Mouse Maternal Diet Influences Offspring’s Risk of Severe Respiratory Infection

Written by: Jyoti Madhusoodanan, Ph.D. | Issue # 115 | 2023

Severe respiratory syncytial virus (RSV) infections are a major reason for young children needing hospitalization, and a global cause of childhood mortality [1, 2]. Frequent infections such as RSV during early childhood also increase the risk of developing chronic lung conditions such as asthma later in life [3]. These early infections occur at a time when the infant gut microbiome is still maturing.

Previous studies have found that disturbances in the development of the gut microbiome are linked to the severity of lower respiratory tract infections. One especially large study in humans found that when a mother’s diet during pregnancy is rich in carbohydrates and deficient in fresh fruits and vegetables, which are key sources of dietary fiber, it can predispose infants to more severe RSV infections [4]. The precise reasons underlying this association are unclear.

In a new study [5], Simon Phipps, an immunologist at the QIMR Berghofer Medical Research Institute in Australia and his colleagues, elucidated the connections between a mouse mother’s diet and her offspring’s susceptibility to severe infections with RSV.

The team began with two groups of mice that were of breeding age. One group was fed a low-fiber diet (LFD) and the other a high-fiber diet (HFD). Pups born to both groups were infected with PVM, a mouse viral equivalent of human RSV, when they were 7 days old. Offspring born to mice fed a low-fiber diet (LFD-reared) suffered more severe respiratory infections. They gained less weight after the infection and showed hallmarks of severe inflammation, including large amounts of mucus, neutrophil activation, higher viral loads, and lower levels of viral proteins in their airways. The researchers also found lower levels of regulatory T cells in the lymph nodes and lungs of the LFD-reared pups compared with HFD-reared pups.

The team then isolated dendritic cells, which help the immune system recognize pathogens, from the HFD-reared pups. They transferred these cells to LFD-reared pups and found that the  viral loads were decreased and the severity of lower respiratory infections was decreased. Similarly, transferring regulatory T cells, another group of immune cells, from HFD-reared pups to LFD-reared pups reduced the severity of the latter group’s infection. The data support “the importance of these two immunoregulatory cell types,” the authors write in their publication.

Higher consumption of dietary fiber can drive the gut microbiome to produce specific metabolites such as short-chain fatty acids, which then modulate immune development and the maturation of dendritic cells and regulatory T cells. The researchers found that one week after birth, HFD-reared pups had higher levels of short-chain fatty acids such as propionate and butyrate in their feces and circulating in their blood.

Both the gut microbiome of pups and their levels of short-chain fatty acids were strongly correlated with maternal dietary fiber. When pups in the LFD-reared group were fostered with mothers fed a high-fiber diet, they were better protected against severe lower respiratory tract infections. But fostering pups from mothers fed a high-fiber diet with those that had consumed a low-fiber diet led to more severe respiratory disease.

To understand how microbes were being transferred from mothers to pups, the researchers performed fecal microbial transplants between the two groups but found that protection from the high-fiber diet was not conferred. Next, they tested the mothers’ milk and found differences in the milk microbiome and short-chain fatty acid composition of the high-fiber and low-fiber groups.

The team enriched and cultured milk microbes from both the high-fiber and low-fiber groups and fed the microbes to LFD-reared pups via a tube to their stomachs. They exposed the animals to PVM. The HFD microbial treatment protected LFD-reared pups from severe infections, altered their gut microbiota, and increased serum and fecal levels of propionate. When the researchers isolated microbial species from milk and repeated the process with individual species, they found that microbes that resulted in greater propionate levels also conferred the most protection against infection. “These findings indicate that the maternal diet affects milk microbiome composition, which, in turn, affects the offspring’s susceptibility to develop [severe lower respiratory infections] sLRI upon [pneumonia virus of mice] PVM infection” , the authors wrote in their paper.

Protection was most closely linked to propionate levels, not other short-chain fatty acids such as butyrate. The authors identified an immunomodulatory cytokine named Flt3L as a key player in the connections between the milk microbiome, propionate, and immunity against severe respiratory infections. Flt3L levels were lower in the stool of LFD-reared pups, and the researchers found Flt3L levels in the gut and serum rose and fell together as HFD-reared pups matured, which “suggests that the gut is the primary source of serum Flt3L in early life,” they wrote in their paper. An anti-Flt3L treatment reversed the effects of propionate treatment in LFD-reared pups, hinting at this cytokine’s key role in helping the gut microbiome protect mouse pups from severe respiratory infections.

Collectively, the study’s data reveal a critical interaction between the milk microbiome and offspring’s immunity in mice. The results reveal how lifestyle factors such as a mother’s diet may influence the health of offspring later in life via her milk.

References

1. Bozzola E, Barni S, Villani A. Respiratory syncytial virus pediatric hospitalization in the COVID-19 era. International Journal of Environmental Research and Public Health. 2022 Nov 22;19(23):15455.

2. Nair H, Simões EA, Rudan I, Gessner BD, Azziz-Baumgartner E, Zhang JS, Feikin DR, Mackenzie GA, Moiïsi JC, Roca A, Baggett HC. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. The Lancet. 2013 Apr 20;381(9875):1380-90.

3. Wilkinson TM, Donaldson GC, Johnston SL, Openshaw PJ, Wedzicha JA. Respiratory syncytial virus, airway inflammation, and FEV1 decline in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2006 Apr 15;173(8):871-6.

4. Ferolla FM, Hijano DR, Acosta PL, Rodríguez A, Dueñas K, Sancilio A, Barboza E, Caría A, Gago GF, Almeida RE, Castro L. Macronutrients during pregnancy and life-threatening respiratory syncytial virus infections in children. American Journal of Respiratory and Critical Care Medicine. 2013 May 1;187(9):983-90.

5. Sikder MA, Rashid RB, Ahmed T, Sebina I, Howard DR, Ullah MA, Rahman MM, Lynch JP, Curren B, Werder RB, Simpson J. Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection. Immunity. 2023 May 9;56(5):1098-114.

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