In Aging Cell, researchers have described how a strain of Lactobacillus gut bacteria sends chemical signals that enter the bloodstream and decrease fibrosis in the lungs.
The gut-lung axis
The gut-brain axis, the term for how the intestines and nervous system interact, is well-known to many longevity enthusiasts, and substantial previous research has explained its workings. There is a similar relationship between the gut and the lungs; gut metabolites have been found to directly impact lung diseases through inflammation [1]. Lactobacillus has been found to have benefits against multiple lung diseases [2], and one particular strain found in centenarians, L9, has been found to alleviate allergies in mice [3] by rebalancing immune responses [4].
This study, however, focuses on a different condition: pulmonary fibrosis. Fibrosis is fairly well-explained in the literature; it is caused by repeated injuries to lung tissue that overactivate the secretion of extracellular matrix (ECM) material by myofibroblasts [5]. This is tightly linked to the dysregulation of collagen synthesis and degradation, which is increased with aging [6].
Fighting against age-related collagen increases
In their first investigation, the researchers used bulk RNA sequencing data and physical samples to analyze the relationship between aging and pulmonary fibrosis. In older people, there was more collagen deposition and more protein markers of fibrosis, even though these were considered to be normal lung samples. This collagen had filled alveolar areas, with visual evidence of fibrosis. Genes related to the expression of ECM-related proteins were upregulated in the older group. Similar results were found in data from wild-type mice.
The researchers then utilized their own mice, which were aged from 15 months to 24 months. Normally, mice at 15 months have few markers of pulmonary fibrosis, but at 24 months, their lungs had become intensely fibrotic, first beginning at the lungs’ peripheral areas and continuing into the center.
In a group of mice that were given L9 between those ages, however, there were considerably fewer markers of fibrosis, with a total lung fibrosis score that was only 70% that of the control group. Collagen fibers were decreased by 40%. Collagen deposition in fibrosis is due to Col-I and Col-III proteins; the researchers found that while Col-III was unaffected by L9 introduction, Col-I was reduced by a a full 59%.
This was found to be due to a 61% reduction in the collagen precursor PINP, which was accompanied by a 27% to 37% reduction in the LOX cross-linking enzyme, depending on measurement type and location. This was entirely due to a reduction in collagen synthesis; degradation enzymes were not significantly affected.
A long causal chain of biochemistry
The researchers then took a closer look at PINP and other collagen precursors. Three enzymes involved in the collagen synthesis process, 5CS, PSAT-1, and PHGDH, and found that all three were not significantly affected by L9. Propeptides involved in collagen formation were similarly unaffected. However, the molecular chaperone HSP47 was, like PINP, reduced by 61%, and the number of fibroblasts that expressed HSP47 was reduced by 88%. HSF1 is the key transcription factor of SERPIN H1, the gene that encodes HSP47, and HSF1 was reduced by 27%. HSF1, itself, is controlled by the JNK pathway, which was reduced by 85%. Looking even farther upstream, the researchers found that two key factors that regulate JNK’s entry into the nucleus, MKK4 and MKK7, were reduced by 43% and 22%, respectively; the factors that regulate the MKK proteins, ASK1, TAK1, and HPK1, were reduced by 31%, 50%, and 41%, respectively.
The researchers were able to link this long molecular cause-and-effect chain to the senescence-associated secretory phenotype (SASP). Four inflammatory cytokines involved in the SASP, IL-17A, IL-6, IL-1β, and TGFβ1, are upstream of ASK1 and HPK1, and they were also significantly reduced by the introduction of L9 into these mice. The 32% decrease in IL-17A was found to be the most significant of these, and it was linked to a decrease in the number of immune cells that have the Th17 phenotype.
Why some bacteria are beneficial
This decrease in immune cell phenotype was linked to the increase in short-chain fatty acids (SCFAs) in mice that had received L9. The treated mice had substantial decreases in bacterial types that were likely to be harmful, such as Clostridia; meanwhile, as expected, there were substantial increases in Lactobacillus and other beneficial bacterial types that produce SCFAs. This was reflected in metabolites taken from treated mice, which had substantial increases in butyric acid and propionic acid in both feces and blood.
Interestingly, these SCFAs were not, themselves, delivered to the lungs. Instead, their effects on immune cells were found to be responsible for the reduction in fibrosis; due to the increases in butyric and propionic acids, the lung tissues of these mice simply recruited fewer immune cells of the Th17 phenotype that encourages fibrosis. Further investigation involving the interruption of the causal chain found that IL-17A, which these cells secrete, was indeed responsible.
These results confirm that the secretions of gut bacteria have real and measurable effects on the rest of the body, including organs that do not directly experience these secretions themselves. The researchers hold that “future investigations should subsequently evaluate the safety and efficacy of L9 as an adjuvant to existing therapeutics in PF patients stratified by gut microbiota profiles.” If these results can be confirmed in clinical trials, it may be possible to at least partially mitigate lung fibrosis and similar issues by introducing beneficial bacteria into the gut flora of older people.
Literature
[1] Zhang, D., Li, S., Wang, N., Tan, H. Y., Zhang, Z., & Feng, Y. (2020). The cross-talk between gut microbiota and lungs in common lung diseases. Front Microbiol 11: 301.
[2] Du, T., Lei, A., Zhang, N., & Zhu, C. (2022). The beneficial role of probiotic Lactobacillus in respiratory diseases. Frontiers in immunology, 13, 908010.
[3] Yang, J., Ren, F., Zhang, H., Jiang, L., Hao, Y., & Luo, X. (2015). Induction of regulatory dendritic cells by Lactobacillus paracasei L9 prevents allergic sensitization to bovine β-lactoglobulin in mice. Journal of microbiology and biotechnology, 25(10), 1687-1696.
[4] Wang, X., Hui, Y., Zhao, L., Hao, Y., Guo, H., & Ren, F. (2017). Oral administration of Lactobacillus paracasei L9 attenuates PM2. 5-induced enhancement of airway hyperresponsiveness and allergic airway response in murine model of asthma. PloS one, 12(2), e0171721.
[5] Henderson, N. C., Rieder, F., & Wynn, T. A. (2020). Fibrosis: from mechanisms to medicines. Nature, 587(7835), 555-566.
[6] Moss, B. J., Ryter, S. W., & Rosas, I. O. (2022). Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annual Review of Pathology: Mechanisms of Disease, 17, 515-546.
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