A new study reported in the International Journal of Molecular Sciences found that a probiotic formulation decreased inflammation in the cerebrospinal fluid, which is associated with neurocognitive disorders in people living with HIV.
Research conducted over the past decade has shown us that the tiny microbes that reside in our bodies can greatly affect our health for the better, or for the worse. Studies have found that the microbiome (colonies of microbes) of people living with HIV differ from HIV-negative individuals and that some of these differences contribute to conditions such as heart disease and neurocognitive disorders.
Approximately half of antiretroviral-treated people with HIV will experience some form of neurocognitive disorder, ranging from mild forms of HIV-associated neurocognitive disorders (HAND) to severe dementia. One major contributing factor to neurocognitive degeneration is inflammation.
Although it is still unclear as to whether there are additional sources of inflammation, studies show that an imbalance of the gut microbiome (dysbiosis) caused by HIV can create a weakening of the lining of the intestinal tract, and a disruption of the Gut-Associated Lymphoid Tissue (GALT), which allows bacteria to seep into the bloodstream.
This is called microbial translocation. The immune system’s response to these bacteria creates a constant state of inflammation which is carried throughout the body, including the brain. The persistent inflammation is believed to be a cause of neurocognitive disorders.
Recent research has identified the importance of the gut microbiome to what is called the "gut-brain axis" (GBA). The GBA consists of bidirectional communication between the central and the enteric nervous system, which links the cognitive and emotions centers of the brain with peripheral intestinal functions. Simply put, the GBA is the connection from the brain to the gut and vice versa and it’s existence is why we can get a stomach ache when we’re nervous or feel "butterflies" in our stomach when we’re in love. It may also link changes in the gut microbiome, which cause dysbiosis, to neurocognitive degeneration.
Researchers at the University of Rome hypothesized that the consumption of a probiotic formulation called Visbiome (which is made by Exegi Pharma) may alter the GALT microbiome, restoring a healthy balance of bacteria and correcting the state of dysbosis, thus eliminating or reducing neurological inflammation.
The probiotic formulation was given to 10 study participants for six months. Everyone who participated in the study was on antiretroviral therapy and was virally suppressed for a minimum of one year, and each participant had a median CD4 count of 674 cells/ml.
Researchers found that the probiotic improved the metabolism of tryptophan, an amino acid that is a necessary component to the human diet, which researchers believe had been disrupted through alterations to the microbiome. These alterations may be responsible for cytotoxic metabolites, such as quinolinic acid, which may cause some neurological inflammation in people with HIV. IDO is an enzyme involved in tryptophan metabolism. It can increase quilinic acid, and controls the synthesis of other metabolites that contribute to neural toxicity and degeneration. It is increased in people with HIV.
The use of Visbiome reduced CNS inflammation and improved the metabolism of tryptophan by reducing IDO, and stimulating the synthesis of serotonin which is formed from tryptophan and is a vital neurotransmitter-like chemical.
"The data being presented by this small but important study emphasizes how broad the implications of microbiome restoration in the context of HIV may prove to be," commented Dr. Nichole Klatt of the University of Washington, Seattle, who's lab specializes in mucosal immunity. "These results establish a connection between the gut immune system and the long term neurological implications of HIV, and suggest a possible therapeutic intervention with this probiotic."
Probiotics studies in HIV-positive people have previously yielded mixed results in determining if there was a benefit to their use. This may be because probiotics formulas vary greatly, depending on the bacterial strains utilized, the concentration of bacteria, the way these strains are processed and the quality of the strains used. The benefits shown by this probiotic warrant further research.
The probiotic used in this study, Visbiome, is a highly concentrated probiotic mix that contains seven strains of 1,800 billion live bacteria. These strains are a mix of Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus bulgaricus, Lactobacillus paracasei, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, and Streptococcus thermophiles.
An ongoing study in the AIDS Clinical Trails Group is currently enrolling to further research the benefits of Visbiome. The study should provide additional information regarding this probiotics effect on microbial translocation and inflammation.
A conference dedicated to research in HIV on the microbiome was held recently in Maryland on the National Institutes of Health campus. The 2nd International Workshop on Microbiome in HIV Pathogenesis, Prevention, and Treatment offered an opportunity for researchers and activists to discuss current HIV microbiome research and its implications. Dr. Alan Landay, Professor and Chairman of the Department of Immunology/Microbiology at Rush University Medical Center, is a member of the conference's organizing committee.
"This is an exciting time in studying the microbiome," he said. "We’re learning a large amount from the trials where the various fields intersect. There has been tremendous interest in all aspects including HIV and co-morbidities. With the HIV Microbiome Workshop taking place on the NIH campus in Bethesda, it would be great to see the discussion stimulate more NIH-sponsored research on HIV and the microbiome."
As researchers learn more about the effect the microbiome has on HIV, as well as other aspects of health, interventions to alter the imbalances in the microbiome caused by HIV infection, appear to be important for managing a variety of HIV-related comorbidities. Research on the microbiome itself has gained much momentum, however at this point, strategies to restore the microbiome other than probiotics, are limited.
Conditions, other than HIV, that are associated with microbiome disruption include cardiovascular disease, auto immune diseases, Clostridium difficile (C. Diff.), colorectal carcinoma, diabetes, inflammatory bowel disease, irritable bowel syndrome, and colitis. More research into these disease states, as with HIV, will help scientists to better understand their connections and how to restore a healthy microbiome ecology. There are a small number of interventions in addition to probiotics being developed to modify, augment, or restore the microbiome.
Numerous studies have focused on a procedure called fecal microbiota transplantation (FMT), where the stool of a healthy individual is transplanted into the gastrointestinal tract of a person with a disrupted microbiome, in hopes of restoring a balanced gut microbiome. This method has thus far been shown to be safe through human studies and shows promise in C. Diff, ulcerative colitis, and Crohns disease. However, it’s large-scale implementation is limited.
Similar to FMT is a new class of drugs in development called Ecobiotic drugs (in development by Seres Therapeutics). Ecobiotic drugs target the dysbiosis in unhealthy microbiome by assisting new microbiome ecologies to flourish.
Ecobiotic drugs works by seeking out functional deficiencies in a disrupted microbiome and facilitate the repopulation of the microbiome to restore it to a healthy state. As this occurs, the damage caused by the disrupted microbiome is expected to lessen or cease. These drugs are individually designed to treat a specific disease or several related diseases.
The genetic information of microbiomes existing in a dysbiosis state due to a specific disease are compared to those from human donors with healthy, balanced microbiomes. This data is then analyzed to ascertain key differences and identify “keystone organisms.” A drug is then designed to provide bacterial spores that will facilitate the growth of healthy microbes to restore a balanced state. The spores utilized are donated from the stool of healthy individuals and are treated with ethanol to eliminate pathogens. Ecobiotic drugs differ from probiotics as they contain a wide diversity of the organisms that naturally reside in the gut whereas probiotics contain a small number.
Currently there are studies on several Ecobiotic drugs in people with reoccurring C. Diff (Phase II and II), ulcerative colitis (Phase I and preclinical), drug-resistant bacteria (Pre-clinical), metabolic diseases, liver disease and non-insulin-dependent type II diabetes (discovery).
Research into better understanding the microbiome such as that conducted by the Human Microbiome Project, and in relation to disease, as well as interventions such as probiotics, Ecobiotic drugs and FMT, appear to hold potential of unlocking an entirely new field of medicine.
With microbes outnumbering human cells in the body, their effects on HIV, health, and the importance of their presence to human disease and survival, may be much greater than we previously anticipated.