IV. 3 When it does not respond: non-response and retreatment

Not everyone responds in the same way and at the same speed. If symptoms stay longer than expected, it is not a dead end: there is a clear plan. In this chapter you will learn to recognise an inadequate response, and understand the logic of retreatment – from the maximum dose to switching to a different LOT.

How you know the response is inadequate

The most important sign you can read from your diary is the consistency of the stool over time. One milestone of treatment is that around the tenth day the Bristol value^[G] begins to approach the 3–4 target band. If, however, even after the tenth day the stool stays persistently watery, formless – that is, with a Bristol value of 6–7 – and the daily stool count does not fall appreciably either, that is the sign of an inadequate response^[G]. This is not about a single bad day, but about improvement being durably absent.

It is important to tell slow improvement apart from genuine non-response. In many patients recovery is gradual, and it is completely normal if not everything returns at once. We speak of an inadequate response when, within the set time frame – typically after the tenth day – there is simply no meaningful movement in the right direction. This is not for you to decide alone: your diary supplies the facts, and your doctor pronounces on it based on the whole picture.

This is exactly why accurate, daily recording is so valuable. The trend in stool count, Bristol value, bloating and bloody stool together maps out whether your body is reacting. If the numbers show the same thing day after day for longer than expected, that is the signal that a step is needed – and that is exactly what the next section is for.

The logic of retreatment: dose, repeat course, different LOT

If the response is inadequate, retreatment has a clear, stepwise logic. The first step is usually raising the dose back to the maximum: if we have meanwhile already reduced the dose, or if you started at a lower level, your doctor can reset the maximum daily capsule count and repeat the whole course. This is often enough for engraftment^[G] to get going and for the symptoms to finally give way.

If even after the repeated, maximum-dose course the improvement is not durable, the next step follows: switching to a different LOT. The LOT denotes a particular, identifiable batch of the product, made from the screened flora of a specific donor. It happens – entirely naturally – that a particular donor's microbiome^[G] composition does not fit a particular patient perfectly, and another batch "takes" better. Switching LOT therefore does not mean the first product was bad; only that biological fit is individual, and there is another option.

This stepwise plan is reassuring because it shows: an inadequate response is not a dead end, but a fork for which we are prepared. Your job in this is to continue accurate diary-keeping and to stay in contact with your treating physician – every decision (dose escalation, repeat course, LOT switch) is made on their judgement, relying on the data in your diary.

🍽️ Eating during these days

The theme of these days – inadequate response and retreatment – is primarily about the dose and the capsule, but eating works in the background here too: the varied, fibre-rich plate helps the delivered flora engraft and helps colonisation resistance^[G] recover – this is the background work that matters even when the dose has to be raised. The concrete eating task for the three days is simple and unchanged: keep the familiar morning intake on an empty stomach with plenty of water, replace fluids after every looser stool with an extra glass, and every day work the day's plant into at least one meal.

For these days (67–69), the Plant Calendar (Appendix F) brings one fermented drink and two algae: kombucha (67), nori (68) and spirulina (69). The kombucha brings live cultures, and the algae bring further plant variety and minerals into the diet. In the second half of the programme (about days 61–90) the goal is to maintain full diversity^[G] and fermentable fibre sources: the more kinds of plant source reach the plate, the more kinds of fibre-degrading bacteria you feed, and the more short-chain fatty acids^[G] (including butyrate^[G]) are produced; butyrate is the main energy source of the colonocytes and strengthens the gut barrier (Koh 2016 [111]; Hamer 2008 [062]), while the metabolism of the restored flora is the basis of colonisation resistance (Reed & Theriot 2021 [003]). A diverse, stable flora is more resilient – and it is precisely this resilience^[G] that works alongside recovery even in the case of an inadequate response. Introduce the new sources (especially the kombucha) in small portions, and if you do not tolerate one of them, leave it out and come back to it later.

Why does this matter?

An inadequate response does not mean the treatment is not working – only that more steps are needed for this patient. The stepwise plan (maximum dose → repeat course → different LOT) exists precisely so that no one is left without a solution. Your role is accurate diary-keeping and open communication with your doctor: the numbers show when and which way to step.

References

[003] Reed AD, Theriot CM. Contribution of Inhibitory Metabolites and Competition for Nutrients to Colonization Resistance against Clostridioides difficile by Commensal Clostridium**. Microorganisms. 2021. Link

This review examines how commensal *Clostridium* species mediate colonization resistance against C. difficile. Commensal *Clostridia* modify primary bile acids into secondary bile acids that suppress C. difficile spore germination and vegetative outgrowth. They additionally produce antimicrobial peptides and short-chain fatty acids that directly inhibit C. difficile and compete for limiting nutrients such as proline, important for C. difficile growth via Stickland fermentation. Loss of commensal *Clostridia* after broad-spectrum antibiotics is a key mechanistic step toward CDI susceptibility. The authors conclude from this that new therapies against CDI are urgently needed; the clinical validation of defined *Clostridium* consortia comes not from this review but from the VE303 phase 2 trial [56].

[015] Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther. 2021. Link

Systematic review of FMT safety summarizing adverse events (AEs) over 20 years from 129 studies including 4,241 patients and 5,688 FMT courses (search of EMBASE, MEDLINE, Cochrane, CNKI, Wanfang from 2000 to 2020). AEs were classified as delivery-related or microbiota-related. The review provides the largest aggregate FMT safety dataset to date and supports the overall favourable safety profile of FMT for recurrent CDI, while flagging that complications may be under-reported in the literature.

[062] Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. The role of butyrate on colonic function. Aliment Pharmacol Ther. 2008. Link

Narrative review summarizing the bioactivity of butyrate — a SCFA produced by colonic microbial fermentation of dietary fibre — and its mechanisms in human colonic function. Butyrate is the primary energy source for colonocytes and modulates inflammation, carcinogenesis, mucosal barrier integrity, oxidative stress, permeability, and satiety. The review consolidates evidence on butyrate as a central effector of colonic homeostasis and a target for dietary interventions in colonic disease.

[084] Wilson BC, Vatanen T, Cutfield WS, O'Sullivan JM. The Super-Donor Phenomenon in Fecal Microbiota Transplantation. Front Cell Infect Microbiol. 2019. Link

FMT is highly effective for recurrent Clostridium difficile infection but its efficacy in chronic dysbiosis-associated diseases has been modest and variable. Multiple studies suggest FMT outcome depends on stool donor microbial diversity and composition, leading to the concept of FMT 'super-donors'. The review explores keystone species as predictors of FMT success and discusses how host genetics and diet may influence engraftment and maintenance — providing a framework for more targeted, donor-stratified bacteriotherapy.

[111] Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016. Link

Mechanistic review of short-chain fatty acids (SCFAs), produced by bacterial fermentation of dietary fibre. Fermentable fibre is the primary energy source for the colonic microbiota; the main fermentation products are **acetate, propionate and butyrate**. **Butyrate is the principal energy substrate of colonocytes**; SCFAs also influence barrier integrity, immune function and, once in the circulation, host metabolism, partly via G-protein-coupled receptors (GPR41/43) and histone deacetylase inhibition. This entry is the source for the textbook-level claims of III.2 (S-0302-01, -02). Important: a **review**, not original experimental data.

[156] Ianiro G, Puncochar M, Karcher N, Porcari S, Armanini F, Asnicar F, Segata N. Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases. Nat Med. 2022. Link

Integrated shotgun-metagenomic meta-analysis of 226 triads (donor, pre-FMT and post-FMT recipient) across eight different disease types, using improved strain profiling. The key finding: **recipients with higher donor-strain engraftment were more likely to achieve clinical success** after FMT (P=0.017). Engraftment depends on the donor, the delivery route (multi-route — e.g. capsule plus colonoscopy together — gives higher engraftment) and the recipient (higher in antibiotic-treated infectious-disease recipients than in antibiotic-naive noncommunicable-disease patients); Bacteroidetes and Actinobacteria species engraft better. This entry is the source for the IV.3 claim that, because of donor-dependent engraftment variability, an alternative donor lot (LOT switch) can improve the outcome. **LIMITATION:** an observational meta-analysis across eight disease types (not CDI alone), measuring association; it did not study product-LOT switching as such.