In surgery, persistent post-surgical pain (or PPSP) is defined as pain that remains significant for at least 3 months after surgery.

It's a condition that affects millions of patients around the world, and one that science is still fairly helpless to tackle, even though we know that there are certain predisposing factors (type of surgery, intensity of pain before the operation, the patient's attitude to pain, genetic factors)

However, a new lead is emerging, one that we might not have thought of at first: microbiota, of the gut rather than the breast, and therefore implicitly the famous gut-brain axis (sidenote: Gut-brain axis Two-way communication network between the gut and the brain, which allows the gut and brain to communicate via three different pathways: 
1. the neuronal pathway (neurons), mainly via the vagus nerve and the enteric nervous system,
2. the endocrine pathway, by secreting hormones such as cortisol, adrenaline and serotonin
3. the immune system pathway, by modulating cytokines The gut-brain axis influences our behavior, cognition (memory), emotions, moods, desires, perception... and pain, among other things. ) .

Thus, manipulating the gut microbiota preoperatively with probiotics or prebiotics could reduce the incidence of PPSP. At least, that's what a preliminary study had suggested, showing that certain bacteria in the digestive tract are associated with pain after wrist fracture surgery. And this seems to be confirmed by an Irish study, ¹ this time on women who had surgery for breast cancer.

Gut bacteria associated with the presence or absence of pain

Three months after their operation, half the women reported persistent pain, while the other half were not particularly affected. This difference was linked to the diversity of their gut microbiota: patients reporting severe pain 1 hour and 3 months after surgery had a less diverse gut flora, compared to women with little pain.

Most importantly, certain bacteria appeared to be associated with the presence or absence of persistent post-surgical pain following breast cancer procedures: women who reported no pain 3 months after surgery had more bacteria known for their beneficial effects (Bifidobacterium longum and Faecalibacterium prausnitzii) in their gut, while women with PPSP harbored more Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii and Roseburia hominis.

Persistent post-surgical pain (or PPSP (sidenote: Persistent post-surgical pain (PPSP) Pain which continues after a surgical operation in a significant form for at least three months, and is not related to pre-existing painful conditions ) ) is as common as it is underestimated: it affects millions of patients worldwide. Predisposing factors include the type of surgery. For example, in the case of breast cancer, 80% of women whose surgery includes axillary lymph node clearance suffer from PPSP.

Previous studies have implicated the gut microbiota in postoperative pain. However, the mechanisms remained unclear: gut dysbiosis could induce an imbalance in the production of microbial metabolites, and play a role in the development of PPSP via the gut-brain axis (sidenote: Gut-brain axis Two-way communication network between the gut and the brain, which allows the gut and brain to communicate via three different pathways: 
1. the neuronal pathway (neurons), mainly via the vagus nerve and the enteric nervous system,
2. the endocrine pathway, by secreting hormones such as cortisol, adrenaline and serotonin
3. the immune system pathway, by modulating cytokines The gut-brain axis influences our behavior, cognition (memory), emotions, moods, desires, perception... and pain, among other things. ) .

To find out more, Irish researchers at University College Cork ¹ conducted a prospective observational study of adult patients undergoing surgery for breast cancer (excluding axillary clearance or reconstructive surgery, which are very painful). Their aim was to determine whether the composition of the gut microbiota was associated with the incidence and extent of PPSP in this cohort of patients.

Less alpha diversity

Twelve weeks after the operation, 21 patients (51.2%) reported no pain, while 20 (48.8%) reported persistent pain. This difference seemed to be linked to the diversity of their gut microbiota: a lower alpha diversity (sidenote: Alpha diversity Number of species coexisting in a given environment ) (3 measures: richness, Shannon index and Simpson index) was observed in patients reporting severe pain 1 hour after surgery and 12 weeks later, compared to those reporting mild pain. On the other hand, there was no difference in beta diversity (sidenote: Beta diversity Rate of variation in species composition, calculated by comparing the number of unique taxa in each ecosystem ) .

Bacteria associated with the presence or absence of pain

But above all, the team highlighted stark differences in the composition of the gut microbiota corresponding to pain, with increased presences of:

• Bifidobacterium longum and Faecalibacterium prausnitzii in women who reported no pain 12 weeks after surgery
• Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii and Roseburia hominis in women with PSPP.

These results seem to support those of previous studies: reduction in the relative abundance of Faecalibacterium prausnitzii in patients with fibromyalgia; reduction of pain after the administration of Bifidobacterium longum in a rat model with arthritis. There is one exception, however: Roseburia hominis reduced visceral hypersensitivity in rats, while it was associated with the presence of PPSP in this study.

More than 80% of urinary tract infections (UTIs) are caused by uropathogenic Escherichia coli (UPEC). (sidenote: Uropathogenic Escherichia coli (UPEC) E. coli often encoded with additional genes (when compared to commensal E. coli) that boost its pathogenicity (flagellum, toxins, surface polysaccharides, etc.) ) These gut bacteria can migrate from the anus, colonize the urethra, and then spread upwards to the bladder. Previous studies have shown that women suffering from UTIs have an increased abundance of E. coli in their digestive tract, with similarities between intestinal species and those colonizing the urinary tract. 

To assess dysbiosis and other potential risk factors in women with a history of urinary tract infections, researchers enrolled 753 female volunteers aged 18 to 45 who had been diagnosed with a UTI in the previous five years but were otherwise in good health.

Eat a healthier diet

71% of the women were found to have a gut dysbiosis, which was associated not only with recurrent UTIs (sidenote: Recurrent urinary tract infection A recurrent urinary tract infection is defined as two or more symptomatic episodes in the previous six months, or more than three episodes in the previous year. ) , but also with a flora that exhibited multi-resistance to antibiotics.

Another particularity of the population studied was their diet, whether in terms of drinks (less than a liter of water per day, consumption of sugary juices, etc.), food (too many salty products, high-calorie diets rich in added sugars and saturated fats, etc.), or dietary supplements to prevent UTIs.

The researchers believe that these observations support the link between diet and the composition of the gut microbiota. This is consistent with previous studies which found that only 12% of the structural variation in gut microbiota can be attributed to genetic changes, while 57% can be explained by dietary changes.

Microbiota as a new therapeutic strategy

Although the gold standard treatment for UTIs involves antibiotics, in the long term, antibiotics disrupt the gut microbiota (dysbiosis) and favor the emergence of multiresistant microorganisms. Hence the importance, according to the authors, of alternative and complementary therapeutic choices.

The vaginal microbiota is still poorly understood, although knowledge is slightly better this year

• Once again this year, only one in five women claim to know exactly what the “vaginal microbiota” is (22%, +2 points vs. 2023, vs. 20% men and women combined). Awareness of the term is greater compared to last year, but remains low: nearly half of women have still never heard of it (48%, -5 points vs. 2023, vs. 51% of men and women combined).
   
• Women are more familiar with the term “vaginal flora”, even if knowledge of the term remains superficial: only one woman in two knows exactly what it is (53% vs. 42% for men and women combined).
   
• A degree of good knowledge about certain characteristics of the vaginal microbiota: almost 7 out of 10 women know that antibiotics can alter the vaginal microbiota (69%) and that vaginal dryness/dehydration has consequences for the vaginal microbiota (69%).
   
• Knowledge is still too weak, but improving on last year: 55% of women know that from childhood to menopause, a woman’s vaginal microbiota does not remain the same (+6 points vs. 2023), and 44% know that bacterial vaginosis is associated with an imbalance in the vaginal microbiota (+8 points vs. 2023).
   
• However, knowledge about many aspects of the vaginal microbiota remains very limited: only 1 in 2 women knows that smoking has an impact on the vaginal microbiota (55%) and 3 in 10 women know that the vaginal microbiota is balanced when its bacterial diversity is low (30%; +2 points vs. 2023)
   

This year, more and more women are adopting behaviors aimed at protecting the vaginal microbiota, even if certain bad practices persist

• The adoption of behaviors to protect the vaginal microbiota varies: while women are very likely to wear cotton underwear (86%, +2 points vs. 2023), other beneficial behaviors are less common. Around 2 out of 3 women avoid self-medication (63%), and 3 out of 5 use a soap-free cleansing solution (61%, +3 points vs. 2023).
   
• Certain behaviors that are harmful to the vaginal microbiota remain ingrained: despite a reduction compared to last year, more than 2 out of 5 women still practice vaginal douching (42%, -3 points vs. 2023), and 53% sleep in their underwear (+1 point vs. 2023).
   

More education from healthcare professionals, which must be stepped up to meet women's needs

• Healthcare professionals delivered more education about the vaginal microbiota this year: 43% of women have received an explanation about the vaginal microbiota (+7 points vs. 2023). Nearly half of women have been made aware of the importance of protecting their vaginal microbiota as much as possible (+8 points vs. 2023). A similar proportion of women stated that a healthcare professional has explained the behaviors to adopt to protect their vaginal microbiota as much as possible (48%, +7 points vs. 2023). Although this progress is noteworthy, it only concerns a minority of women, illustrating room for improvement in the information passed on by healthcare professionals concerning the vaginal microbiota.
   
• This is especially true since women have been widely requesting this kind of awareness-raising. 88% would like to be better informed about the importance of the vaginal microbiota and its impact on health (+2 points vs. 2023).

Age is a determining factor when it comes to the vaginal microbiota: people aged 60 and over are less aware, in contrast to 25-34 year-olds and young mothers

Once again this year, women aged 60 and over remain the least informed and aware of the vaginal microbiota, even though they are more exposed to health problems.
 

• Only 41% of women aged 60 and over know what the vaginal microbiota is, compared with 52% of women overall.
   
• They also lack knowledge of the role and functions of the vaginal microbiota: less than half of women aged 60 and over (49%) know that the vagina is self-cleaning (vs. 56% of all women), and only 39% know that bacterial vaginosis is associated with an imbalance in the vaginal microbiota (vs. 44% of all women).
   
• Despite these knowledge gaps, women aged 60 and over stand out for adopting certain behaviors aimed at preserving the balance of the vaginal microbiota. Thus, 3 out of 4 of them avoid relying on self-medication (76%, vs. 63% of all women) and 67% avoid practicing vaginal douching (vs. 58% of all women). However, fewer of the women aged 60 and over use a soap-free cleansing solution (56%, vs. 61% of all women) and sleep without underwear (43%, vs. 47% of all women).
   
• This population has received less education from healthcare professionals: only a third of women aged 60 and over have received an explanation about the vaginal microbiota from a healthcare professional (32%, vs. 43% of all women).
   

Women aged 25 to 34 and mothers of children under 3 appear to be more informed and aware of the vaginal microbiota.

• 62% of 25-34 year-olds and 60% of mothers of children under 3 know what the vaginal microbiota is (vs. 52% of all women).
   
• A better understanding of the vaginal microbiota: 69% of 25-34 year-olds and 67% of mothers know that every woman has a unique vaginal microbiota (vs. 64% of all women). More of these women also know that the vagina is self-cleaning: 61% of 25- 34 year-olds and 60% of mothers know this (vs. 56% of all women).
   
• More of these women have adopted certain behaviors that are beneficial for their vaginal microbiota: 2 out of 3 use a soap-free cleansing solution (67% of 25-34 yearolds and 71% of mothers of children under 3, vs. 61% of all women), and 54% sleep without underwear (vs. 47% of all women).
   
• 54% of 25-34 year-olds and 55% of mothers of children under 3 have received information from a healthcare professional about the vaginal microbiota (vs. 43% of all women).
   

The International Microbiota Observatory also revealed striking contrasts between countries in terms of knowledge, behaviors and information provided by healthcare professionals. The complete results are available on the Biocodex Microbiota Institute website.

About the Biocodex Microbiota Institute

The Biocodex Microbiota Institute is an international knowledge hub dedicated to human microbiotas. Available in 7 languages, the Institute is aimed at both healthcare professionals and the general public, to raise awareness of the vital role that this part of the body plays in our health. The primary mission of the Biocodex Microbiota Institute is educational: to promote the importance of the microbiota for everyone.

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The gut microbiota could one day be a therapeutic target of choice in the fight against cardiovascular disease. So suggests a study conducted by American researchers at Massachusetts General Hospital. ¹

They have just demonstrated that there are numerous associations between gut bacteria and metabolic parameters of cardiovascular health. The strongest links concern certain bacteria capable of metabolizing cholesterol. 

In-depth data on the relationship between the microbiota and the host metabolism

To reach this conclusion, the researchers drew up a complete profile of the gut environment of over 1,400 individuals in the Framingham Health Study. They carried out metagenomic sequencing (analysis of the genomes of all gut microorganisms) and metabolomic sequencing (analysis of all metabolites) of the stools of all the volunteers.

They then investigated whether there were any correlations between the microbiota data and the volunteers' health parameters (triglycerides, cholesterol, C-reactive protein, blood sugar, glycated hemoglobin, blood pressure, etc.).

Bacteria equipped to break down cholesterol

By cultivating three in vitro isolates, the team demonstrated that Oscillibacter were able to absorb cholesterol and transform it into cholestenone, cholesteryl glucoside and hydroxycholesterol, metabolites that could be broken down by other bacteria and ultimately excreted by the body. 

Furthermore, it appeared that the simultaneous presence in the volunteers' microbiota of Oscillibacter and Eubacterium coprostanoligenes (bacteria carrying a gene called ismA involved in cholesterol metabolism) was associated with a more marked reduction in blood cholesterol levels. According to the researchers, the two types of bacteria could have a positive synergistic effect on cholesterol levels.

A vast field of research ahead

The advantage of this study compared with previous studies is that it provides a more complete and detailed understanding of the metabolic pathways by which bacteria act on the body. 

It also lays the foundations for future studies targeting how changes in the microbiota contribute to cardiovascular disease, including how different bacterial communities interact with each other to affect health. 

Murine models have demonstrated that the breasts harbor a microbiota capable of modulating carcinogenesis and the efficacy of chemotherapy. Hence the work published in 2024 by a Chinese team ¹ investigating the involvement in breast cancer of the bacterium Bacteroides fragilis, and more specifically its enterotoxigenic strain (ETBF), which produces the proteolytic toxin BFT-1, known to induce diarrhea and colonic lesions when present in the digestive system.

Tumor microbiota predicts resistance to treatment

First finding: in breast cancer, the presence of ETBF bacteria in tumors is associated with a poor response to neoadjuvant (sidenote: Neoadjuvant therapy Treatment administered prior to surgery or radiotherapy. It generally aims to reduce the size of the cancer, enabling less extensive surgery and/or a smaller radiotherapy field.   Explore MSD Manual ) taxane-based chemotherapy, one of the main therapeutic strategies for breast cancer, particularly triple-negative breast cancer. Further experiments, this time in mice, indicate that the presence of the toxin BFT-1 and activation of the NOD1 receptor in mammary tumors predict a poor response to chemotherapy. The BFT-1 toxin and the NOD1 receptor are thus thought to be involved in chemoresistance in breast cancer, which could justify profiling the tumor microbiota in breast cancer: these biomarkers could predict potential failure and enable treatment to be fine-tuned in advance, thereby improving the response to chemotherapy.

A new chain of mechanisms deciphered

Further in vitro research and research using mouse models also enabled the team to understand the underlying mechanisms. This research showed how the ETBF tumor bacterium is capable of mediating chemoresistance in breast cancer: the toxin BFT-1, secreted by ETBF, binds to the NOD1 receptor; NOD1 interacts with the protein kinase GAK, which phosphorylates the NUMB tumor suppressor to enhance its lysosomal degradation; the NOTCH1-HEY1 signaling pathway is inactivated, inducing multiplication of breast cancer stem cells.

Conversely, inhibition of NOD1 and suppression of the ETBF bacterium significantly increase the efficacy of chemotherapy by suppressing breast cancer stem cells.

Many more questions remain

However, contradictory roles for NOD1 in tumor progression have been reported: NOD1 can, as in this study, promote tumor progression (ovarian, esophageal, and colon cancers) or conversely induce cell apoptosis and inhibit cell proliferation (papillary thyroid carcinoma, hepatocellular carcinoma).

Another point to elucidate: the microbiota of the mammary glands and their tumors are complex, so much so that the dysbiosis associated with cancer is unlikely to be limited to a single species. Thus, other tumor taxa such as Clostridia, Alphaproteobacteria and Actinobacteria are also enriched in patients who do not respond to treatment. Further studies are therefore required to determine all the bacteria involved.

Having microbiota is not only the prerogative of the digestive tract or the skin. Our lungs, our bones, but also our breasts, have their own microbiota too, albeit much smaller than that of the digestive tract, but present nonetheless. And this has serious implications: these organ microbiota are capable of modulating the development of cancer, as well as the efficacy of chemotherapy treatments.

That is why one team has been investigating the involvement of the bacterium Bacteroides fragilis in breast cancer. More specifically, the team focused on a specific strain of B. fragilis, capable of producing a toxin that induces diarrhea and colonic lesions when the bacterium settles in the digestive tract.

A gut bacterium that reduces the effectiveness of chemotherapy

Why this bacterium? Because, in the case of breast cancer, the more this bacterium is present in the tumor, the poorer the response of women to certain chemotherapies (taxane-based treatment, used in particular for triple-negative cancers (sidenote: Triple-negative breast cancer This type of cancer is highly aggressive because it spreads rapidly to other organs. It affects women under 40 of African or Asian origin, in particular. Sources:
(1) https://www.who.int/news-room/fact-sheets/detail/breast-cancer 
(2) https://cancer.ca/en/cancer-information/cancer-types/breast/what-is-breast-cancer/cancerous-tumours/triple-negative-breast-cancer ) ).

To better understand the mechanisms involved, the researchers carried out experiments in mice and demonstrated the cascade of reactions triggered by the bacterial toxin, which ends up promoting the multiplication of cancer cells. Among the players in this cascade is a receptor called NOD1, which is much more present in the tumors of women whose tumors do not respond to chemotherapy.

Should we profile breast microbiota to refine treatment?

Many questions remain, of course. For example, is this tumor bacterium the only one to interact with cancer cells and chemotherapy, given that several other bacteria (Clostridia, Alphaproteobacteria and Actinobacteria) are more numerous in tumors? Why does the NOD1 receptor promote certain cancers (ovarian, esophageal and colon cancers) but seem to slow down others (papillary thyroid carcinoma, hepatocellular carcinoma)?

A recent study led by Prof. Arnout Bruggeman and his team at Ghent University Hospital reveals promising results for using faecal microbiota transplantation (FMT) to treat motor symptoms in Parkinson’s disease (PD). This innovative approach highlights the potential of gut microbiome modulation as a therapeutic strategy for this debilitating neurological disorder.

A new approach to Parkinson’s

The GUT-PARFECT trial, a double-blind, placebo-controlled phase 2 study, evaluated the safety and efficacy of a single FMT in patients with mild to moderate Parkinson’s disease. Participants, aged 50-65 years, were randomly assigned to receive FMT with either healthy donor stool or their own stool (placebo). The primary goal was to assess changes in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score over 12 months.

Surprising findings

One of the most surprising findings was the sustained response in the placebo group. Up to six months post-FMT, patients who received their own stool also showed notable improvements, although less pronounced than those in the healthy donor FMT group. This suggests that even autologous FMT can influence the gut microbiome in ways that may impact motor symptoms, emphasizing the complex role of the gut-brain axis in Parkinson’s disease.

The study also found significant improvements in colon transit time in the healthy donor FMT group compared to the placebo group.  Better gastrointestinal function is particularly relevant for PD patients, who often suffer from severe constipation. However, from the patients’ perspective this difference, was too minimal to result in a noticeable clinical improvement, and the patient-reported scores on the Wexner Constipation Scale have remained no significant between the groups.

Safety first and treatment next

Safety was a crucial aspect of this study. The FMT procedure was well-tolerated, with only mild and transient gastrointestinal symptoms reported, such as abdominal discomfort, which resolved within a week. No severe adverse events were observed, supporting the safety profile of FMT.

The GUT-PARFECT trial's results open up exciting possibilities for Parkinson’s disease treatment. If larger studies corroborate these findings, FMT could become a valuable tool in the therapeutic arsenal against PD. The future of Parkinson’s treatment may well lie in our gut. By harnessing the power of the microbiome, patient could pave the way for more effective and comprehensive management strategies for this challenging condition.

While the strong usually eat the weak, every year the minuscule mosquito causes hundreds of millions of cases of severe or even fatal disease by transmitting parasites (malaria) or a wide variety of viruses to humans through their bites, e.g. flaviviruses (sidenote: Flavivirus is a genus of viruses which consists of >70 members including several that are considered significant human pathogens. Transmitted to humans through the bite of infected mosquitoes, Flaviviruses display a broad spectrum of diseases that can be roughly categorised into two phenotypes:
- systemic disease involving haemorrhage (Dengue and yellow Fever virus)
- and neurological complications (West Nile and Zika viruses) Explore https://pubmed.ncbi.nlm.nih.gov/34696709/ ) (Dengue (sidenote: Dengue viral infection transmitted to humans through the bite of infected mosquitoes. Most people with dengue have mild or no symptoms and will get better in 1–2 weeks. Rarely, dengue can be severe and lead to death. If symptoms occur, they usually begin 4–10 days after infection and last for 2–7 days: high fever (40°C/104°F), severe headache, pain behind the eyes, muscle and joint pains, nausea, vomiting, swollen glands, rash. Individuals who are infected for the second time are at greater risk of severe dengue. There is no specific treatment for dengue. Explore https://www.who.int/en/news-room/fact-sheets/detail/dengue-and-severe-dengue ) , Zika (sidenote: Zika viral infection transmitted primarily by Aedes mosquitoes, which bite mostly during the day. Most people with Zika virus infection do not develop symptoms; those who do typically have symptoms including rash, fever, conjunctivitis, muscle and joint pain, malaise and headache that last for 2–7 days. Zika virus infection during pregnancy can cause infants to be born with microcephaly and other congenital malformations as well as preterm birth and miscarriage. There is no specific treatment available for Zika virus infection or disease. Explore https://www.who.int/news-room/fact-sheets/detail/zika-virus ) , etc.), alphaviruses (sidenote: Alphavirus genre de virus comprenant 27 virus dont le redouté (et imprononçable) Chikungunya, qui après un délai d’incubation de 2 à 10 jours, provoque une fièvre et des atteintes articulaires sévères. Les alphavirus sont transmis par la piqûre d’un moustique infecté. Explore https://www.ncbi.nlm.nih.gov/books/NBK7633/ ) (Chikungunya), etc. What if the solution is not to eliminate the mosquito (insecticides) or keep it at bay (mosquito nets, repellent), but simply to prevent it from catching the virus and transmitting it to humans? 

Protecting the mosquito...

This serious solution has been put forward by a Chinese team based on their work on the gut microbiota of mosquitoes. Among the 55 bacteria present in the insects’ digestive tract, one – Rosenbergiella YN46 – caught their attention. Why? Because it permanently prevented the mosquitoes that ingested it from catching flaviviruses.

How is this possible? This bacterium takes up permanent residence in the mosquito’s digestive tract, where it transforms glucose (sugar) into an acid. As a direct consequence, the digestive tract contents become highly acidic, spoiling the flaviviruses. Unable to infect mosquitoes, these viruses will not then infect humans.

...to protect humans

The researchers did not confine themselves to laboratory work. They confirmed their idea in the field. They observed that, in the prefectures of the Chinese province of Yunnan in which Dengue wreaks havoc, mosquitoes rarely harbor the bacterium in their digestive systems. Conversely, in prefectures where only a few isolated cases of dengue fever have been reported, the majority or almost all mosquitoes (91.7% in Wenshan prefecture) carry the bacterium.

The good news is that not only is it easy to inoculate mosquitoes with the bacterium (you just need a bowl of sugar water containing the bacterium), but that the insect retains it throughout its life (from aquatic larvae to winged adult) and passes it on to the next generation. In other words, inoculation with the protective Rosenbergiella YN46 bacterium lasts for life and is passed on to the mosquito’s offspring.

Infections caused by Gram-negative bacteria (sidenote: Gram-negative bacteria A group of bacteria characterized by their unique cell wall structure, which makes them resistant to many antibiotics and often more challenging to treat. ) are becoming more common and are often treated with broad-spectrum antibiotics, which can disrupt the gut microbiome and lead to secondary infections. There is a pressing need for antibiotics that are selective for pathogenic Gram-negative bacteria while sparing commensal bacteria and the gut microbiome.

This new study ¹ aimed to design and discover a Gram-negative-selective antibiotic that targets the Lol lipoprotein transport system, thereby preserving the gut microbiome and preventing secondary infections.

Crafting a selective antibiotic

The development process began with a series of whole-cell screens at AstraZeneca, identifying compounds that inhibit the LolCDE complex, a critical component of the Lol system. Researchers prioritized compounds that showed initial promise but faced challenges in solubility and resistance. Through an iterative chemical modification process, they engineered a hybrid scaffold, appending primary amines to enhance compound accumulation and targeting efficiency.

The culmination of these efforts was the identification of lolamicin (sidenote: Lolamicin A newly developed Gram-negative-selective antibiotic that targets the Lol lipoprotein transport system, effectively killing pathogenic bacteria without disrupting the gut microbiome. ) , a compound that effectively disrupts the Lol system, thereby selectively killing pathogenic Gram-negative bacteria. This selective targeting is made possible by the significant sequence homology divergence between pathogenic bacteria and commensal gut bacteria, ensuring that beneficial bacteria remain unharmed.

Achieving breakthrough results in infection models

The efficacy of lolamicin was put to the test in rigorous preclinical studies, and the results were nothing short of groundbreaking. Lolamicin demonstrated potent activity against a diverse panel of over 130 multidrug-resistant (sidenote: Multidrug-resistant Describes bacteria that have developed resistance to multiple classes of antibiotics, making infections caused by these bacteria particularly difficult to treat. ) clinical isolates of Gram-negative bacteria, including notorious pathogens such as E. coli, Klebsiella pneumoniae, and Enterobacter cloacae.

One of the standout features of lolamicin is its microbiome-sparing capability. Unlike broad-spectrum antibiotics that wreak havoc on the gut microbiome, lolamicin treatment resulted in minimal changes to the gut microbial composition. This was evidenced by full-length 16S rRNA sequencing of fecal samples from treated mice, which showed that lolamicin preserved the diversity and richness of the gut microbiome. Remarkably, mice treated with lolamicin retained their ability to spontaneously clear Clostridioides difficile colonization, a common and severe complication associated with antibiotic use.