A prebiotic supplement consisting of simple sugars produced from lactose, chicory, and citrus fruit has been found to improve gut health, which in turn significantly improved immune system function in a small study of treatment-naive HIV-positive individuals.
Early results of the pilot COPA trial were presented to the BHIVA Autumn Conference held last week in London by Dr Mario Clerici of the Milan University Medical School during a plenary session on gut immunity and HIV.
Dr Clerici began by explaining that the gut is the largest immune system organ in the human body. Soon after an individual becomes infected with HIV, the virus directly infects gut-associated lymphoid tissue (GALT), where between 70% and 80% of all immune cells exist, destroying a massive amount of CD4 cells – up to 80% within a month of infection.
It is now thought that these major changes seen in the gut following primary infection can greatly influence immune response. Two years ago, investigators from the United States discovered that leakage of microbes from the gut as a result of HIV-related damage to the gut wall may be one of the major causes of the systemic immune activation that drives the HIV disease process.
Earlier this year, investigators from the University of Minnesota linked the dramatic and enduring depletion of CD4 cells from the gut with the rapid and extensive deposition of collagen in the gut’s lymphatic tissue.
Furthermore, research from two teams, one at the University of California, and another at the US National Institutes of Health, found that HIV persists in gut CD4 cells even in the presence of effective antiretroviral therapy, resulting in a reservoir of infection that eludes current treatments.
The COPA trial
In order to understand better the relationship between HIV, the leaking of gut microbes, and its effect on the immune system, Dr Clerici and his colleagues at the University of Milan, as well as other colleagues in Italy and the Netherlands, have enrolled a cohort of 57 healthy, asymptomatic HIV-positive, antiretrovirus-naive individuals.
They first studied the effect of HIV infection on various ‘good’ and ‘bad’ microbes in the cohort’s gastrointestinal (GI) tracts and found a very high prevalence of the ‘bad’ microbes P. aeruginosa and C. albicans compared to levels reported for healthy individuals. On the other hand, they found very low levels of the ‘good’ bacteria, bifidobacteria and lactobacilli, compared to levels reported for the general population – less than half the average normal amounts of bifidobacteria, and only about 1 - 2% of the normal amounts of lactobacilli.
When they looked at faecal calprotectin – a marker of intestinal inflammation – half of the cohort had levels indicating inflammation, with a third indicating significant inflammation, similar that seen in inflammatory bowel disease. Since intestinal inflammation is known to reduce the intestinal barrier function, Dr Clerici argued that these data confirmed the breakdown of the intestinal barrier.
Once they had established that their cohort’s guts were not functioning well, Dr Clerici and his colleagues then attempted to come up with a solution – a way to improve gut health that they hoped would reduce inflammation and improve immune response.
They teamed up with the Danone Research Centre for Specialised Nutrition in the Netherlands to produce a unique prebiotic supplement, consisting of nine parts short-chain Galactooligosaccharides (scGOS) from lactose; one part long-chain Fructooligosaccharides (lcFOS) from chicory; and ten parts Acidic Oligosaccharides from pectin hydrolysate (AOS) from citrus fruit.
Prebiotics are non-digestible food ingredients that can selectively stimulate the growth or activity of ‘good’ and ‘bad’ bacteria in the colon. Probiotics, such as 'live' yoghurts and similar dairy products, work in a similar way, but in the small intestine.
The 57 individuals in the COPA trial cohort were randomised to receive either a single (15g/day) or double (30g/day) dose of the prebiotic supplement, or a placebo (maltodextrin) for 12 weeks.
The prebiotic supplement was found to be safe and well-tolerated (side-effects can include gas and bloating) and although there was no major effect on absolute CD4 counts or on viral load, Dr Clerici’s team did measure significantly improved levels of ‘good’ bifidobacteria (after 12 weeks, levels increased to a median of 14.1% and 15.8% for single and double dose, respectively, compared to under 5% in the control group; p C. perfringens and C. difficile (from 0.012% to undetectable in the double dose group; p = 0.009).
Most intriguing, however, were two slides at the end of Dr Clerici’s plenary showing the effect of the prebiotic supplement on immune activation in 20 of the participants in the COPA trial.
After twelve weeks, the double dose of prebiotics was found to have significantly reduced the number of activated CD4/CD25 T cells (p
Nevertheless, the single dose was found to have significantly increased natural killer (NK) cell activity (p
Nevertheless, Dr Clerici ended his presentation by noting that this proof of concept study paved the way to enrolling larger studies into the effect of prebiotics on gut health, which may hold the key to further understanding – and possibly have a major effect on – the gut and HIV-related immune activation.
Clerici M. BHIVA Foundation Lecture: The role of the gut in HIV pathogenesis BHIVA Autumn Conference, London, October 2008.
Gori A et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in Human Immunodeficiency Virus pathogenesis. J Clin Microbiol. 46(2): 757–758, 2008.