Lactobacillus iners in sufficient colonies may predispose someone to bacterial vaginosis.
L. iners and sulfur (and cysteine)
L. iners growth is dependent on L-cysteine in vitro. Researchers traced this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms1.
Cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo, and cystine uptake inhibitors selectively inhibit L. iners growth in vitro1.
Cysteine is a sulfur-containing amino acid.
Cysteine is catabolised by several desulfuration reactions that release sulfur in a reduced oxidation state, generating sulfane sulfur or hydrogen sulfide (H2S), which can be further oxidised to sulfate2.
B6 is required to convert methionine into homocysteine.2
Cystiene levels in vaginal fluids of women with BV were significantly less than cysteine levels in those without BV. This is because lactobacilli species need cysteine.
Crispatus and iners both correlate strongly with cysteine availability.
Prevotella was associated with low vaginal fluid cysteine levels.
Other taxa, including various BV-associated bacteria, showed no correlation or significant negative correlation with cysteine.
Cysteine availability is important for Lactobacillus colonisation success in vivo.
L-cystine (oxidised L-cysteine) supports growth by acting as a direct nutritional supplement rather than by chemically reducing the media.
Thus L. iners does not require a reduced environment to grow when it has access to a bioavailable source of L-cysteine (e.g., L-cystine), but L-cysteine bioavailability in un-supplemented MRSQ broth is inadequate for L. iners.
L. iners possesses a uniquely restricted repertoire of Cys-related transport mechanisms.
Iron-sulfur proteins
L. iners has genes that encode iron-sulfur proteins and unique σ-factors3.
Iron-sulfur proteins have iron-sulfur clusters that contain sulfide-linked di, tri, and tetrairon centres in variable oxidation states.
Iron-sulfur clusters are found in metalloproteins – ferredoxins, NADH dehydrogenase, hydrogenases, Coenzyme Q – cytochrome C reductase, succinate – Coenzyme Q reducatase and nigrogenase.
(These are enzymes?)
NADH – nicotinamide adenine dinucleotide (NAD) + hydrogen (H)
Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase.[1] Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.[2]
The prevalence of these proteins on the metabolic pathways of most organisms leads to theories that iron–sulfur compounds had a significant role in the origin of life in the iron–sulfur world theory.
In some instances Fe–S clusters are redox-inactive, but are proposed to have structural roles. Examples include endonuclease III and MutY.[3][4]
L. iners and iron – NEEDS REWRITING
Gardnerella spp. cannot grow in iron-limiting conditions, but can use iron sources such as hemoglobin for growth. Gardnerella spp. increases local vaginal iron levels by secreting vaginolysin to dissolve erythrocytes.
And since L. iners grew best on medium supplemented with horse serum and seemed to require iron for growth, it was easy to speculate that the iron released by Gardnerella-degrading erythrocytes promoted the growth of L. iners. This explains why L. iners can be easily detected at BV.4
L. iners produces toxic compounds5.
L. iners has a drastically reduced genome, likely making it dependent on exogenous sources (e.g., cervical mucus or other vaginal species) for nutrients6. But, it seems to be quite good at sequestering these nutrients in a low-nutrient environment by producing inerolysin, a pore-forming cytolysin. It may have picked up this gene from Gardnerella vaginalis. This gene is not found in any other lactobacilli species.
This derived trait of L. iners may allow it to liberate resources from host cells (64). We speculate that this may give L. iners a competitive advantage in the vaginal environment when nutrients are scarce and the ability to liberate them directly from host tissue is favored.
Indeed, microbial surveys have suggested that L. iners is capable of persisting under other potentially adverse conditions in the vagina (27, 65, 66).
Additionally, because the glycogen content of the vaginal epithelium is linked to circulating estrogen levels (14), the abundance of nutrients in the vagina may vary across the female reproductive cycle as well as through a woman’s lifetime. If L. iners does indeed have a competitive advantage in times of low nutrient abundance, it may also be selected for during times of low circulating estrogen.
These genotypic differences may provide the species with differential competitive abilities across the range of conditions common to the vaginal environment, facilitating the partitioning of their shared niche space6.
D-lactic acid is produced by L. crispatus, L. gasseri, and L. jensenii, but not L. iners7,8.
L. iners, but not L. crispatus, commonly cooccurs with many of the bacterial species that colonize the vagina during incidences of bacterial vaginosis (23, 26, 27).
Communities dominated by L. iners are associated with a higher vaginal pH than that in communities dominated by L. crispatus (2).
L. iners has almost exclusively been isolated from human vaginal secretions, L. crispatus has also been identified in other habitats, like the vertebrate gastrointestinal tract (28), although it is unclear whether L. crispatus is a frequent colonizer of these other habitats.
L. crispatus and L. iners are not sisters of one another; rather, Lactobacillus johnsonii is sister to L. iners, and both Lactobacillus helveticus and Lactobacillus acidophilus are sisters to L. crispatus6.
L. iners relies heavily on fermentation to generate energy, but has only 59 enzymes, having the genetic capability to metabolize glucose, mannose, maltose, and trehalose. L. iners can only produce l-lactic acid6.
The 14 core genes in L. iners that were potentially acquired by horizontal gene transfer matched genes in Gardnerella vaginalis (n = 4), Chlamydia trachomatis (n = 2), Aerococcus christensenii (n = 2), Parvimonas micra, Facklamia hominis, Finegoldia magna, Streptococcus sp., and Enterococcus faecium. Most of these species are commonly identified in the human vagina, further reinforcing the notion that they may have been horizontally acquired. These 14 genes include several toxin-antitoxin proteins, a zinc and a phosphate transporter, two DNA repair proteins, and several uncharacterized proteins. Furthermore, our analysis indicated that the cytolysin gene of L. iners is also likely to have been horizontally acquired. We found that the L. iners sequence for this gene most closely matches cytolysins identified in G. vaginalis and various Streptococcus species. We extracted these matching sequences from the database and constructed a maximum likelihood tree to identify their phylogenetic relationships (Fig. 7). Our analysis indicated that the L. iners cytolysin is most closely related to the G. vaginalis cytolysin but has diverged substantially in sequence since being acquired by L. iners.
ABLE 2
Functional category and metabolic pathways encoded in the core genome
| Functional category/pathwaya | No. of core genes | |
|---|---|---|
| L. crispatus | L. iners | |
| Carbohydrate metabolism | 85 | 59 |
| Glycolysis | 17 | 14 |
| Citric acid cycle | 3 | 1 |
| Pentose phosphate pathway | 14 | 12 |
| Fructose and mannose metabolism | 18 | 14 |
| Galactose metabolism | 11 | 8 |
| Starch and sucrose metabolism | 16 | 10 |
| Amino acid metabolism | 54 | 43 |
| Ala, Asp, and Glu metabolism | 11 | 10 |
| Gly, Ser, and Thr metabolism | 9 | 3 |
| Cys and Met metabolism | 8 | 5 |
| Lysine biosynthesis | 12 | 4 |
| Arginine biosynthesis | 3 | 1 |
| Lipid metabolism | 21 | 17 |
| Nucleic acid metabolism | 51 | 56 |
| Metabolism of cofactors and vitamins | 33 | 27 |
| Thiamine metabolism | 5 | 3 |
| Riboflavin metabolism | 5 | 1 |
| Vitamin B6 metabolism | 2 | 1 |
| Nicotinate metabolism | 5 | 5 |
| CoA biosynthesis | 5 | 5 |
| Folate biosynthesis | 2 | 5 |
| Membrane transporter | 70 | 54 |
| ABC transporter | 39 | 31 |
| Phosphate transport system | 23 | 15 |
| Bacterial secretion system | 8 | 8 |
| Replication and repair | 41 | 36 |
| DNA replication | 14 | 14 |
| Base excision repair | 9 | 7 |
| Nucleotide excision repair | 7 | 7 |
| Mismatch repair | 16 | 15 |
| Homologous recombination | 19 | 19 |
| Transcription | 4 | 5 |
| Translation | 78 | 79 |
| Peptidoglycan biosynthesis | 14 | 14 |
aEntries in bold font represent functional categories while indented entries are specific metabolic pathways within each category. Enzymes can appear in multiple pathways but are only counted once in the functional category total. CoA, coenzyme A.
References
- 1.Bloom SM, Mafunda NA, Woolston BM, et al. Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation. Nat Microbiol. Published online March 3, 2022:434-450. doi:10.1038/s41564-022-01070-7
- 2.Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J of Inher Metab Disea. Published online February 17, 2010:17-32. doi:10.1007/s10545-009-9006-9
- 3.Petrova MI, Reid G, Vaneechoutte M, Lebeer S. Lactobacillus iners : Friend or Foe? Trends in Microbiology. Published online March 2017:182-191. doi:10.1016/j.tim.2016.11.007
- 4.Zhang Q qiong, Chen R, Li M, Zeng Z, Zhang L, Liao Q ping. The interplay between microbiota, metabolites, immunity during BV. Medicine in Microecology. Published online March 2022:100049. doi:10.1016/j.medmic.2021.100049
- 5.Rampersaud R, Planet PJ, Randis TM, et al. Inerolysin, a Cholesterol-Dependent Cytolysin Produced by Lactobacillus iners. J Bacteriol. Published online March 2011:1034-1041. doi:10.1128/jb.00694-10
- 6.France MT, Mendes-Soares H, Forney LJ. Genomic Comparisons of Lactobacillus crispatus and Lactobacillus iners Reveal Potential Ecological Drivers of Community Composition in the Vagina. Schloss PD, ed. Appl Environ Microbiol. Published online December 15, 2016:7063-7073. doi:10.1128/aem.02385-16
- 7.Abdelmaksoud AA, Koparde VN, Sheth NU, et al. Comparison of Lactobacillus crispatus isolates from Lactobacillus-dominated vaginal microbiomes with isolates from microbiomes containing bacterial vaginosis-associated bacteria. Microbiology. Published online March 1, 2016:466-475. doi:10.1099/mic.0.000238
- 8.Witkin SS, Mendes-Soares H, Linhares IM, Jayaram A, Ledger WJ, Forney LJ. Influence of Vaginal Bacteria and <scp>d</scp> – and <scp>l</scp> -Lactic Acid Isomers on Vaginal Extracellular Matrix Metalloproteinase Inducer: Implications for Protection against Upper Genital Tract Infections. Blaser MJ, ed. mBio. Published online August 30, 2013. doi:10.1128/mbio.00460-13
| Condition type | Bacteria |
|---|---|
| Affected systems | Reproductive |
| Sexually Transmissible | Yes |
| Genitourinary Incidence | very common |
| Age group affected |
|
Microbial information
| Anaerobe / Aerobe | Anaerobe |
|---|---|
| Gram stain | Gram-positive |
| Best tests to detect | |
| Pathogen of | Commensal of (Can naturally inhabit, but not necessarily as a healthy addition) |
|
| Optimal growth pH | |
| Conditions correlated with | |
| Cellular adherence capacities | |
| Found in healthy vaginas | |
| Biofilm-forming capacities | |
| Cellular Morphology | |
| Microbe Motility | |
| Colony Colour | |
| Substances Produced | |
| Sexually Transmissible |
What are the symptoms of Lactobacillus iners?
What causes Lactobacillus iners?
- No causes found for Lactobacillus iners, yet.
What are the risk factors associated with Lactobacillus iners?
- No risk factors for Lactobacillus iners, yet.
How do you diagnose Lactobacillus iners?
- No diagnoses found for Lactobacillus iners, yet.
How do you treat Lactobacillus iners?
Treatments for Lactobacillus iners are only for practitioners and people who purchased the book Killing BV and Killing BV for men.
Which treatments are likely to be ineffective for Lactobacillus iners?
- No resistances found for Lactobacillus iners, yet.
What complications are associated with Lactobacillus iners?
- No complications found for Lactobacillus iners, yet.
References
Jakobsson, T. & Forsum, U., 2007. Lactobacillus iners: A marker of changes in the vaginal flora? Journal of Clinical Microbiology, 45(9), p.3145, http://jcm.asm.org/content/45/9/3145.fullPetrova, M.I. et al., 2017. Lactobacillus iners: Friend or Foe? Trends in Microbiology, 25(3), pp.182–191, https://www.cell.com/trends/microbiology/pdf/S0966-842X(16)30181-0.pdf
