By Anthony Thomas, Ph.D.
Director, Scientific Affairs /Jarrow Formulas Inc.

The microbes colonizing the gastrointestinal tract (i.e., gut microbiota) impact immune functions, both locally and at distal sites such as the lungs.  A recent blog post highlighted the importance of the gut microbiota to the body’s defenses against respiratory infections and the influence of (orally administered) specific probiotic strains and prebiotics on the incidence, severity, and duration of acute respiratory infections.  However, mechanisms by which the gut microbiota impact respiratory immunity are not fully understood.

Short-chain fatty acids (SCFAs), namely acetate, propionate, and butyrate, produced from gut bacterial fermentation of digestion-resistant carbohydrates (e.g., dietary prebiotic fibers, prebiotics and resistant starch) are an important link between the microbiota and the immune system via modulation of immune cell development and functions [1].  For example, it was shown that mice fed a diet high in fermentable resistant starch had increased levels of SCFAs circulating in the blood, particularly acetate, and were protected against the development of allergic inflammation in the lung upon allergenic challenge, whereas low- or no-fiber diets led to decreased levels of SCFAs and the development of allergic airway disease [2].  It vitro exposure of monocytes to butyrate was shown to partially impair their differentiation into dendritic cells, thereby reducing their capacity to stimulate adaptive immune responses [3].

Influenza viruses (IFV) are highly contagious respiratory pathogens responsible for seasonal flu epidemics each year, causing mild to severe illness, especially in high-risk populations such as infants, the elderly, and those with compromised immune function.  The most severe IFV disease outcomes are associated with secondary bacterial pneumonia caused primarily by Staphylococcus aureus or Streptococcus pneumoniae [4].  In fact, S. pneumoniae was the most commonly detected bacterium in the devastating 1918 influenza pandemic as well as the 2009 influenza pandemic.  Evidence suggests, infections with IFV disrupt the composition and function of the gut microbiota [5-10], which is associated with increased susceptibility to secondary bacterial infection in the gut [6, 9].  

Given the important role of the gut microbiota in the body’s defenses against respiratory tract infections,  Sencio et al. [11] investigated if IFV-induced disruptions to the gut microbiota compromised respiratory immunity and increased susceptibility to secondary bacterial pneumonia in mice.  Indeed, sublethal infection with influenza A virus (IAV) disrupted the composition of the gut microbiota (gut dysbiosis) and significantly decreased production of SCFAs, resulting in significantly decreased levels of SCFAs circulating in the blood (comprised primarily of acetate) 7 days post infection.  Reduced levels of SCFA-producing bacteria, including bifidobacteria and lactobacilli that are capable of fermenting complex carbohydrates to produce SCFAs, was observed during IAV-infection.  Additional experiments suggest this was likely due to decreased food intake, a well-recognized symptom of the flu [12].

To determine if the dysbiotic gut microbiota from IAV-infected mice compromised pulmonary antibacterial defenses, they next performed microbiota transfer experiments.  Mice were treated with antibiotics, to disrupt the microbiota, and then intranasally challenged with S. pneumoniae.  Antibiotic treated mice had a greater bacterial load in their lungs and transfer of gut microbiota from healthy mice restored clearance of the bacteria.  Transfer of gut microbiota from IAV-infected mice significantly increased bacterial counts in the lung as well as dissemination form the lungs to the blood.  Thus, it was concluded that influenza-induced gut dysbiosis increases susceptibility to respiratory bacterial infections.  

The reduced respiratory immunity observed in response to transfer of gut microbiota from antibiotic treated or IAV infected mice was linked to reduced levels of acetate circulating in the blood.  Specifically, reduced acetate signaling via a receptor on alveolar macrophages, innate immune cells that play an essential role in the killing of invading microbes in the lungs, impaired their bactericidal activity.  

Acetate supplementation significantly reduced the bacterial load in the lungs and spread of bacteria from the lungs in antibiotic treated mice with a microbiota transferred from IAV-infected mice.  Furthermore, acetate supplementation during IAV infection significantly improved survival by ~50% in mice double-infected with S. pneumoniae!

This study highlights an important link between diet/nutritional status, the composition and function of the gut microbiota, and respiratory immunity, which raises important questions about the consequences of inadequate food and fermentable fiber intake (e.g., due to habitual diet, disease, stress, fasting).  Thus, manipulation of the gut microbiota composition and/or function (e.g., SCFA production) via the administration of select probiotic strains and/or prebiotic fibers/resistant starch may offer a therapeutic approach to blunt the negative impact of disease-induced fluctuations in dietary patterns, a generally deficient diet, and exposure to various medications that disrupt the gut microbiota (e.g., antibiotics, stomach-acid reducing drugs).  

Source: International Probiotics Association


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2.         Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, Roberts LK, Wong CH, Shim R, Robert R, et al: Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun 2015, 6:7320.

3.         Millard AL, Mertes PM, Ittelet D, Villard F, Jeannesson P, Bernard J: Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin Exp Immunol 2002, 130:245-255.

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5.         Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z: Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med 2014, 211:2397-2410.

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7.         Bartley JM, Zhou X, Kuchel GA, Weinstock GM, Haynes L: Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses. Front Immunol 2017, 8:1164.

8.         Groves HT, Cuthbertson L, James P, Moffatt MF, Cox MJ, Tregoning JS: Respiratory Disease following Viral Lung Infection Alters the Murine Gut Microbiota. Front Immunol 2018, 9:182.

9.         Yildiz S, Mazel-Sanchez B, Kandasamy M, Manicassamy B, Schmolke M: Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome 2018, 6:9.

10.       Qin N, Zheng B, Yao J, Guo L, Zuo J, Wu L, Zhou J, Liu L, Guo J, Ni S, et al: Influence of H7N9 virus infection and associated treatment on human gut microbiota. Sci Rep 2015, 5:14771.

11.       Sencio V, Barthelemy A, Tavares LP, Machado MG, Soulard D, Cuinat C, Queiroz-Junior CM, Noordine ML, Salome-Desnoulez S, Deryuter L, et al: Gut Dysbiosis during Influenza Contributes to Pulmonary Pneumococcal Superinfection through Altered Short-Chain Fatty Acid Production. Cell Rep 2020, 30:2934-2947 e2936.

12.       Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J: Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000, 160:3243-3247.

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