and that maintenance antiulcer therapy may not be needed.

Helicobacter pylori infection is associated with peptic ulcer disease, and eradication of the infection reduces ulcer recurrence. The need for maintenance acid-reduction therapy in this setting is controversial.

To explore this issue, investigators at 10 university hospitals in Spain prospectively studied 1000 patients with endoscopically documented bleeding peptic ulcers and H. pylori infection. Participants were treated until eradication of the infection was confirmed by breath test. Thereafter, they received no acid-reduction therapy and were told not to take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). They returned at 1-year intervals for a clinical examination and a breath test for H. pylori. If signs or symptoms of upper gastrointestinal bleeding occurred, urgent endoscopy was performed.

All participants were followed for at least 12 months (total, 3253 patient-years of follow-up). Recurrence of peptic ulcer bleeding was rare, occurring in three participants during year 1 and two during year 2. All five cases of rebleeding involved either H. pylori reinfection or NSAID use. The cumulative incidence of rebleeding was 0.5% (95% confidence interval, 0.16%–1.16%) overall and 0.15% (95% CI, 0.05%–0.36%) per patient-year of follow-up.

Comment: These findings provide excellent evidence that H. pylori eradication is sufficient therapy for peptic ulcer patients — even if they had bleeding — in the absence of other causes for ulcers. Forty-one percent of the patients in this study had previously used NSAIDs or aspirin. Without a control group in which NSAIDs are continued, we cannot assess the effect of H. pylori eradication alone, but if such agents are avoided, H. pylori eradication appears to be definitive ulcer therapy. The real clinical challenge is to keep these patients from taking NSAIDs and identify those at high risk for H. pylori reinfection to determine who should be considered for continued antiulcer therapy.

Source: Journal Watch Gastroenterology