Although immunotherapy has revolutionized cancer treatment, its effectiveness varies greatly from one patient to the next. The gut microbiota seems to be involved in outcomes, with gut microbiota composition thought to modulate immune responses to tumors. Various manipulations of the gut flora have been explored in recent years, among them fecal microbiota transplantation (FMT). A counter-intuitive Chinese study ¹ has shown that the microbiota of elderly donors may be particularly beneficial when it comes to immunotherapy responses.

Better results in elderly patients

To reach this conclusion, the researchers first carried out a meta-analysis of 25 studies involving 2,985 patients. They found that elderly cancer patients respond better to immunotherapy and have a longer life expectancy after treatment. A regression analysis even showed a quasi-linear relationship between age and progression-free survival. The pivotal age is sixty: before this age, the younger you are, the poorer the results; whereas after this age, the older you get, the more the results exceed those observed on average. 

The immunity avenue

To understand the underlying mechanisms, the researchers turned their attention to the immune system, the target of immunotherapy. They showed that aging is accompanied by increased immune dysfunction and what they describe as a depletion of T cells over time. These age-associated T cell alterations could be mediated by the gut microbiota: an FMT of gut microbiota from elderly donors improves responses to immunotherapy, regardless of the recipient’s age.

Which bacteria?

Which gut bacteria promise the best response to treatment? Those present in an enterotype (sidenote: Enterotype A specific gut bacterial composition type in humans, similar to blood groups. Three distinct types have been identified in humans, characterized by a dominance of either Bacteroides, Prevotella, or Ruminococcus. ) that tends to become richer with age, characterized by Bacteroides, Clostridiales, Bilophila, and Faecalicatena. 

A series of experiments on a mouse model confirms the potential of these bacteria: fecal transplantation of this specific enterotype, whether from an elderly donor or a young donor (young people also possess this enterotype, but in less abundance), modifies the gut microbiota of recipient mice and improves their response to immunotherapy (the tumor grows less in weight and volume). How? By boosting T cell cytotoxicity.

The microbiota, made up of trillions of micro-organisms (bacteria, viruses, fungi, etc.), lives in our intestines, on our skin, and in our mouths, noses, and lungs. These organisms play a crucial role in our well-being by facilitating digestion, stimulating our immune system, and protecting us against infectious diseases. Beyond these functions, however, the microbiota also influences our mood, our metabolism, and even our longevity. Alteration of this delicate balance, often due to factors such as diet, lifestyle or medication, can lead to major health problems, ranging from gastrointestinal disease to cardiovascular disorders and depression. Therefore, maintaining a healthy microbiota in all these areas of the body is essential for our overall health and well-being.

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.

Medication, lifestyle, and hormonal changes during pregnancy are just some of the factors that can disrupt the temperature, humidity, pH, and protective barrier of the vaginal environment. These changes can facilitate the development of pathogenic bacteria and threaten the healthy dominance of Lactobacillus in the vaginal microbiota. This can lead to genital and urological diseases, since the anatomical proximity of the urethra and vagina facilitates close relations between their respective microbiomes.

Incontinence often accompanied by dysbiosis

Is stress urinary incontinence (SUI) part of the growing list of such pathologies? Yes, according to the results of a study ¹ of 32 post-partum patients in a hospital in Hunan province, China, 13 of whom suffered from SUI and 19 of whom did not. While 42.1% of the non-SUI group presented a vaginal dysbiosis, an imbalance in the vagina’s microbial flora, this figure rose to 84.6% for patients with SUI. In other words, vaginal dysbiosis was twice as common – indeed, almost systematic – in the mothers suffering from SUI. Their flora showed an increased relative abundance of Gardnerella, Streptococcus, Prevotella, Dialister, and Veillonella.

An over-connected microbiota?

To unravel the relationships between the various vaginal microorganisms potentially involved in SUI, the researchers carried out what is known as a network co-occurrence analysis of the patients’ microbiota. In other words, they mapped the potential links between various bacteria. They found that the vaginal microbiota of the SUI patients was much more interconnected and complex: when the links between the bacteria were mapped, the network of the non-SUI group displayed 96 nodes and 133 edges, compared with 200 nodes and 409 edges for that of the SUI patients. In general, microbial communities with a high degree of interconnectedness are considered less stable and therefore more susceptible to imbalance.

Stimulating and remobilizing the immune system to recognize and eliminate cancer cells: this is the principle behind immunotherapy, which has been revolutionizing cancer treatment since the 2010s. There is, however, one limitation: in some patients, it is not very effective.

Studies suggest that the gut microbiota may influence the outcome of this treatment, with certain bacteria living in our digestive tract secreting molecules capable of boosting our immune system in its fight against the proliferation of cancer cells. Some researchers have attempted to modify their patients’ gut flora prior to immunotherapy so as to stimulate the treatment. One way of doing this is via fecal microbiota transplantation.

Microbiota of seniors is preferable

If you were to receive a fecal microbiota transplantation (now a recognized therapeutic solution, or under study as such, for many diseases), you would tend to choose a young, healthy donor. So would researchers. However, they may have to revise this position and instead opt for stools from healthy eighty-year-old donors.

A recent study ¹ has shown that people over sixty respond better to immunotherapy, and that the older they are, the more their survival defies prognosis. But why?

Since with age, their gut microbiota seems to evolve towards a set of bacteria more favorable to the outcome of immunotherapy. In fact, by transplanting these bacteria typical of senior citizens into cancer-stricken mice prior to immunotherapy, tumor growth was reduced to a greater extent than without fecal transplantation.

What explains these results? At first glance, because these “elderly” bacteria give a “youthful” boost to an immune system that tends to become depleted with age. In this respect, it seems that the value of healthy microbiota increases with age.

Often considered taboo, urinary stress incontinence affects somewhere between 1 in 5 or 1 in 3 women, depending on the study. Motherhood and age increase the risk of these uncontrolled leaks, which can occur when lifting a full shopping bag, coughing, jumping, sneezing, or even laughing. Two mechanisms have traditionally been implicated: a weakening of the perineum (the muscular “hammock” which holds back the urogenital organs), particularly during pregnancy, and a weak urinary sphincter, the ring-shaped muscle that opens or closes the urethra, through which the bladder empties. According to a Chinese study ¹ published in 2024, the vaginal microbiota may also play a role.

Incontinence linked to vaginal dysbiosis

The study shows that 84.5% of young mothers suffering from urinary incontinence present a vaginal microbiota imbalance, compared with 42.1% of mothers not suffering from urinary incontinence. Instead of a healthy vaginal flora where Lactobacillus dominates, the vast majority of young mothers suffering from incontinence present a vaginal flora in which Gardnerella, Streptococcus, Prevotella, Dialister, and Veillonella hold more ground.

Careful readers will ask what connects the vaginal flora to urinary leakage (i.e. to the urinary flora). The answer is simple: the anatomical proximity between the urethral and vaginal orifices. These two regions are separated by just a few millimeters, facilitating close relations between their microbiomes. In fact, previous studies have repeatedly shown the existence of links between vaginal bacteria and urogenital diseases, i.e. diseases of the urinary and/or vaginal system.

An overly interconnected vaginal microbiota?

Now back to the subject of bacteria in women suffering from post-partum urinary incontinence. Another characteristic of these women’s flora is a hyper-interconnectedness between the microorganisms inhabiting their vagina. In other words, a highly developed network of relationships between the various microorganisms. This is not a good sign: in general, microbiota with a high degree of interconnectedness are considered less stable and therefore more susceptible to imbalance and dysbiosis.

Could you talk about the claims made on the video from a clinical perspective?

This drug increases GLP-1, which is a hormone primarily produced by the endocrine cells (also called enteroendocrine cells) in the gut. It boosts the secretion of insulin (incretin effect), slows down gastric emptying and stimulates the sensation of being full, making you feel less hungry.

What about fibre and taking a probiotic?

It is well known that dietary fibre, especially soluble fibre, can slow down gastric emptying, making you feel full and help control your appetite. Fibre can also help stabilise blood sugar levels by slowing down the absorption of carbohydrates, which can be beneficial in diabetic patients. What’s more, fibre-rich food often has a lower energy density, which can help reduce the overall calorie intake and potentially help patients to lose weight when eaten as part of a balanced diet. In terms of the gut microbiota, I agree with Dr. DeDecker about the fact that most fibre has a prebiotic effect and will nourish certain gut bacteria, which are then able to produce short-chain fatty acids (SCFAs) through fermentation, and these SCFAs can increase GLP-1 levels.

I would, however, qualify the statements about the bacterium she mentions, Akkermansia muciniphila, which she credits with tremendous benefits in terms of regulating energy metabolism and insulin sensitivity, as some studies have suggested it plays an indirect role in regulating the secretion of intestinal peptides such as GLP-1. However, this is preclinical data, and the link could be a fairly indirect one. Thus, there is no evidence to claim that supplementation with this bacterium could increase GLP-1 secretion and lead to weight loss.

Why do you think that this video has attracted so much attention? 

In my opinion, it was very easy for this video to create a buzz because it deals with weight loss, and in the West with our high rates of overweight and obese people (50-60% of the population), there are many who dream of being able to lose weight without changing their lifestyle, particularly their diet. So if you suggest that a natural method exists to lose 20% of your bodyweight without taking a drug, you can easily see why it appealed to so many people.

Would you give this information to your patients?

What could be the risks and/or pitfalls? That’s my personal opinion and I think that Dr. DeDecker’s comments are somewhat misleading, because neither taking any kind of probiotic nor increasing dietary fibre has shown any benefit in terms of weight loss, let alone a 20% one. However, despite these misgivings, I do think what she has to say is interesting as it could have the positive effect of reducing the misuse of anti-diabetic medication, as well as raising public awareness of the impact of the gut microbiota on our health. And, more importantly, she is encouraging people to eat more fibre. The current consumption of fibre in Western countries (less than 20 g/day) is well below the World Health Organisation’s recommendations (25-30 g/day), and only 5% of Americans eat enough fibre.

Predicting the risk of preterm birth through vaginal microbiota

^{Liao J, Shenhav L, Urban JA, et al. Microdiversity of the vaginal microbiome is associated with preterm birth. Nat Commun 2023; 14: 4997.}

Respiratory, gastrointestinal and neurodevelopmental complications: preterm birth is the main cause of neonatal morbidity and mortality. The vaginal microbiota seems to be involved, but the underlying mechanisms remain poorly understood. A team of American researchers tracked the genome of the vaginal microbiota of 175 American women throughout their pregnancies (40 of whom subsequently experienced spontaneous preterm delivery, and 135 of whom delivered at full term). The study shows that the two types of pregnancy differ in terms of vaginal microbiota composition: certain bacterial species of the Lactobacillus genus, such as L. helveticus, L. crispatus, L. gasseri and L. jensenii, are associated with fullterm pregnancies, while Megasphaera genomosp, Gardnerella spp. and Atopobium vaginae are linked to preterm births. Another finding is that the genetic diversity of the vaginal microbiota is higher in the first half of pregnancies that end preterm, due to Gardnerella species. More precisely, the nucleotide diversity of Gardnerella spp. increases at the start of pregnancies that end preterm whereas it remains stable in pregnancies that are carried to term. The genetic diversity of Gardnerella spp. could perhaps be used as a biomarker for the early diagnosis of preterm birth. But how can we explain this peak in Gardnerella nucleotide diversity? Compared to other bacteria, Gardnerella shows a 1.5-fold higher growth rate at the start of pregnancy, more frequent genetic recombination and greater selection of mutations that benefit this bacterium (and increased elimination of deleterious mutations). Antibiotics and other xenobiotics are thought to be involved. In fact, the more diversified gene pool of G. swidsinskii seems to correspond to an adaptation to drugs, confirming a previously suggested effect of xenobiotics in the vaginal environment; and vaginal microbiota associated with preterm birth exhibit higher antibiotic resistance potential. Genomic variation in vaginal bacteria is therefore believed to affect the host’s phenotypes (including pregnancy outcomes). However, the authors do not rule out another explanation, even if they consider it unlikely: the associations between microbial genetic diversity and pregnancy outcomes could also result from unmeasured confounding factors (drugs, chemical compounds, etc.) that might act on both variables.

Gut microbiota as predictor of acute pancreatitis severity

^{Ammer-Herrmenau C, Antweiler KL, Asendorf T, et al. Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis. Gut 2023 : gutjnl-2023-330987.}

Severe acute pancreatitis (AP) patients are at risk of elevated mortality, for which determining the course of disease within the first few hours would be very important. The current complex scoring systems cannot predict AP severity early enough, and thus, novel markers are needed. While there seem to be a bilateral link between AP and gut microbiome, larger prospective clinical studies have been lacking. This paper presents results of orointestinal microbiome from 450 patients with AP from 15 European centers. The samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore. The revised Atlanta classification (RAC) redefines severity of AP into three categories: mild, moderate, and severe (RAC I-III, respectively). This study found that Bray-Curtis distance of the rectal microbiomes was different in RAC III compared with RAC I and RAC II. Further, several bacterial species were differentially abundant depending on the RAC category. Bray-Curtis distances were also different between alive and deceased patients in rectal but not buccal microbiomes. In addition to mortality, the length of hospital stay associated with early alterations of rectal microbiome. In the end, the authors found that 16 bacterial species were differentially abundant in severe vs. non-severe AP. In Ridge regression, these species together with systemic inflammatory response syndrome could faithfully predict disease severity. Interestingly, all these species are producers of short-chain fatty acids (SCFA). Accordingly, functional pathways of SCFA production were more expressed in severe AP. While the finding is intriguing, it is still unknown whether SCFA producing bacteria are cause or consequence of severe AP.

Links between gut microbiome in type 2 diabetic Emirates

^{Dash NR, Al Bataineh MT, Alili R, et al. Functional alterations and predictive capacity of gut microbiome in type 2 diabetes. Sci Rep 2023; 13: 22386.}

The incidence of type 2 diabetes (T2D) is increasing drastically in Middle East countries. Several Western studies have shown the contribution of gut microbiome in T2D-associated insulin resistance and low-grade inflammation, but studies in Middle East populations are scarce. Further, the existing studies show inconclusive results of how the microbial community composition and functions contribute to the pathogenesis of T2D. To gain more insight, the authors analyzed stool samples of 84 individuals from the United Arab Emirates with or without T2D using nanopore metagenomic sequencing. Unlike many earlier Western studies, this study reported no differences in gut microbiota alpha-diversity between healthy controls and T2D. Further, after correcting for multiple comparisons, the authors did not find differential abundance of any microbial species or KEGG orthology (KO) features between the groups. However, a gene set enrichment analysis revealed 8 functions with higher abundance in the control group and 5 in the T2D group. These differentially abundant modules associated with the degradation of amino acids, such as arginine, the degradation of urea and homoacetogenesis. These functions seem to have pro-inflammatory effects, and thus, may contribute to low-grade inflammation, a hallmark of T2D. Ultimately, the authors used prediction analysis to identify 3 potential biomarkers of T2D. These included a depletion of Enterococcus faecium and Blautia as well as an enrichment of Absiella spp or Eubacterium limosum in T2D. Interestingly, E. faecium is shown to have lipid-lowering and anti-obesity effects, and therefore, might partly contribute to the pathogenic T2D phenotype. To conclude, this study was successful in identifying specific microbial biomarkers, including functions and taxa that may help in predicting the development of specific T2D-associated disease conditions.

Microbial butyrate inhibits immunosuppressive factors in gastric cancer

^{Lee SY, Jhun J, Woo JS, et al. Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer. Gut Microbes 2024; 16: 2300846.}

Gastric cancer (GC) is one of the leading causes of cancer death worldwide. Early detection is important for successful treatment of GC. Programmed death-ligand 1 (PD-L1), a target of cancer immunotherapy, is highly expressed in tumor-associated macrophages that can be regulated by the gut microbiome. One possible way through which the microbiome may have anti-cancer effects is the production of short-chain fatty acids, including butyrate. In this study, advanced GC patients expressed more immunosuppressive markers, namely PD-L1 and interleukin (IL)-10, in macrophages, dendritic cells and cancer mucosa than healthy controls. The gut microbiota of the GC patients was characterized by lower diversity and dysbiosis. At genus level, lower abundances of butyrate-producing bacteria, such as Faecalibacterium and Bifidobacterium were detected in GC patients. Interestingly, administration of butyrate and Faecalibacterium into the peripheral blood mononuclear cells of GC patients decreased the number of PDL1- and IL-10-expressing macrophages. In addition, butyrate suppressed the growth on cultured GC cells. However, it remained unclear which Faecalibacterium strain was used in the in vitro experiment. Ultimately, a humanized tumor mouse model was injected with GC cells and peripheral blood mononuclear cells of from healthy controls or GC patients with or without butyrate. The experiment showed that butyrate significantly decreased tumor size and the immunosuppressive markers PD-L1 and IL-10. Thus, butyrate may have therapeutic potential via suppressing cancer cell growth in GC.

Gastrointestinal motility and functional disorders

One of the highlights of this year’s event are numerous sessions dedicated to GI motility, with a main focus on functional diseases. In the opening ceremony, an update on refractory gastroesophageal reflux disease (GERD) was presented as a presidential lecture from Prof Somchai Leelakusolvong, President of Local Organizing Committee. Prof Somchai emphasized the importance of the Lyon consensus version 2.0, which has expanded the criteria of endoscopic findings to include Los Angeles reflux esophagitis grade B, which is more practical in Asian countries. The event also introduced many updated data on optimizing the treatment of refractory GERD based on various mechanisms. The advancements in treatment strategies were also highlighted, including the use of drugs targeting lower esophageal sphincter (LES) pressure, esophageal contractions, endoscopic interventions, and electrical stimulation. Transient lower esophageal sphincter relaxations were considered as one of the key mechanisms of GERD. This condition can be improved by baclofen by increasing resting LES pressure, thus reducing episodes of reflux. Preliminary data on a small cohort of patients suggested that electric stimulation could improve LES pressure; however, the practical application of this intervention in the future is still debated.

The event also paid considerable attention to the comparison between proton pump inhibitors (PPI) and potassium‐competitive acid blockers (PCAB) in different studies, with the target population being patients with erosive esophagitis. Current evidence showed a higher efficacy of PCAB compared to PPI in treating severe erosive esophagitis with acceptable adverse events.

One of the most engaging sessions was “All about GERD”, chaired by Prof Somchai Leelakusolvong and Prof Kwang-Jae Lee on December 8th. This session primarily focused on the updates of the modern Lyon consensus, non-acid reflux management, and optimizing treatment of functional heartburn.

Dr. Ping-Huei Tseng, Taiwan, presented the detailed changes of the Lyon consensus 2.0 with the clarification on the expanded criteria in endoscopic findings for Los Angeles grade B esophagitis. The role of high-resolution manometry to exclude mimic esophageal disorders and identify risk factors of GERD such as low LES pressure, hiatal hernia, or weak oesophageal contraction was also explained with case examples for further clarity. Some promising metrics on 24-hour pH impedance, such as mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristalsis (PPSW) index, are still debating and require further clinical data.

For non-acid reflux management, Prof. Justin Wu from Hong Kong highlighted the differences between the definition of refractory GERD and refractory GERD symptoms, of which the latter can be caused by various diseases. The roles of high-resolution manometry (HRM), endoscopy, and 24-hour pH impedance in the diagnosis and management of these conditions are explained in detail by the ESNM/ASNM guideline. The decision to perform 24-hour pH impedance on or off PPI depends on the diagnostic aim, whether to confirm GERD in patients with no prior diagnosis, or to confirm refractory GERD. It will be helpful to have a stepwise strategy for patients with refractory GERD to determine the optimal time for endoscopic interventions or surgery. Non-acid reflux management should be considered comprehensively for possible mechanisms, including characteristics of reflux episodes, oesophageal motility patterns, and overlapping symptoms. Furthermore, Prof Wu emphasized the need to establish a cut-off value for acid exposure time (AET) in GERD diagnosis for the Asian population, which can be a debating point when compared to the Lyon consensus.

Functional heartburn is also a challenging condition due to several factors: overlapping with other functional gastrointestinal disorders, presenting with mental disorders (anxiety, depression, stress) in the scope of the “gut-brain pathway” mechanism, and requiring exploration tests for exclusion. According to recent data, 70% of patients with functional symptoms had normal endoscopic findings. Within this population, 50% had normal 24-hour pH impedance results, and 60% showed no correlation with the occurrence of symptoms, meaning only 21% was classified as functional heartburn. That is why, besides PPI, neuromodulators play an essential role. Tricyclic antidepressants (TCAs) and selective serotonin uptake inhibitors (SSRIs) have shown efficacy in treating functional heartburn. However, their potential side effects should be carefully considered. For prevention, it is recommended to initiate treatment with a low dose and maintain follow-up during treatment.

Artificial intelligence in Endoscopy: ASPDE – WEO Symposium Highlight

Artificial intelligence (AI) is also a hot topic with many invited speakers. On the final day of APDW, December 9th, ASPDE cohosted with WEO to organize a session called “ASPDE-WEO International Clinical Symposium Artificial Intelligence in Endoscopy: Implementation in the Asia Pacific and the World”. This session was moderated by Prof Hisao Tajiri, Prof Yuichi Mori, and Assoc. Prof Nonthalee Pausawasdi. Prof Yuichi Mori gave the first presentation to introduce the WEO AI committee to the two ongoing projects. One project is an international study aimed at evaluating the perceptions of endoscopists and patients regarding the use of AI in endoscopy. The other is a longitudinal study on the role of AI in real-world settings. The WEO AI committee focuses on implementing AI in clinical practice, considering different aspects including accuracy, cost-effectiveness, doctor-machine interactions, training programs, and ethical considerations.

Prof Han-Mo Chiu, Prof Rungsun Rerknimitr, and Prof Kherk-Yu (Lawrence) Ho each presented different topics on developing and using AI effectively in several fields, including colorectal cancer screening, gastric cancer screening, and biliary endoscopy. The presentations showed many updated data, inspiring clinicians and endoscopists to consider implementing AI in the near future.

Assoc. Prof Dao Viet Hang presented another aspect of utilizing AI in endoscopy training, especially in limited-resources settings. She highlighted that the conventional metrics in endoscopy training, based on the minimum number of cases or the duration of practice, do not reflect the skills and personal development over time, requiring a more interactive approach. E-learning training programs and simulation-integrated activities have shown promising results in enhancing junior endoscopists’ knowledge and lesion detection skills. Until now, AI has shown promising data on improving lesion detection with more and more data in clinical practice; however, its integration in endoscopy training is still lacking. Some key considerations for applying AI in endoscopy training include economic feasibility, safety and accountability, technical concerns and validation, and clinicians’ role in digitalization. The framework suggested that adopting AI in endoscopy training should balance users’ factors, technology factors, social factors, and contextual factors (educational environment and standards). A needs assessment is required to outline educational needs and establish clear educational goals to inform Al’s technology selection. Al should be integrated into training based on the best evidence and within a curriculum, incorporating user training for both trainees and trainers to promote uptake.

All the talks in this session received substantial feedback, comments, and questions, reflecting a great interest in the future application of AI in endoscopy.