Connecting the Gut Microbiome with Response to Infectious Respiratory Disease in Humans and Pigs
The gut microbiome is the term used to describe the collection of microorganisms living in the gastrointestinal tract. These microorganisms are vastly diverse and have been reported to equal or outnumber the cells of the host. Importantly, the gut microbiome plays a critical role in providing a protective intestinal barrier, digesting and metabolizing nutrients, and developing as well as maintaining immunity. Birth route, diet, environment, infection, and genetics all play important roles in initial microbial colonization of the piglet gut as well as the continued shaping of the microbiome during the first several weeks of life (Niederwerder, 2017). The relationship, balance and mechanistic interactions between these microbes in the gut are extremely complex and not well understood in states of health or disease. However, there is growing evidence indicating the beneficial role that gut microbiome diversity plays in outcome of infectious diseases.
Figure 1. General Illustration of the Gut-Lung Axis. Figure provided by M.C. Niederwerder.
In humans and pigs, the impact of the microbiome on infectious disease has historically focused on enteric infections causing diarrhea, due to the seemingly inherent interactions of beneficial and pathogenic microbes in the gut. For example, pigs characterized as susceptible to enterotoxigenic Escherichia coli had a reduction in intestinal bacterial diversity compared to those pigs considered non-susceptible (Messori et al, 2013). More recently, the interest in the microbiome and its effects on infectious disease has expanded, to include pathogens primarily affecting the respiratory tract (Niederwerder, 2017). As infectious respiratory disease is a major cause of morbidity and mortality in both livestock and humans, the gut microbiome has emerged as an alternative strategy in the control and prevention of these infections. The gut-lung axis (Figure 1) is the term used to describe how the gut microbiome, likely through products of microbial metabolism and modulation of systemic immunity, communicates with the respiratory tract and has the potential to affect outcome following respiratory infections. Several published studies have shown a beneficial association between microbiome diversity and outcome following infection with viral, bacterial and even fungal respiratory pathogens. For example, in a mouse model of human disease, increased gut microbial diversity has been associated with reduced mortality and decreased lung lesions after respiratory infection with Streptococcus pneumoniae (Schuijt et al, 2016). Similarly in pigs, increased gut microbial diversity has been associated with reduced clinical signs and decreased lung lesions after respiratory infection with Mycoplasma hyopneumoniae (Schachtschneider et al, 2013).
Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are two of the most important pathogens affecting the swine industry worldwide. Co-infections are common on a global scale, resulting in pork production losses through reducing weight gain and causing respiratory disease in growing pigs. Both viruses modulate the immune system, increasing the risk of primary and secondary pathogens, and the subsequent need for antimicrobial treatment. Since PRRSV was introduced nearly 3 decades ago, it has cost an estimated $14 billion in losses to swine production. The most recent analysis of the cost of PRRS to the U.S. industry alone is $664 million per year (Holtkamp et al, 2013). The currently available PRRS vaccines are generally considered inadequate for disease control, and programs designed for long-term elimination of PRRSV from a herd are often unsuccessful. The gut microbiome offers an alternative approach to improve weight gain and reduce morbidity and mortality associated with respiratory disease in the presence of PRRS.
Considering the potential impact of the gut microbiome on respiratory pathogens, our work has focused on identifying associations between the gut microbiota and disease outcome in pigs, such as the presence of clinical signs and weight gain, using a PRRSV/PCV2 co-infection model. Our initial work demonstrated that the fecal microbiome was associated with clinical outcome of pigs 70 days post-infection with PRRSV and PCV2 (Niederwerder et al, 2016). Specifically, reduced clinical signs, improved weight gain, and reduced pathology were associated with increased microbiome diversity and the presence of Escherichia coli in feces. Following this initial work, our second objective was to determine if microbiome characteristics present at the time of virus exposure were associated with outcome after co-infection with PRRSV and PCV2 (Ober et al, 2017). Overall, pigs with high growth rates, reduced virus replication, and less severe pneumonia had several microbiome characteristics that may have predisposed outcome, including increased microbial diversity, reduced Methanobacteriaceae species, increased Ruminococcaceae species, and increased Streptococcaceae species. Most recently, our group evaluated fecal microbiota transplantation as a prophylactic tool to reduce the effects of co-infection on health and growth of nursery pigs (Niederwerder et al, 2018). Transplanted pigs had reduced morbidity and mortality, combined with increased antibody production, demonstrating how microbiome modulation may be an alternative tool in preventative medicine.
Profiling the pre-infection gut microbiome characteristics in swine provides a unique opportunity to consider possible avenues for how the microbiome may be used to prevent disease. Often in studies published in the species of interest, microbiome associations with disease are defined after the disease has already occurred, limiting our ability to understand how the microbiome may predispose disease development or exclude the effect of the disease on the microbiota. For example, several studies have characterized the microbiome of obese humans as having an enhanced capability to extract energy from food due to the relative abundance of two primary bacterial phyla, Firmicutes and Bacteroidetes (Turnbaugh et al, 2006; Ley et al, 2006). However, these microbiome characteristics are typically defined in obese patients already exhibiting the disease condition.
Alternatives to antimicrobials and unconventional tools for disease control are an essential need for health care in both human and veterinary medicine. Microbiome modulation is a promising alternative strategy, due to its role in immunity and ability to promote health and improve response to infection. Modern-day swine production can draw interesting parallels to the hygiene hypothesis in humans, where increased sanitation, reduced exposure to microbes in early life, and frequent use of antimicrobials have been associated with an increased susceptibility to certain disease conditions (Niederwerder, 2017). Moreover, the overarching theme of our work has been that increased microbial diversity is associated with improved outcome following infectious pathogen exposure. Overall, the gut microbiome and overall gut health has the potential to impact the health of the whole individual, including the respiratory tract. As we move forward with reducing antimicrobial usage and increased antimicrobial stewardship, we need to continue to learn more about how we can best promote beneficial gut microbes to improve health.
Holtkamp, D.J., Kliebenstein, J.B., Newmann, E.J., Zimmerman, J.J., ... & Haley C.A. (2013). Assessment of the economic impact of porcine reproductive and respiratory syndrome virus on United States pork producers.J Swine Health Prod, 21(2), 72-84.
Ley, R.E., Turnbaugh, P.J., Klein, S., & Gordon, J.I. (2006). Microbial ecology: human gut microbes associated with obesity. Nature, 444(7122), 1022-3.
Niederwerder, M.C., Jaing, C.J., Thissen, J.B., Cino-Ozuna, A.G., McLoughlin, K.S., & Rowland, R.R. (2016). Microbiome associations in pigs with the best and worst clinical outcomes following co-infection with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2). Vet Microbiol, 188, 1-11.
Niederwerder, M.C. (2017). Role of the microbiome in swine respiratory disease. Vet Microbiol, 209, 97-106.
Niederwerder, M.C., Constance, L.A., Rowland, R.R., Abbas, W., Fernando, S.C., ... & Cino-Ozuna, A.G. (2018). Fecal microbiota transplantation is associated with reduced morbidity and mortality in porcine circovirus associated disease.Front Microbiol, 9, 1631.
Messori, S., Trevis, P., Simongiovanni, A., Priori, D. & Bosi, P. (2013). Effect of susceptibility to enterotoxigenic Escherichia coli F4 and of dietary tryptophan on gut microbiota diversity observed in healthy young pigs. Vet Microbiol, 162(1), 173-9.
Ober, R.A., Thissen, J.B., Jaing, C.J., Cino-Ozuna, A.G., Rowland, R.R., & Niederwerder, M.C. (2017). Increased microbiome diversity at the time of infection is associated with improved growth rates of pigs after co-infection with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2). Vet Microbiol, 208, 203-211.
Schachtschneider, K.M., Yeoman, C.J., Isaacson, R.E., White, B.A., Schook, L.B., & Pieters M. (2013). Modulation of systemic immune responses through commensal gastrointestinal microbiota. PLoS One, 8(1), e53969.
Schuijt, T.J., Lankelma, J.M., Scicluna, B.P., de Sousa e Melo, F., ... & Wiersinga, W.J. (2016). The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia.Gut, 65(4), 575-83.
Turnbaugh, P.J., Ley, R.E, Mahowald, M.A., Magrini, V., Mardis, E.R., & Gordan, J.I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444(7122), 1027-31.
Megan C. Niederwerder, DVM, PhD
Assistant Professor, Department of Diagnostic Medicine and Pathobiology
College of Veterinary Medicine, Kansas State University