The Bacterial Microbiome and Human Disease
Bacteria of the microbiome are essential aspects of human health. The best example is in the human gut. Home to nearly three pounds of bacteria (with recent estimates at 3.8·1013 bacteria), our gut uses its microbiome to neutralize toxic byproducts of digestion, stimulate digestion, assist with nutrient absorption, and produce vitamins B and K—this symbiosis is essential to human function. Other important microbial communities include the mouth, lung, vaginal, and skin microbiomes, as well as the microbiome shared between mother and child. As we learn more about the intersections of medicine and microbiology, we are unmasking the links between the bacterial microbiome and specific diseases and conditions. According to the February 2017 feature in the Journal of American Medical Association, genetic variation and environmental factors (including diet and stress) can affect the microbiome and result in health disparities. The National Human Genome Research Institute is spearheading efforts to integrate genomics, the human microbiome, and the behavioral and social processes of health and disease. As we learn more about the role of the microbiome in disease processes, we have begun to document differences in the incidence and prevalence of cardiovascular disease, asthma, diabetes, obesity, preterm birth, and sickle cell disease. Furthermore, these differences can correlate with certain socioeconomic groups and populations of certain race or ethnicity.
Health Status Disparities
Health status disparities refer to the variation in rates of disease occurrence and disabilities between socioeconomic or geographically defined population groups. Such disparities, including differences in longevity and likelihood of developing cancer, may be reflected in the unique microbiome signature of a person. Researchers at the NIH stress the importance of considering psychosocial, socioeconomic, cultural, and behavioral factors in microbiome research. According to the CDC, social determinants of health (including poverty, unequal access to health care, lack of education, stigma, and racism) are linked to health disparities. Because health status disparities persist despite ongoing efforts, the CDC researchers suggest that a multifactorial etiology should be considered.
What can we say about disease-specific microbiome composition? Scientists are using downstream analyses to determine functional interactions behind the host and its microbiome. Profiled below are some of the more recent findings on the intersection between health disparities and the microbiome.
Bacterial Vaginosis and Preterm Birth
Research has long supported the link between the risk for the development of bacterial vaginosis (BV) and the vaginal microbiome in African American women and women of European ancestry. Bacterial vaginosis (BV) can result in preterm births, pelvic inflammatory disease, increased susceptibility to HIV infection, and other conditions. A landmark 1995 article linked the gram-negative, rod-shaped anaerobes, G. vaginalis and M. hominis, to preterm delivery. Because of changes in vaginal pH, there is a coordinated cycle of microbiome changes during the menstrual cycle. Healthy women have an abundance of gram-positive rods (usually Lactobacillus), a low pH (<4.5), and an abundance of both facultative and obligately anaerobic gram-negative rods. As the cycle progresses, increases in pH lead to decreased numbers of lactobacilli and a concomitant increase in other facultative and anaerobic species. More than 100 separate phenotypes can be isolated from the vaginal microbiome. In BV, obligately anaerobic rods of the genera Atopobium, Prevotella, Mobiluncus, and Sneathia are commonly present.
In 2014, researchers conducted a comparison of African American and European groups and found that ethnicity, pregnancy, and alcohol use correlated significantly with the relative abundance of bacterial vaginosis-associated species. One confounding factor of such epidemiological studies has been the imprecise ways in which the diagnosis of BV is made. Although Gram staining, culture, clinical criteria, phenotyping methods, and molecular diagnostic methods have been used, no single defining characteristic of BV has been determined. Even more confounding, BV can alter immunological defense mechanisms and is more prevalent in populations of low socioeconomic status, reproductive age, non-white ethnicity, inadequate nutrition, psychosomatic stress, and those with a higher number and frequency of sexual partners.
HIV and the Microbiome
The gastrointestinal tract is a reservoir for CD4+ T cells, which play a critical role in immunological memory and the adaptive immune response. CD4+ T cells are depleted in HIV, increasing the body’s susceptibility to opportunistic infections. One subset of CD4+ T cells, Th17 cells, are involved in mucosal immunity. In an HIV infection, Th17 cells fail to regenerate, which increases permeability to microbial products. Because of this, HIV infection can profoundly dysregulate a healthy microbiome.
Figure 1. Gut microbiota alterations during HIV infection and their potential effects on the host. Source
Positive HIV status is associated with alterations in the gut microbiome, and taxa have been shown to discriminate between HIV-positive and HIV-negative individuals and chronic HIV infection. HIV-positive individuals have increased abundances of Prevotella, Catenibacterium, Dialister, Mitsuokella, Clostridium cluster XIII, and Desulfovibrio when compared to HIV-negative individuals, and HIV-negative individuals had increased Bacteroides, Alistipes, and Parabacteroides. Additionally, the microbiota of HIV-positive, HIV-negative, and even ART-treated individuals varies within different regions of the gut, so one person may have multiple microbiome patterns within subsystems. Mucosal microbial composition in biopsy specimens from the junction between the rectum and the sigmoid colon were different than those in the ileum and colon. Between individuals, HIV-positive terminal ileum and colon featured reduced “alpha diversity” (average species diversity). HIV-positive status, therefore, may induce predictable patterns of gastrointestinal dysbiosis.
What does this mean for patients? Many questions are yet unanswered. Increases in Prevotella species and decreases in Bacteroides species may contribute to metabolic diseases (such as diabetes), as well as hypertension, endothelial dysfunction, and increased cardiovascular risk. Further, depletion of species that are protective against metabolic disorders may be one mechanism of pathogenesis. Collectively, these changes in the microbiome have been linked to increased inflammation and disease progression in HIV-individuals.
Gut Microbiome Diversity among Cheyenne and Arapaho Individuals from Western Oklahoma
In 2015, the first gut microbiome diversity study of Cheyenne and Arapaho individuals was published. It offers valuable information for microbiome research in populations that are not typically considered in clinical studies. The authors compared gut taxonomic profiles from individuals of Cheyenne and Arapaho ancestry and individuals of non-native ancestry. The authors compared the protein functions and pathways of each comparison group (using filtered shotgun metagenome sequences) to produce a “microbiome functional potential characterization.” Pertinent metadata were collected, including dietary composition, body mass index, self-reported Type II diabetes status, etc. Significant differences were noted within fecal metabolite profiles. Comparisons of metadata and taxa showed little association, but there were notable differences in abundances of genera between native and non-native populations. All in all, both groups of individuals shared similar microbiome functional profiles—no statistically significant differences were observed in functional potential. However, this study represents an important step in factoring race and ethnicity into microbiome research.
The elderly are a vulnerable population that undergo changes in their microbiomes. Throughout one’s lifetime, measurable changes take place in the gut microbiome. One study addressed microbiome changes from infants through centenarians via bacterial co-abundance groups. Scientists observed “age-associated dysbiosis,” or age-associated imbalance in the gut flora (dysbiosis has also been noted in non-age related disease states). In the study, there were differences in the relative abundances of Enterobacteriaceae (which creates a greater endotoxin challenge for weakened intestinal barriers among the elderly and results in an increased inflammatory response). Elderly individuals also had a reduction in the genus Bifidobacterium, which has an anti-inflammatory role in the gut. By increasing inflammation in older populations, gut microbiome changes increase the likelihood of disease.
Ongoing efforts and continued downstream analyses will help expand our current understanding of the far-reaching effects of the human microbiome. The sociological impacts of such variation are important, and each person’s unique microbiome signature must be considered as diagnoses, prognoses, and treatment are developed.
- “For Health Disparities, Don’t Ignore the Microbiome.” JAMA, February 28, 2017, Volume 317, Number 8.
- Fortenberry, J.D. (2013). “The uses of race and ethnicity in human microbiome research.” Trends Microbiol. 21, 165–166. 5.
- Kwong and Moran. “Gut microbial communities of social bees.” (2016). Nature Reviews Microbiology. 14, 374–384.
Front page image: Bacterial strains in the guts of humans and chimpanzees diverged and began to evolve separately 5 million years ago and 15 million years ago in humans and gorillas. Humans and apes evolved into a new specie at about the same time. A mutually beneficial relationship between gut bacteria and animal hosts may contribute to the formation of a new species. Credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health. Source